What is the nurses priority focused assessment for side effects in a child taking methylphenidate

Sociodemographics: not stated

Treatment compliance: not stated

Further trials with methylphenidate caused hallucinations, which immediately disappeared after discontinuation

Inclusion criteria:

1. Children with a diagnosis of ADHD according to DSM‐IV who were prescribed MP after October 2000

Treatment compliance: not stated

In 3 cases, medication was stopped due to side effects

Key conclusions of the study authors: the guidelines were followed, but not fully. However this was improved significantly in the second part due to increased professional awareness about ADHD because we held many seminars on this subject. The mental health team worked more closely than before with community paediatricians via joint ADHD clinics with child and adolescent psychiatrists. Families were getting better support via the ADHD family project which was jointly funded by health, education, and social services. The audits lead to a better provision of services for children with ADHD via specialist ADHD clinics

1. Methylphenidate plus Acetyl‐L‐carnitine (ALC)

2. Methylphenidate plus placebo

Methylphenidate + placebo

Inclusion criteria:

1. DSM‐IV‐TR diagnostic criteria for ADHD

2. Total and/or subscale scores on Attention‐Deficit/Hyperactivity Disorder Rating Scale‐IV (ADHD‐RS‐IV) School Version being ≥ 1.5 SD above norms for patient's age and gender

3. Parents and children had to be willing to comply with all requirements of the study

1. A history or current diagnosis of pervasive developmental disorders, schizophrenia or other psychiatric disorders (DSM‐IV axis I)

2. Any current psychiatric comorbidity that required pharmacotherapy

3. Any evidence of suicide risk

4. Any evidence of mental retardation (IQ < 70)

5. A clinically significant chronic medical condition, including organic brain disorder, seizures or current abuse or dependence on drugs in the last 6 months

6. Hypertension or hypotension

Treatment compliance: not stated

1. Side effect checklist administered by a child psychiatrist on days 7, 21 and 42

2. Haematology tests, baseline and weeks 2, 4 and 6

3. Serum chemistry, urinalysis, 12‐lead ECG, and physical examinations at baseline and week 6

4. Body weight and vital signs, baseline and weeks 1, 2, 4, and 6

Key conclusions of the study authors: the principal measure of outcome was the Teacher and Parent attention deficit/hyperactivity disorder Rating Scale‐ IV. No difference was observed between the 2 groups. Side effects consisting of headache and irritability were observed more frequently in the methylphenidate plus placebo group. The results of this study do not support the application of ALC as an adjunctive therapy to methylphenidate in children and adolescents with ADHD.

Sociodemographics: Uneventful pregnancy

Treatment compliance: treatment was administered until 9 to 10 years of age when parents discontinued treatment due to obsessive compulsive symptoms

1. Tics (both motor and vocal). Started at 40 mg/daily and subsided spontaneously after a year of treatment

2. Obsessive compulsive symptoms (predominantly about symmetry) started about 6 months after tics and lasted 2.5 years and resolved at age 10

3. Sudden and severe aggressive and violent outbursts. The explosive outbursts paralleled the development of preoccupation with symmetry

4. Sedation/semi‐catatonia

5. Increased impulsivity

Supplemental information regarding diagnostic criteria and treatment duration obtained through personal email correspondence with the authors in October 2013 (Adrian 2013 [pers comm])

Sociodemographics: not stated

Treatment compliance: not stated

Case 2

Sociodemographics: not stated

Case 2

Treatment compliance: not stated

Case 2

1 day after discontinuation: the symptoms remitted

Methylphenidate group

Inclusion criteria

1. DSM‐IV

2. IQ > 70

3. Parents and children had to be willing to comply with all requirements of the study

4. Minimum score of 20 on the teacher and parent ADHD rating scale

1. Previously diagnosed with a psychiatric disorder

2. Clinically significant chronic medical condition, incl. a past history of cardiovascular disease, organic brain disorder, or seizures

3. Current abuse or dependence on drugs within 6 months

4. Current treatment with psychotropic medications

Treatment compliance: not stated

1. Anxiety: 3

2. Decreased appetite: 5

3. Increased appetite: 0

4. Difficulty falling a sleep: 4

5. Abdominal pain: 3

6. Nausea: 2

7. Headache: 6

Key conclusions of the study authors: the results of the study must be considered preliminary, but they do suggest that selegiline may be beneficial in the treatment of ADHD. In addition, a tolerable side effect profile may be considered as one of the advantages of selegiline in the treatment of ADHD

1. Methylphenidate + zinc sulfate

2. Methylphenidate + placebo

Exclusion criteria

1. Previously diagnosed with a psychiatric disorder

2. Mental retardation (IQ < 70)

3. Clinically significant chronic medical condition, including a past history of cardiovascular disease, organic brain disorder, seizures, current abuse or dependence on drugs within 6 months

4. Current treatment with psychotropic medications

Treatment compliance: not stated

1. Anxiety: 3

2. Decreased appetite: 7

3. Difficulty falling asleep: 6

4. Abdominal pain: 4

5. Nausea: 3

6. Headache: 9

7. Metallic taste: 0

Key conclusions from study authors: this double‐blind, placebo‐controlled study demonstrated that zinc as a supplementary medication might be beneficial in the treat‐ ment of children with ADHD. However, further investigations and different doses of zinc are required to replicate these findings in children with ADHD.

Sociodemographics: both parents had advanced no further than elementary school. The parents' history was unremarkable

Treatment compliance: good according to regular visits record

Supplemental information regarding IQ, ethnicity and treatment compliance received through personal email correspondence with the authors in April 2016 (Alpaslan 2016 [pers comm])

Inclusion criteria:

1. Attending school for at least the previous 4 weeks

2. Continue to attend classes for ≥ 4 weeks before summer vacation

3. Initiating or switching ADHD treatment (monotherapy with methylphenidate, atomoxetine or nootropic agent)

4. Without significant or unstable mental or general medical comorbidities

5. Not involved in a current clinical trial

Treatment compliance: not stated

Key conclusions of the study authors: after 12 months of treatment, clinical and functional outcomes were improved in children and adolescents from non‐Western countries who initiated and remained on their prescribed pharmacological monotherapy

Inclusion criteria:

1. Between the ages of 6‐15

2. DSM‐IV‐TR diagnostic criteria for ADHD

3. Total and/or subscale scores on Attention‐Deficit/Hyperactivity DisorderRating Scale IV (ADHD‐RS‐IV) School Version ≥ 1.5 SD above norms for patient's age and gender

4. Parents and children had to be willing to comply with all requirements of the study

1. History or current diagnosis of pervasive developmental disorders, schizophrenia or other psychiatric disorders (DSM‐IV axis I)

2. Any current psychiatric comorbidity that required pharmacotherapy

3. Any evidence of suicide risk or mental retardation (IQ < 70 based on clinical judgement)

4. A clinically significant chronic medical condition, including organic brain disorder, seizures and, current abuse or dependence on drugs within 6 months

5. Hypertension, hypotension and habitual consumption of more than 250 mg/day of caffeine

Treatment compliance: not stated

Non‐serious adverse events:

Key conclusions of the study authors: no significant differences were observed between the 2 groups (modafinil vs methylphenidate) on the Parent and Teacher Rating Scale scores. Side effects of decreased appetite and difficulty falling asleep were observed more in the methylphenidate group. The results of this study indicate that modafinil significantly improved symptoms of ADHD and was well tolerated and it is beneficial in the treatment of children with ADHD

Inclusion criteria:

1. Outpatient preschoolers

2. ADHD according to DSM‐IV‐TR criteria established by 2 child and adolescent psychiatrists

1. Presence of any physical disease

2. Presence of mental retardation

3. Presence of any psychiatric comorbid disorders except conduct disorder and oppositional defiant disorder

Treatment compliance: not stated

More common side effects were anorexia (55.55%), nervousness (33.33%) and disturbed sleep (27.77%)

Key conclusions of the study authors: this double‐blind, randomised and controlled study suggests risperidone is effective in alleviating total symptoms of ADHD and related co‐morbid symptoms in preschoolers and that there is no statistically significant difference between the 2 groups in alleviating ADHD symptoms

Inclusion criteria:

1. Children and adolescents admitted to the Child and Adolescent Psychiatry Department of Ege University Medical Faculty between January and June 2010

2. ADHD diagnosis according to the schedule for affective disorders and schizophrenia for school aged children (Kiddie‐SADS)

1. Psychotic disorder, bipolar disorder or pervasive developmental disorder

2. Mental retardation (defined as having an IQ lower than 80)

3. Not taking another medication for anxiety, depression, or other disruptive behaviour disorders

Treatment compliance: not stated

Non‐serious adverse events:

Key conclusions of the study authors: OROS‐MPH was effective and safe for Turkish children and adolescents, compared to MPH‐IR

Inclusion criteria:

Exclusion criteria:

1. Participants with cardiac and neurologic diseases affecting the autonomic nervous system were excluded

Treatment compliance: not stated

Non‐serious adverse events:

Key conclusions of the study authors: our study showed a significantly increased heart rate and decreased heart rate variability due to methylphenidate treatment in children with ADHD, suggesting an increased sympathetic tonus especially at the daytime. Risk of sudden cardiac death and serious arrhythmia has not been demonstrated

1. Dexmethylphenidate

2. Placebo

Inclusion criteria

1. 6‐17 years of age

2. Enrolled in school

3. DSM‐IV diagnosis of ADHD any subtype

4. Within 30% of normal body weight

5. Able to participate for the full 8 weeks

1. History or evidence of cardiovascular, renal, respiratory (other than asthma/allergy), endocrine, or immune system disease

2. History of substance abuse

3. Hypersensitivity to dl‐methylphenidate or other stimulants

4. Treatment with any investigational drug within 30 days of screening

5. Other significant central nervous system disorders

6. Treatment with antidepressants, neuroleptics/ antipsychotics, mood stabilisers, anticonvulsants, beta blockers, alpha2 agonists, other stimulants, thyroid medications, chronic oral steroids, or sedatives/hypnotics

7. Concurrent treatment with other psychoactive drug

Treatment compliance: not stated

Key conclusions of the study authors: d‐MPH is safe, tolerable, and effective, with a 6‐hour duration of effect suggested by the significant difference from placebo at 6 hours on a double‐blind discontinuation

Inclusion criteria:

1. Children aged 6‐12 years

2. Any type of ADHD (DSM‐IV‐TR)

3. On a stable dose of an oral extended release methylphenidate (not exceeding 54 mg/day) for ≥ 30 days and total scores of or less than 1.5 SDs from age appropriate norms on the ADHD Rating Scale‐IV

4. Normal laboratory parameters, vital signs, electrocardiogram (ECG), and a body mass index (BMI) not exceeding the 90th percentile

5. Whose parent/legally authorised representative was considering a change in treatment based on efficacy, tolerability, or compliance

6. Females of childbearing potential must have a negative serum beta Human Chorionic Gonadotropin pregnancy test

1. Children with a comorbid psychiatric disorder (excepting ODD), intellectual disability, concurrent illness or skin disorder that might compromise tolerability or study assessments

2. Taken clonidine, atomoxetine, antidepressants, antihypertensives, medications with CNS effects, sedatives, antipsychotics, anxiolytics, anticonvulsants, or other investigational medications within the previous 30 days

3. A recent history of suspected substance abuse or dependence disorder

Treatment compliance: compliance with the treatment regimen was measured by patch counts weekly. Data not stated

1. One 12 year old girl experienced acute depression and suicide attempt which was considered possibly related to transdermal methylphenidate treatment, 30 mg for 16 days

1. Application site reaction

2. Other adverse event

Key conclusions of the study authors: abrupt conversion from a stable dose of oral ER‐MPH to transdermal MPH was accomplished using a predefined dose‐transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH

Comments from the study authors: study limitations: open‐label, with no control group, non‐randomised design. Relatively short duration. Spontaneous AE reporting. These results may not be generalisable to participants who are not on a stable dose of oral methylphenidate or who have a poor response

Sociodemographics: good socioeconomic status

Treatment compliance: not stated

Supplemental information regarding IQ, ethnicity, comorbidity and comedication received through personal email correspondence with the authors in August 2016. No information regarding exact IQ level was available, but authors state that it was above 70 (Artul 2016 [pers comm])

Case 2

Sociodemographics: living in nuclear family

Case 2:

Treatment compliance: not stated

Non‐serious adverse events

Authors' affiliations: Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India

1. Titration period to optimal dose

2. RCT for 4 weeks with a different sequence of patch wear time

Inclusion criteria:

1. Children aged 6‐12 years

2. Met the DSM‐IV criteria for attention deficit hyperactivity disorder (any subtype)

3. Demonstrated difficulty sleeping (as reported by the caregiver)

1. Patients with previous intolerance, adverse response, or allergy to methylphenidate or skin sensitivity to the methylphenidate transdermal system

2. Severe comorbid psychiatric disorders (e.g. psychosis, bipolar illness, pervasive developmental disorders, severe obsessive compulsive disorder, severe depression, or severe anxiety disorder) or other symptomatic manifestations that would, in the opinion of the examining physician, contraindicate the use of methylphenidate or confound efficacy or safety assessments (i.e., common, less severe comorbidities of attention deficit hyperactivity disorder were permitted)

3. A history of seizure disorder, tics/Tourette syndrome, known structural cardiac abnormalities, hypertension, hyperthyroidism, glaucoma, and pregnancy/lactation

4. Use of psychotropic medications (other than study medications) and medications that might affect sleep (e.g. antihistamines or decongestants)

Treatment compliance: 1 participant discontinued because of non‐compliance. No information about the others

Non‐serious adverse events:

Sleep was assessed according to a daily sleep diary, with entries for time of patch application and removal, sleep timing (e.g. bedtime, time to fall asleep, number of awakenings, time awake at night, and final wake time), and ratings of sleep quality (on a 5‐point scale). Entries were recorded at baseline, after determination of the optimal patch dose, daily during wear time titration, and at endpoint. The sleep diary was documented by caregivers Monday through Sunday of every week throughout the wear time titration

Key conclusions of the study authors: patch wear time exerted no significant effect on sleep latency or total sleep time, although a trend toward improved sleep quality was evident (P ¼ 0.059) with longer patch wear times. Sleep parameters were not adversely affected by longer methylphenidate transdermal system patch wear times

Inclusion criteria:

1. ADHD diagnosis using DSM‐IV

2. Taking ≥ 1 dose of methylphenidate between 1998‐2005

1. Severe side effects after test dose

2. Lack of symptom improvement after ≥ 1 week of treatment

3. Parental decision immediately after test dose or during the first 2 weeks of treatment

Treatment compliance: 14.9% non‐adherent (non‐adherence as taking less than 80% of medication for ≥ 8 months per year)

Funding/vested interests: supported in part by Sardinian Public Health Secretariat and by the Agenzia Italiana del Farmaco

Key conclusions of the study authors: clinical outcome of ADHD treatment is heterogeneous. Specific clinical and social predictive parameters for long‐term methylphenidate use and compliance can be identified. An accurate tailoring of clinical intervention to the individual child appears crucial for good outcome

Inclusion criteria

1. ADHD medication first administered ≥ 12 months prior beginning study

2. Evaluation of efficacy and side effects

1. Previous ADHD treatment

2. ADHD treatment from another clinic after initiating medication

3. > 18 years old

4. Treatment discontinued by clinicians

5. Insufficient data, or evaluation scores not appropriately calculated

6. Adopted, living in institutions, or not living with parents

7. Mental retardation, pervasive developmental disorders, psychosis, substance abuse/addiction, bipolar disorder

Treatment compliance: 265 continued treatment 12 months after the initiation of the prescription

Key conclusions of the study authors: medication persistence, in Turkish children, can be influenced by younger age, higher hyperactivity/impulsivity scores, use of long acting MPH, addition of another ADHD medication, and addition of other psychotropic medications, absence of adverse events, efficacy level perceived by the parents

Inclusion criteria

1. Aged 6‐18 years

2. ADHD DSM‐IV diagnosis (using the Mini International Neuropsychiatric Interview Kid 2.0)

3. Receiving methylphenidate

4. Recruited from a child and adolescent psychiatric hospital and outpatient clinic

1. Past or present mental or neurological disorders

Treatment compliance: 3 children left the study after baseline measurements were taken

Key conclusions of the study authors: methylphenidate‐treated children with ADHD had more dyskinesia than children in the control group. Dyskinesia did not worsen after a single dose of methylphenidate

Comments from the study authors: we found no relationship between prior methylphenidate exposure of the children with ADHD and the total severity of dyskinesia. We believe that this lack of association is because most of our patients had been receiving long‐term methylphenidate treatment before enrolment in the study. Limitations: no inclusion of treatment‐naïve children with ADHD

Inclusion criteria:

1. ADHD symptoms

2. Positive results in ADHD questionnaires

3. Documented diagnoses of ADHD

1. Diagnosis of pervasive developmental disorder

2. Severe mental retardation

3. Schizophrenia, or other psychotic disorder

Treatment compliance: not stated

6.1% of 717 MPH treatment episodes (i.e. period of time during which participant was treated with MPH at a specific dose) were associated with a side effect

Key conclusions of the study authors: clinicians made appropriate treatment decisions; there are disparities in the rates ADHD treatment for boys/girls; efficacy was comparable to clinical trials

Inclusion criteria:

1. ADHD diagnosis according to DSM‐III‐R

2. Aged 7‐17 years

1. IQ < 70

2. Any other major Axis I, II or III diagnoses

3. Seizure disorders (bupropion contraindication) or history of seizures, eating disorders (predisposed to bupropion seizures), current use of an MAOI

Treatment compliance: not stated

Revised Children's Manifest Anxiety Scale (R‐CMAS), rated each week by physician

Key conclusions of the study authors: bupropion and methylphenidate were both effective and did not differ in their overall efficacy as treatment for ADHD. Thus, results of nearly all of the rating scales trended in favour of methylphenidate. There is a possibility that this insignificant difference might be a function of the relatively small dose of bupropion used in this study

Inclusion criteria

1. Children and adolescents aged 6‐18

2. Confirmed diagnosis of ADHD (any subtype) by ICD‐10

3. In whom treatment with OROS methylphenidate was medically indicated and planned by the treating physician

Treatment compliance: not stated

Sleep quality and appetite were assessed at each visit, using a 5‐point scale with categories: very good, good, satisfactory, sufficient and insufficient

Key conclusions of the study authors: our study suggest a clinically meaningful increase in efficacy upon transitioning onto OROS methylphenidate in the treatment of children/adolescents with ADHD who had insufficient response to and/or poor tolerability with extended release methylphenidate or atomoxetine

Inclusion criteria:

1. ADHD according to DSM‐IV, confirmed by 2 child psychiatrists

1. Prematurity

2. Low birth weight

3. Any systemic disease

Treatment compliance: not stated

Height and weight measurements were transformed to SDs before the statistical analyses using normative data for Turkish children. BMI values were transformed to SDs according to data from Cole 2007

Key conclusions of the study authors: prepubertal children with ADHD had normal height, weight, BMI, serum IGF‐I and IGFBP‐3 and thyroid functions. Methylphenidate treatment had no sustained effects on growth parameters, IGF‐I and IGFBP‐3 during the follow‐up period of this study. However, it caused a mild decrease in total and free T4, which may warrant further monitoring

Sociodemographics: unknown

Treatment compliance: not stated

Authors' affiliations: Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

Inclusion criteria

1. Aged between 6 and 13

2. Fulfill diagnostic criteria for ADHD

3. Fulfill criteria for ODD or CD

4. Obtain parent reported ratings of clinically significant aggression (R‐MOAS)

5. Previous stimulant treatment at a minimum of methylphenidate dosage 30 mg/day or equivalent with insufficient response

1. Major depression, bipolar disorder, Tourette syndrome, psychotic disorders, pervasive developmental disorder, mental retardation and aggressive behaviour arising chiefly as a complication of an anxiety disorder

2. Contraindications to stimulant treatment

3. Seizure disorders

4. Pregnancy

Treatment compliance: 3 withdrawals due to low adherence

A BBAEQ‐M item was considered present when the parent rated it at least moderate

Authors' affiliations:all authors have received research support in the past from pharmaceutical companies and/or consulting and/or speaking fees.

Inclusion criteria:

1. Over 7 years old

2. Diagnosis of ADHD (DSM‐IV)

1. Any other psychiatric disorder, including ODD, dyslexia, dyscalculia, and OCD

2. Any combinations with neurological diseases, including tic disorder/Tourette syndrome

Treatment compliance: children were inpatients for the duration of the study and received supervision when taking their medication

Key conclusions of the study authors: the methylphenidate group had the short interval cortical inhibition, intracortical facilitation and long interval cortical inhibition changes restored by the medication ‐ this was a very similar finding, compared to control group

Sociodemographics: not stated

Treatment compliance: not stated

Comments from the study authors: it is important to note that, as in this case, adolescent males may be too embarrassed to report this side effect particularly when they do not know it may be linked to methylphenidate

Case 2

Sociodemographics: not stated

Case 2

Treatment compliance: not stated

Supplemental information regarding diagnosis and IQ received through personal email correspondence with the authors in September 2013 (Gualtieri 2013 [pers comm])

Inclusion criteria

1. Age between 5 and 17 years

2. ADHD diagnosis according to DSM‐IV

3. Primary indication of treatment with methylphenidate

1. Refusal or contraindication for methylphenidate use

2. Estimated IQ < 70

Treatment compliance: 76.4% adherence

Key conclusions of the study authors: our results suggest that ADHD combined subtype, maternal ADHD symptoms, and social adversities are independent negative predictors of methylphenidate response in children and adolescents with ADHD. Our study provides evidence for the involvement of clinical characteristics, maternal psychopathology, and environmental stressors in the response to methylphenidate

Inclusion criteria:

1. ADHD diagnosis of DSM‐III‐R ADD or DSM‐IV

2. Stimulant treatment

Treatment compliance: not stated

• 9 children developed psychotic symptoms

• 3 children had amphetamine intoxication

• 1 had psychotic symptoms

• 3 had mood‐congruent psychotic symptoms

• 1 was unclassifiable because information about the event was insufficient

• 11 children developed either mood‐only symptoms or mood‐congruent psychotic symptoms while being treated with MPH (11.7%)

• 1 child with severe depression required hospitalisation

Key conclusions of the study authors: awareness of the potential for psychotic side effects from stimulant medications is important when prescribing for children. A large prospective study would be useful to predict the frequency and classification of the side effects in children

Inclusion criteria:

1. ADHD according to DSM‐IV‐TR

2. Aged 6‐12 years

3. Severity of symptoms equal to or more than 'moderate degree' on the Clinical Global Impression‐Severity (CGI‐S) scale and severe enough to warrant medication treatment

4. The absence of any history of exposure to psychostimulants such as methylphenidate

1. Other mental disorders than transient tic disorder, oppositional defiant disorder, mild anxiety disorder and enuresis

2. A past or present history of brain damage or convulsive disorder

3. Mental retardation, autism, language difficulties or developmental problems including learning disabilities

Titration: initial dosage was determined by child's body weight: if ≥ 30 kg, 27 mg was administered; if < 30 kg, 18 mg was administered. The dosages were increased every 2 weeks for 9 weeks until they were sufficient to achieve a therapeutic effect, on the basis of the investigators and parents' assessments of symptoms and side effects, and then these doses were maintained until the 12th week. Treatment compliance: not stated

Key conclusions of the study authors: the overall cardiovascular effects of OROS‐methylphenidate were modest. However, our findings show a positive association between norepinephrine‐related gene polymorphisms and cardiovascular response induced by methylphenidate in Korean children with ADHD. Consideration must be given to such children or adults with specific norepinephrine‐related genotypes, especially if they show significant changes in heart rate or diastolic blood pressure after OROS‐methylphenidate administration

Inclusion criteria:

1. Age 6‐19 years

2. ADHD according to DSM‐IV

3. Treatment with immediate‐release methylphenidate (< 70 mg/day) for ≥ 1 month, without severe adverse events or possible contraindications

4. Participant/parent written informed consent

5. Participants must be living with the parent/caregiver who can complete the questionnaires during the study

6. Participants or parent/caregivers without any psychotic disease or any mental situation which may cause the concern to properly complete the questionnaires

1. Any systemic disease or clinically significant gastrointestinal problem

2. Any comorbid psychiatric disorders, except for conduct disorder and oppositional disorder

3. Known to be non‐responders to methylphenidate

4. Known or suspected mental retardation or significant learning disorder

5. Glaucoma or ongoing seizure disorder

Treatment compliance: not stated

Key conclusions of the study authors: the findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced‐titration scheme

Inclusion criteria

1. Participants who are diagnosed with ADHD according to DSM‐IV

2. Participants who have been treated with immediate‐release methylphenidate for ≥ 4 weeks before enrolment, but previous treatment is considered unsatisfactory due to ≥ 1 of the following reasons: lack of effectiveness, lack of tolerability or safety, lack of compliance, and/or other reasons

3. Participants who are able to comply with the study visit schedule and whose parents/caregiver and community school teacher are willing and able to complete the protocol‐specified assessments

4. Participants who are still at school

5. Participants who are treated with ≥ 10 mg immediate release methylphenidate daily before enrollment

1. Cannot understand or follow the instructions given in the study

2. Serious or unstable medical illness

3. Clinically significant gastrointestinal problems, including narrowing of the gastrointestinal tract

4. Gaucoma, an ongoing seizure disorders, or a psychotic disorder

5. Hypersensitive to methylphenidate

6. Any co‐existing medical condition or are taking a concomitant medication that is likely to interfere with safe administration of methylphenidate

Treatment compliance: not stated

Key conclusions of the study authors: comparing with the baseline, OROS‐methylphenidate had been demonstrated that it could significantly improve participants' ADHD behavioural symptoms and their social adjustment at school and at home

Inclusion criteria:

Exclusion criteria:

Treatment compliance: not stated

Wits Faces Sleepiness: a subjective, pictorial scale designed specifically for children which consists of 5 cartoon faces depicting increasing levels of sleepiness. Rated at 8:30 am and 1:00 pm

Key conclusions of the study authors: in a group of children with ADHD taking methylphenidate, there was a significant increase in sleepiness a few hours after taking the medication, which may then have a significant impact on their learning. The data also imply that part of the mechanism of action of methylphenidate effects in these children may be by reduction of daytime sleepiness

Sociodemographics: unknown

Treatment compliance: unknown

Case 1

Case 2

Sociodemographics: high cultural level

Treatment compliance: not stated

Key conclusions of the study authors: this study revealed the limits of category‐based approach and international classifications as they do not express clinical singularities or possible neurobiological continuums. It also seems to confirm the possible risk of emergence of a psychosis for schizotypal participants, due to pharmaceutical induction by psychostimulants (methylphenidate). This emergence could be stopped by a combined antipsychotic treatment

Sociodemographics: not stated

Treatment compliance: not stated

Key conclusions of the study authors: allergy to methylphenidate is rare. Whenever feasible, an alternate drug should be used if a reaction to the drug occurs. When an alternative is not available or the offending drug is still the best available choice, desensitisation should be considered (for mild rather than life‐threatening conditions/reactions)

Inclusion criteria:

1. Boys aged 7‐12 years (prepubertal)

2. ≥ 1 year of methylphenidate use and drug‐responsive

3. No history of specific speech and language impairments and voice‐related disorders

4. No history of other psychiatric disorders (conduct disorder, any anxiety disorder, depressive disorder, learning disorder etc.) except oppositional defiant disorder

5. No mental retardation, neurological disorders, sensorimotor handicaps, and chronic medical illness (respiratory diseases etc.)

1. Those who took medication other than methylphenidate before and at the time of recording were excluded

2. At the time of recording, none of the participants had cold, allergy, or flu symptoms

Treatment compliance: not stated

We have not used these data

Key conclusions of the study authors: this clinical trial is the only study that examined the effects of stimulant medication on vocal acoustic parameters in children with ADHD and evaluated a small sample on and off their clinical doses of methylphenidate. We suggest that methylphenidate decreases fundamental frequency in children with ADHD, but our findings should be replicated under blind drug administration and by supporting other vocal analyses

Sociodemographics: not stated

Treatment compliance: abuse

Key conclusions of the study authors: euphoria induced by methylphenidate can occur in young prepubertal children and this may lead to abuse of medication

Inclusion criteria:

Exclusion criteria:

Treatment compliance: not stated

Non‐serious adverse events:

Key conclusions of the study authors: our naturalistic postmarketing phase IV pharmacovigilance observational study showed that while mild and severe adverse events were observed in children treated with methylphenidate and in those treated with atomoxetine, those who received atomoxetine were significantly more likely to experience adverse events

Sociodemographics: not stated

Treatment compliance: not stated

Sociodemographics: not stated

Treament compliance: not stated

Restart of immediate release methylphenidate 10‐20 mg/day and gabapentin 300 mg/day, 4 months: no skin eruptions

Sociodemographics: unknown

Case 2

Osmotic release oral system methylphenidate: 18 mg/day. Treatment compliance: unknown

Case 2

Discontinuation of osmotic release oral system methylphenidate: no morning erections or hypersexual behaviours

Inclusion criteria

1. Meet criteria for diagnoses of ADHD, anxiety and/or depressive disorders based on DSM‐IV

Treatment compliance: not stated

1. Sleep problems:

   1. developed sleep problems (n = 4)

   2. worsening of pre‐existing sleep problems (n = 2)

2. Appetite problems:

   1. significant decrease in appetite (n = 3)

   2. weight loss: same 3 patients (1 = −2 kg, 1 = −3 kg, 1 = −4 kg)

Key conclusions of the study authors: young participants with diagnosis of ADHD and comorbid anxiety and depressive disorders may benefit from mirtazepine addition particularly in the presence of methylphenidate‐ or SSRI‐related sleep and/or appetite problems

Sociodemographics: unknown

Treatment compliance: unknown

Re‐administering of osmotic release oral system methylphenidate, 27 mg/day: mild facial grimace, similar obsessive‐compulsive symptoms. After 3 weeks: Children's Yale‐Brown Obsessive‐Compulsive Scale (CY‐BOCS), total score = 21

Inclusion criteria

1. ADHD diagnosis according to DSM‐IV‐TR

2. Score of or above 20 on the teacher and parent ADHD‐Rating Scale

3. ADHD treatment‐naïve

1. Evidence of a mental retardation or a major psychiatric problem other than oppositional defiant disorder and conduct disorder

2. Retrieving any psychotropic medication through 2 weeks before initiation treatment

3. Medical disorders that would preclude the safe use of MPH or buspirone

Treatment compliance: not stated

Non‐serious adverse events

Decreased appetite (n = 11), decreased sleep (n = 7)

Key conclusions of the study authors: no significant differences were observed between the 2 protocols on the total scores of parent and teacher ADHD Rating Scale, but methylphenidate was superior to buspirone in decreasing the symptoms of inattention. The side effects of buspirone were mild and rare in comparison with methylphenidate

Inclusion criteria

1. DSM‐IV diagnosis of ADHD

2. Comorbid ADHD and epilepsy

1. Inattention explained by EEG abnormalities or antiepileptic medication

Treatment compliance: not stated

Key conclusions of the study authors: methylphenidate is safe and effective in children with epilepsy and ADHD

Inclusion criteria

1. Children and adolescents aged 6‐17 years

2. A confirmed DSM‐IV diagnosis of ADHD

3. Either untreated or currently receiving treatment with an approved methylphenidate product

4. Vital signs and laboratory assessments within the normal range

5. Blood pressure within the 90th percentile for height and gender

6. Females pre‐menarchal, sexually abstinent, or using a medically acceptable form of birth control and having a negative pregnancy test

1. Comorbid psychiatric disorder

2. Concurrent illness

3. IQ less than 80

4. Inability to understand or follow directions

5. History of tic disorder, Tourette syndrome, seizures, glaucoma, hyperthyroidism or significant cardiovascular disease

6. Non‐response to methylphenidate

7. Use of excluded medications or medications that affect blood pressure or heart rate

8. Personal or family history of substance abuse

9. Pregnancy or a significant risk of pregnancy

10. Participated in another drug study in the previous 30 days

Dosage was titrated on a weekly basis according to clinical judgement

Key conclusions of the study authors: methylphenidate hydrochloride is effective and well‐tolerated for clinical use in ADHD

Inclusion criteria

1. Medication‐naïve child and adolescent outpatients

2. Aged 6‐17 years

3. A diagnosis of ADHD according to ICD‐10 or DSM‐IV criteria

4. Newly initiated on medication approved for the treatment of ADHD in Germany

Treatment compliance: 178 (74.2%) had a PCSR (Pediatric Compliance Self‐Rating instrument) score ≥ 5 at every visit

Key conclusions of the study authors: all outcome parameters (effectiveness) considered in this open‐label, non‐interventional trial with respect to ADHD core symptoms, ADHD‐related difficulties, and emotional expression significantly improved over time in children and adolescents with ADHD who were treated with pharmacotherapy (i.e. atomoxetine or psychostimulants) in a naturalistic setting with regard to their degree and time course, which corresponds with the well‐established findings from double‐blind controlled clinical trials

1. Duloxetine

2. Methylphenidate

Inclusion criteria

Treatment compliance: not stated

Drug side effects evaluated each 2 weeks during the study

Key conclusions of the study authors: our study showed that duloxetine may be as effective as methylphenidate in treatment of ADHD in adolescents.

Inclusion criteria

1. 6‐16 years old

2. DSM‐IV‐TR diagnosis of ADHD

3. Treated in the ADHD clinic of the Neuro‐paediatric Unit, Hadassah Medical Center, from 1 January 2004 to 31 December 2008

1. Presence of additional mental or somatic chronic health conditions (e.g. epilepsy, mental retardation, cerebral palsy, prior significant brain injury, hearing/visual impairments, pervasive developmental disorder, mental disorders) other than overweight

2. Use of dietary supplements or chronic medications (other than methylphenidate)

Treatment compliance: not stated

Key conclusions of the study authors: physicians should be aware of the possibility of height and weight abnormalities in children with ADHD, with or without treatment

Inclusion criteria:

1. ADHD according to DSM‐IV

2. IQ > 85

3. Positive response to stimulant medication

1. History of problematic prenatal, perinatal, or neonatal periods

2. A history of central nervous system (CNS) diseases

3. Convulsion or convulsive disorders

4. Evidence of a consciousness disorder

5. Head injury with cerebral symptoms

6. Paraxysmal headaches or tics

7. DSM‐IV criteria for CD or ODD, an anxiety or depressive disorder, Asperger or Tourette syndrome

Treatment compliance: not stated

Key conclusions of the study authors: intrahemispheric and interhemispheric coherences in ADHD stimulant medicated girls. Girls had elevated frontal coherence across all frequency bands

Inclusion criteria

1. DSM‐IV‐R diagnosis of ADHD, inattentive or combined subtype

2. Start of OROS‐methylphenidate treatment at the time of ADHD diagnosis

3. Continuous OROS‐methylphenidate treatment for ≥ 48 months

4. Evaluated at the Pediatric Neurology Unit of the Navarra Hospital Complex in Pamplona, Spain, between January and December 2009

1. Methylphenidate treatment stop during school holidays or summer periods

Treatment compliance: not stated

Key conclusions of the study authors: at the time the participants were diagnosed with ADHD, 1 out of every 3 patients was in a deficient nutritional situation (subnutrition or malnutrition). Continued treatment with OROS‐methylphenidate for 30 months had a negative influence on height and weight. However, we observed a recovery of anthropometric variables from the 30th to the 48th month of OROS‐methylphenidate treatment (growth‐rebound); this means that the effects of stimulant drugs, and specifically methylphenidate, on the growth curve would be a transitory condition that attenuates as time passes.

Inclusion criteria

1. Confirmed diagnosis of ADHD according to DSM‐IV‐TR (314.00 or 314.01) or ICD‐10 (F90.0, F90.1 or F90.8)

2. Therapy with Equasym XL already intended by the attending physician

3. Patients had to be attending school

1. Contraindications according to the summary of product characteristics

2. Presence of a mental handicap

Treatment compliance: not stated

Key conclusions from study authors: this open‐label, observational, post‐marketing surveillance study investigates the effectiveness and safety of Equasym XL which is a combination of 30% immediate‐release MPH and 70% modified‐release MPH, in the treatment of ADHD in daily clinical practice. The effectiveness of Equasym XL was rated better than prior or no therapy and generally well tolerated

Supplemental information regarding data were attempted to retrieve from the authors by email. Sent twice, no answer

Inclusion criteria

1. Children participating in this trial were aged between 6.0 and 17.11 years

2. Body weight > 20 kg

3. Diagnosis of a Hyperkinetic Disorder according to ICD‐10 was confirmed in a structured clinical interview based on a German Diagnostic Checklist for ADHD (DCL‐ADHD)

4. IQ > 80 in a German version of the Culture Fair Intelligence tests (CFT1 or CFT20)

5. Attending a primary, secondary, or special school for handicapped pupils

6. Have teacher(s) who were willing to participate and fill out rating scales

7. Had to be methylphenidate responders after clinical evaluation and careful titration

8. Had to take methylphenidate ≥ twice daily or a single dose of Concerta or Medikinet retard

9. Had to have received daily doses of methylphenidate of 18‐36 mg before inclusion

10. Had to have had no change in the dose of methylphenidate in the previous month

11. Had to agree to eat breakfast every day during the study period

12. Had to be able to swallow the capsules

1. Any contraindication to methylphenidate

2. Treatment with psychostimulants other than methylphenidate in the previous 4 weeks

3. Needed another ADHD treatment (e.g. behavioural therapy or immediate inpatient treatment)

Treatment compliance: the compliance was more than 99%

Heart rate, rated weekly by investigator

Key conclusions from study authors: in summary, based on the efficacy and safety data from this trial it can be claimed that Medikinet retard with a higher IR component than Concerta and an equivalent daily dose is superior to Concerta in the morning and that children and adolescents may also be treated with a lower daily dose of Medikinet retard without resulting in a clinically relevant worse effect during school time as assessed by SKAMP‐D. "Since there is no placebo group or no 'no‐intervention' group in the trial, we can only use the data on adverse events. We extract data from this study as if it was an observational study

Inclusion criteria

1. Age 6‐17

2. Diagnosed with ADHD

3. Indication for treatment with Medikinet retard

1. Patients were excluded if they had any contraindications listed in the summary of product characteristics

Treatment compliance: was assessed by prescribing physician. In 57% of cases there was improved compliance after the medication switch; no change was observed in 39%, and compliance deteriorated in 4%

In 79 patients, adverse events were recorded by the physician, and these events were described as severe in 13 cases. The most frequent adverse events were appetite disorders, head‐ and stomachache and sleep disorders

Key conclusions of the study authors: the overall evidence showed that Medikinet retard was well tolerated in routine clinical practice, can be used effectively to treat symptoms of ADHD, can improve compliance to medication and can contribute to a further improvement in symptoms in previously suboptimally treated patients

1. Methylphenidate

2. Dexamphetamine

Inclusion criteria

1. 5‐15 years

2. DSM‐IV criteria for ADHD

3. T‐score of ≥ 1.5 SD units above the mean on the attention problems scale of the Child Behavior Checklist (CBCL) or Teacher Report Form (TRF)

4. Decision made to undertake stimulant medication trial on clinical grounds

1. History of intellectual disability, gross neurologic abnormality, or Tourette syndrome

Treatment compliance: not stated

Parent rated at baseline and the end of each 14 day period

Key conclusions of the study authors: nightmares, stomachaches and anxiousness decreased in frequency on methylphenidate, whereas poor appetite increased on methylphenidate. Most children with ADHD improve significantly on both methylphenidate and dexamphetamine. There was a slight advantage to methylphenidate on most measures. Many symptoms commonly attributed to stimulant medication are actually preexisting characteristics of children with ADHD and improve with stimulant treatment

Inclusion criteria

1. No contra‐indications to stimulant's therapy

2. DSM diagnosis

3. 5‐15 yo

4. Both sexes

5. Consent of parents

1. IQ below 90

2. Chronic general medical conditions

3. Forms of pervasive developmental or tics disorder

4. Epilepsy

5. Previous poor response or intolerance to stimulants

6. Non‐consenting families

Treatment compliance: not stated

Key conclusions of the study authors: no statistically significant gender differences; females recorded less improvement and showed more 'talk less' and 'less interest' as side effects. Conclusive evidence for the role of gender in ADHD require bypassing methodological limitations as well as confounding factors.

Inclusion criteria

1. ADHD diagnosis according to DSM‐IV criteria

Treatment compliance: not stated

Type of effect: 3 cytogenetic endpoints (chromosome aberrations, sister chromatid exchanges and micronuclei frequencies) measure method (peripheral blood lymphocytes obtained pre and post treatment)

Key conclusions of the study authors: in all participants, treatment induced a significant 3, 4.3 and 2.4‐fold increase in chromosome aberrations, sister chromatid exchanges and micronuclei frequencies, respectively (PZ0.000 in all cases). These findings warrant further investigations of the possible health effects of methylphenidate in humans, especially in view of the well‐documented relationship between elevated frequencies of chromosome aberrations and increased cancer risk

Inclusion criteria

1. ADD disorder according to DSM III

1. IQ < 90

2. Anxiety or panic disorder

3. Seizure disorder

4. Major affective disorder

5. Thought disorder

6. Post‐traumatic stress syndrome, or medical or neurological disease

7. No other DSM III diagnosis

Treatment compliance: not stated

There were minimal and clinically insignificant increases in pulse

Key conclusions of the study authors: the results of this study provide tentative support for 2 conclusions: ADD without hyperactivity appears to be a potentially stimulant‐treatable condition, even though hyperactivity is specifically excluded from its symptomatology; and school grades in children with ADD without hyperactivity may be influenced by the use of stimulants

Inclusion criteria

1. 6‐12 years old

2. DSM‐IV diagnosis of ADHD

Treatment compliance: not stated

Key conclusions of the study authors: methylphenidate transdermal system treatment is associated with growth deficits in both weight, height, and BMI, but growth deficits attenuate over time. Baseline growth influences the effect of MTS treatment on both height, weight, and BMI, whereas prior stimulant therapy, dose, and total time treated influences only weight and BMI

Sociodemographics: unknown

Treatment compliance: not stated

Key conclusions of the study authors: first reported seizure in a patient with combined methylphenidate and sertraline treatment

Sociodemographics: not stated

Case 2

Case 3

Re‐administration of extended release osmotic release oral system methylphenidate, 18 mg/day. Treatment period: not stated. Treatment compliance: not stated

Non‐serious adverse events:

Case 2

Case 3

Key conclusions of the study authors: these cases should make us be cautious and investigate the possible existence of family or personal cardiovascular pathology

Sociodemographics: adopted

Treatment compliance: not stated

Discontinuation of methylphenidate treatment: no disruptive behaviour, aggressive attitude, nor inner voices

Key conclusions of the study authors: caregivers of children treated with psychostimulants should be informed of possible side effects in order to ensure proper treatment in case of appearance. Professionals must be familiar with the adverse reactions that may occur with methylphenidate treatment. Paediatric neurologists and child psychiatrists must be agile in handling these reactions when it comes to withdrawal of the medication, treatment of the adverse reactions and prevention of misdiagnosis or the establishment of a chronic antipsychotic or stimulant treatment

Sociodemographics: not stated

Treatment compliance: not stated

Key conclusions of study authors: these cases support previous suggestions that adjunctive treatment with psychostimulants might be a safe and effective intervention for children treated with fluoxetine or sertraline who have persistent ADHD symptoms and suggest that such combined treatment might be suitable for adults as well

Inclusion criteria:

1. DSM‐IV‐TR ADHD diagnosis

2. 6‐12 years old

3. Previously participated and completed 1 of 4 specific methylphenidate transdermal system trials

4. Fewer than 28 days between completion of treatment in the previous study and entry into the present one

1. Early termination from the aforementioned trials because of non‐adherence with study‐related procedures or occurrence of ≥ 1 serious adverse event(s) Female participants pregnant or lactating

2. Comorbid psychiatric diagnoses (with the exception of oppositional defiant disorder in 3 of 4 studies)

3. Seizure disorder, chronic tic disorder, Tourette syndrome, allergic disease with skin manifestations, sensitive skin‐syndrome

4. Sensitivities to ingredients in soaps, lotions, cosmetics, or adhesives

5. Any skin disease or history of any chronic disease that could interfere with patch application

6. Any hypersensitivity or clinically significant intolerance to methylphenidate or any components of the study treatments

7. Considerable general medical illness (except mild stable asthma) or an unstable medical condition, disability, or other condition that the investigator felt might interfere with or prevent completion of the study

8. The use of concomitant medications (including anticonvulsants, amphetamine, clonidine, pemoline, antidepressants, antipsychotics, sedating antihistamines, investigational medications, herbal preparations, and medications that affect blood pressure, heart rate, or the central nervous system)

Treatment compliance: not stated

Non‐serious adverse events:

ECG. There were no apparent trends toward changes in ECG indices at any MTS dose. ECG abnormalities were considered clinically significant in 4 participants and were recorded as 4 AEs. 3 of these AEs were tachycardia (123, 136, and 122 beats/min) and 1 was prolongation of the corrected QT (QTc) interval.

Sleep behaviour. No apparent overall effect on sleep behaviour. Regarding insomnia, see below

At visit 16, mean (SD) weight changes from baseline in participants receiving MTS 10 mg, 15 mg, 20 mg, and 30 mg were 2.73 (2.53), 1.62 (3.44), 2.49 (3.44), and 1.61 (3.41) kg, respectively. At visit 16, mean (SD) weight changes from baseline in participants receiving MTS 10, 15, 20, and 30 mg were 2.73 (2.53), 1.62 (3.44), 2.49 (3.44), and 1.61 (3.41) kg, respectively

Key conclusions of the study authors: long‐term efficacy in paediatric patients was demonstrated by improvements in the ADHD‐RS‐IV, CGI‐I, and PGA assessments. Most adverse events (98.3%) were mild to moderate. With the exception of application‐site reactions associated with transdermal delivery of methylphenidate, adverse events were generally typical of those associated with methylphenidate

1. Methylphenidate transdermal system (10‐, 15‐, 20‐, or 30‐mg/9‐hour patches)

2. Placebo transdermal system

1. Screening and washout

2. Dose optimisation (5 weekly visits)

3. Dose maintenance (5 monthly visits)

4. A 7‐day post‐treatment follow‐up.

Inclusion criteria

1. Male or female adolescents 13‐17 years

2. Primary diagnosis of ADHD according to DSM‐IV

3. IQ score of > 80

4. A total score of ≥ 26 on the ADHD‐Rating Scale‐IV (ADHD‐RS‐IV) at baseline

5. Participants were required to have electro‐cardiogram (ECG) results within normal range or variants that were not clinically significant as judged by investigators in conjunction with the central laboratory

6. Blood pressure measurements within the 95th percentile for age, gender, and height

7. No current or history of skin disease or other skin problems including sensitive skin or signs of skin irritation

8. Females must have a negative urine pregnancy test at entry and agree to use acceptable contraceptives throughout the study period and for 30 days the last dose of IP

9. Participant and parent of legally authorised representative are able, willing and likely to fully comply with study procedures and restrictions

10. Regarding the 6‐month open‐label study: participants must have completed all required study visits or completed a 5‐week dose‐optimisation period without achieving an acceptable condition (i.e. . ≥ 25% decrease from baseline in a participant's ADHD‐Rating Scale IV score with minimal side effects)

1. Conduct disorder or comorbid psychiatric illnesses (such as clinically significant obsessive compulsive disorder, depressive, or anxiety disorders; posttraumatic stress disorder; psychosis; bipolar illness; or pervasive developmental disorder)

2. A history of structural cardiac abnormality, cardiomyopathy, cardiac rhythm abnormalities, or other serious cardiac problems; suicidal ideation; alcohol or other substance abuse (except caffeine or nicotine) within the last 6 months

3. Seizures during the previous 2 years and those who had a history of being non‐responsive to psychostimulant treatment use of clonidine, atomoxetine, antidepressants, sedatives, antipsychotics, anxiolytics, P450 enzyme‐altering agents, or other investigational medications within 30 days prior to screening

4. Female participants who are pregnant or lactating

5. Regarding the 6‐month open‐label study: participants were not eligible to participate in the extension study if they were discontinued from the antecedent study due to protocol violation (including non‐compliance), an AE for which continued treatment would be medically contraindicated, or a serious adverse event (SAE). Participants with considerable general medical illness (except mild, stable asthma) or an unstable medical condition, disability, or other condition the investigator believed might interfere with or prevent completion if the study were also excluded

Treatment compliance: 88 fulfilled the protocol

Any changes noted between evaluation data at study entry and data obtained at schedule visits deemed to be clinically significant by the investigator were considered an adverse event

Key conclusions of the study authors: regarding the 6 months open‐label study: methylphenidate transdermal system was generally well tolerated, and AEs were generally typical of those associated with oral methylphenidate, with the exception of application‐site reactions associated with transdermal delivery of methylphenidate

1. Methylphenidate in 2‐3 dosages

2. Placebo

1. Washout if medications prior to trial

2. 8 week RCT with 2 weeks in each arm

3. Open‐label follow‐up at 24 months

Inclusion criteria

1. Meet DSM III‐R diagnostic criteria for ADHD

2. Either chronic motor tic disorder or Tourette disorder

3. ADHD had to be a primary reason for seeking clinical services

4. In general, be above the cutoff on 2‐3 parent‐ and teacher completed hyperactivity and/or ADHD behaviour rating scales

5. Written signed statement from the parents consenting to their child's participation

1. Dangerous to self or others

2. Tics as the major clinical management concern

3. Psychosis

4. IQ below 70

5. Seizure disorder, major organic brain dysfunction or major medical illness

6. Contraindications to medication (other than tics)

7. Pervasive developmental disorder

24 month follow‐up: total daily dose of methylphenidate, MED (minimal effective dose ‐ after RCT): (mean 16.5 mg, range 5‐40 mg); second visit (mean 28.5 mg, range 15‐60 mg); third visit (mean 29.2 mg, range 10‐90 mg); and fourth visit (mean 34.5 mg, range 15‐92 mg)

Physician evaluations

During the 24‐months follow‐up

Parents' ratings

GTRS

Key conclusions from study authors: during the course of this short‐term drug evaluation, physician, teacher, and parent ratings were in uniform agreement that methylphenidate did not lead to a worsening in the severity of the children's tic disorder. Furthermore methylphenidate is an effective drug for the treatment of ADHD and oppositional and aggressive behaviour. Furthermore the follow‐up study showed that long‐term treatment with methylphenidate seems to be safe and effective for the management of ADHD behaviours in many (but not necessarily all) children with mild to moderate tic disorder. Nevertheless, careful clinical monitoring is mandatory to rule out the possibility of drug‐induced tic exacerbation in individual patients

1. Methylphenidate

2. No medication

Part of a case‐control study: ADHD group randomly assigned to 2 nights on and 2 nights off of methylphenidate versus non‐medicated non‐ADHD control group

RCT

Inclusion criteria

1. Children aged 6‐12 years

2. Diagnosis of ADHD (DSM‐IV)

3. Prescribed methylphenidate

4. Full‐scale IQ of ≥ 70 (Wechsler Intelligence Scale for Children, 3rd edition)

1. Gross sensory or motor problems

2. Significant developmental delay, autism or psychosis

Treatment compliance: urinary methylphenidate was reported as detected/or not detected. No control children returned a positive test on either night

General adverse events, parent rated, observational data

Key conclusions from study authors: findings suggest that methylphenidate reduces sleep quantity but does not alter sleep architecture in children diagnosed with ADHD

Comments from the review authors: we considered this a RCT study even though the authors describe it as a case‐control study, because the ADHD children were randomly assigned to on‐ or off‐methylphenidate. Only observational data on adverse events is used here

Inclusion criteria

1. 6‐14 years old

2. Diagnosed with ADHD according to DSM‐IV‐TR

3. Having moderate to severe illness as assessed by Clinical Global Impressions Severity Scale (CGI‐S)

1. Patients with history of non‐response or adverse reactions to methylphenidate in the past

2. Those who had taken any medication for ADHD in the past month

3. Those with history of heart disease, seizures, pervasive developmental disorder, substance abuse, mental retardation or tic disorder were excluded

Treatment compliance: not stated

The commonest reported adverse effect was reduced appetite

Key conclusions of the study authors: methylphenidate and atomoxetine are efficacious in Indian children with ADHD at lesser doses than previously used. Their efficacy and tolerability are comparable

1. Immediate release methylphenidate

2. Osmotic release oral system (OROS) methylphenidate

Inclusion criteria

1. Been taking methylphenidate 10‐40 mg for the past 3 months

2. Able to comply with the study visit schedules

3. Their mothers and teacher were willing and able to complete the weekly assessments

1. Significant gastrointestinal problems

2. A history of hypertension

3. Known hypersensitivity to methylphenidate

4. Co‐existing medical condition

5. Concurrent medication (such as monoamine oxidase inhibitors, and medicines used to treat depression, prevent seizure, or prevent blood clots) likely to interfere with the safe administration of methylphenidate

6. Glaucoma, Tourette syndrome, active seizure disorder or psychotic disorder

7. Girls who had reached menarche

Treatment compliance: parents were required to record the time of drug administration on an adherence sheet. Pill counting was performed for each participant. Days forgetting to take medication: immediate release group 8.6 (SD 5.7); OROS group 2.0 (SD 3.9)

Vital signs. At baseline, on day 14 and day 28

Key conclusions of the study authors: OROS methylphenidate has similar efficacy to immediate release methylphenidate, with less severity of decreased appetite. OROS methylphenidate is superior over immediate release methylphenidate in treating ADHD children and adolescents in the context of Chinese culture

Inclusion criteria

1. Age 5‐16 years old

2. Clinical diagnosis of ADHD based on DSM‐IV criteria

3. Immediate release methylphenidate treatment for ≥ 3 of the preceding 6 months

4. Immediate release methylphenidate for the last month without severe adverse events or possible contraindications

5. Patients whose parent or guardian has signed and dated an informed consent to participate in the survey of drug compliance

6. Patients who are still in school

1. Systemic disease or clinically significant gastrointestinal problem, including narrowing (pathologic or iatrogenic)

2. Comorbid psychiatric disorders, except for conduct disorder and oppositional defiant disorder.

The following data areon all patients from phase 2, n = 240.

Methylphenidate‐naïve: none

Phase 2

Patients who took IR‐MPH 5 mg once, twice or thrice daily and IR‐MPH 10 mg once, twice or thrice daily were switched to OROS‐MPH 18 mg and 36 mg per day, respectively

Key conclusions of the study authors: poor adherence to medication may be an important reason for suboptimal outcome in ADHD treatment, physicians should ensure adherence with therapy before adjusting dosage or switching medication

Patients with outcomes on weight

Patients with outcomes on height

Patients from the Campania Region

Patients from the Lombardy Region

Article on adverse events

Inclusion criteria:

Exclusion criteria:

MPH dosage: mean MPH dosage: 39.9 mg. Administration schedule: both stated. Duration of intervention: treatment compliance: daily dose of MPH ranged from 10 mg to 75 mg. All participants were drug‐naïve

Non‐serious adverse events:

Sample from the Campania region

Comments from the study authors:

Comments from the review authors:

Supplemental information regarding additional data and additional publications received through personal email correspondence with the authors in December 2013 and January 2014. Asked authors how they distinguished between serious adverse events and serious adverse reactions. Answer from authors: "We have catalogued the events reported compulsorily Italian Drug Agency as Serious adverse events. The serious adverse reactions are severe events for which reporting was not mandatory. I acknowledge that is a classification unorthodox [sic]" (Panei 2014 [pers comm])

1. Transition from immediate release methylphenidate to osmotic release oral system methylphenidate

2. Initiation of OROS methylphenidate

Inclusion criteria

1. Male or female patients

2. 6‐14 years old

3. ADHD diagnosis according to ICD‐10

4. OROS‐methylphenidate therapy already planned by treating physician (initiation of OROS‐methylphenidate therapy or transition from immediate release to OROS‐methylphenidate)

5. The patients were allowed to be pre‐treated with immediate release methylphenidate preparations once to thrice daily

Treatment compliance: 2 patients discontinued due to lack of compliance

Serious adverse events:

Key conclusions of the study authors: transitioning from immediate release methylphenidate or no methylphenidate‐treatment to OROS‐methylphenidate in patients aged 6‐14 years with a diagnosis of ADHD was associated with significant improvements in daily functioning in several areas of life, severity of disease and quality of life

Sociodemographics: not stated

Treatment compliance: not stated

Key conclusions of study authors: this report is about a child with ADHD who experienced insomnia, night terrors, and depression associated with the long‐term use of clonidine. He revealed resolution of insomnia and night terror when clonidine was removed

Sociodemographics: not stated

Treatment compliance: not stated

Discontinuation of MPH: enuresis stopped immediately

Key conclusions of study authors: clinicians should be aware of this potential side effect of methylphenidate

Sociodemographics: not stated

Treatment compliance: not stated

Re‐administration of methylphenidate: immediate reoccurrence of photophobia

Key conclusions of study authors: to the authors' knowledge, no report of methylphenidate‐related photophobia has been found. This is the first report of methylphenidate‐associated photophobia. Although the underlying pathophysiology cannot be defined in a patient report, this possible side effect should be considered in patients on methylphenidate

Sociodemographics: not stated

Treatment compliance: not stated

Re‐challenge was conducted more than 20 times and hyper‐talking reoccurred every time he took the medication

Key conclusions of study authors: this is a report of excessive talking after taking methylphenidate in a child with ADHD. Further research is necessary to study if there is any possible association

1. Methylphenidate + nortriptyline

2. Methylphenidate + placebo

No control/no‐intervention group

Inclusion criteria

1. Children diagnosed with both ADHD and primary enuresis

2. 5‐14 years old

3. Both genders

4. Written consent from parents

1. Any major psychosocial stressors

2. Urinary complaints

3. Concurrent behaviour therapy for enuresis (desmopressin or carbamazepine)

4. Enuresis alarms

5. Concurrent behaviour therapy for enuresis

6. Fluid‐intake restriction during the clinical trial

7. Clinically estimated mental retardation

8. Active medical problems such as hepatic, renal, cardiac, or pulmonary dysfunction

9. Urinary tract infection in the last month

10. Urinary urgency and frequency

11. Enuresis due to an underlying condition, such as diabetes

Treatment compliance: not stated

Bedwetting, parent rated, daily

Key conclusions from study authors: nortriptyline decreases the frequency of enuresis in the children with ADHD and its effect disappears after the discontinuation of treatment

1. Methylphenidate and folic acid

2. Methylphenidate and placebo

Methylphenidate + placebo group

Inclusion criteria

1. Diagnosis of ADHD according to DSM‐IV

2. Aged 5 to 16 years

3. Children and parents providing informed consent

1. Self‐reported allergic reaction to folic acid

2. Kidney disease, estimated mental retardation, mild pervasive developmental disorder, infection, anaemia, alcoholism or epilepsy

3. Being on dialysis

4. Taking medication such as phenytoin, methotrexate, nitrofurantoin, tetracycline, barbiturates, such as phenobarbital, and antiepileptic medication such as phenytoin or primidone

5. Diagnosed psychotic disorder or diagnosed mood disorder

6. Other conditions that preclude participation (or increase risk) in the clinical trial (Type 1 diabetes mellitus, metabolic diseases, gastro‐intestinal disorders affecting nutrient absorption, cancer)

7. Extensive use of nutritional folic acid supplements within the previous 3 months

8. Behaviour therapy or any other psychotherapy in the last 3 months or during the study

Treatment compliance: not stated

Key conclusions of the study authors: considering the marked limitations of this trial, this report suggests that methylphenidate may improve ADHD symptoms and the quality of life of children with ADHD. Current evidence does not support that folic acid as an adjuvant is effective for treating ADHD symptoms or aggression, or improving quality of life of children with ADHD

Sociodemographics: not stated

Treatment compliance: not stated

Non‐serious adverse events:

Key conclusions of study authors: careful sleep history should be taken before treatment, and reevaluated in the course of therapy, especially when the dose is increased, or switched to long acting formulas

1. Modafinil (100 mg); or

2. Methylphenidate (10 mg)

Inclusion criteria

1. Children and adolescents aged 6 to 15 years with classic combined subtype ADHD (DSM‐IV) and a score of ≥ 65 on the parent and teacher‐rated Conners Rating Scale

1. Children and adolescents with DSM‐IV major psychiatric conditions, mental retardation, autism spectrum disorder, epilepsy, heart disease, hypertension, sleep disorders, Steven Johnson syndrome or hypersensitivity to modafinil, methylphenidate or other psychostimulants

Treatment compliance: not stated

All appear to have been rated up to 90 minutes following administration of methylphenidate

Key conclusions of the study authors: Modifinil may serve as an effective alternative treatment for ADHD in paediatric patients who do not respond well to methylphenidate or other stimulants

Inclusion criteria

1. DSM‐IV‐TR criteria for both trichotillomania and ADHD

1. Psychotic disorders, neurological diseases, movement disorders, autistic spectrum disorders, mental retardation, or any other severe physical disorder

2. History of moderate or severe adverse events, related to previous methylphenidate treatment

Treatment compliance: not stated

Loss of appetite, headache, excessive preoccupation with one's hair, abdominal pain, motor tic exacerbation

Key conclusions of the study authors: some efficacy of methylphenidate treatment was shown in trichotillomania patients with low rate of stressful life events. A large scale study is mandatory to evaluate the efficacy of methylphenidate for trichotillomania in ADHD/trichotillomania patients

Sociodemographics: not stated

Second prescription

Treatment compliance: intermittently compliant

Second prescription

No cardiac complaints in the following 5 months

Key conclusions of the study authors: stimulant medication may evoke onset of atrioventricular nodal tachyarrhythmias in patients who have the potential to develop them, possibly in combination with a selective serotonergic reuptake inhibitor

Inclusion criteria

1. Children and adolescents with ADHD receiving Adderall or methylphenidate and were treated in a private, outpatient psychiatric clinic between 1992 and 1998

1. Patients presenting for initial evaluation only or receiving ADHD medications other than methylphenidate or Adderall

Treatment compliance: not stated

Key conclusions of the study authors: Adderall and methylphenidate provided comparable efficacy and safety in children and adolescents with ADHD

1. Immediate release methylphenidate

2. Placebo

Patients participating in the 1‐day RCT

Inclusion criteria: not stated

Treatment compliance: 1 withdrew due to poor compliance.

None of the patients exhibited psychotic symptoms or manic, hypomanic exacerbation during the 6‐month study period

Key conclusions of the study authors: the use of methylphenidate in children with velocardiofacial syndrome (VCFS) appears to be effective and relatively safe. A comprehensive cardiovascular evaluation for children with VCFS before and during stimulant treatment is recommended

Supplemental information regarding ADHD diagnostic criteria and safety data (from the study sample excluding participants over 18 years of age or with an IQ below 70, or both), were received through personal email correspondence with the authors in November 2013 (Green 2013 [pers comm])

Inclusion criteria

1. DSM‐III diagnosis of ADD

2. Over 10 years old

Treatment compliance: not stated

Key conclusions of the study authors: not relevant

Inclusion criteria

1. ADHD diagnosis according to DSM‐III

2. Parents had to rate the global severity of their child's behaviour disorder on the Conners' Parent Questionnaire (CPQ) in the moderate to severe range

3. Children had to score 1.8 or higher on hyperkinetic factor 4 of the Conners' Teacher Questionnaire (CTQ)

4. IQ > 70

5. After initial acceptance, children had to demonstrate ≥ 25 % decrease in summary score on the 10‐item abbreviated Conners' Rating Scale (ACRS), during an open 2‐week trial of MPH

1. Children with seizure disorders, psychosis, endocrine abnormalities, manic depressive disorders, pervasive developmental, or major neurological disorders

2 weeks washout period off methylphenidate before entering study. Ongoing titration until satisfied dose was obtained

All sleep parameters were recorded during a 48‐hour stay in a sleep unit. The sleep parameters were recorded pre‐drug (run 1) and on drug (run 2)

Key conclusions of the study authors: across and within (pre‐post) group comparisons showed that methylphenidate therapy was associated with delayed sleep onset, lengthened sleep, and changes in certain REM sleep variables

Sociodemographics: adopted (33%)

Treatment compliance: not stated

Case 1

Case 2

Case 3

2‐year follow‐up: no recurrence

Key conclusions of the study authors: we describe 3 children with ADHD who were treated with low doses of methylphenidate and developed complex visual and haptic hallucinations

Sociodemographics: not stated

Treatment compliance: not stated

Key conclusions of study authors: it is hoped that the report of this case will stimulate others to report their experience, or lack thereof, regarding the association of methylphenidate and idiopathic thrombocytopenic purpura. Because of the importance of this drug to the management of certain children with attention deficit disorder and its widespread use in thousands of children, it seems important to justify with data the current precaution that "periodic CBC, differential and platelet counts are advised during prolonged therapy" or eliminate the precaution as a recommendation to clinicians

Inclusion criteria

1. Diagnosis of ADHD according to DSM‐IV criteria between June 1997 and June 2000

2. Diagnosis of epilepsy or EEG abnormalities without defined seizure

Treatment compliance: not stated

Adverse events:

Key conclusions of the study authors: methylphenidate had a beneficial effect on EEG. Seizure frequency did not change from baseline. The side effects of methylphenidate were mild and transient. Methylphenidate is safe and effective in children with ADHD and concomitant active seizures or EEG abnormalities.The present data indicate that methylphenidate is a safe and effective agent in children with ADHD and active seizures of EEG abnormalities. Coadministration of methylphenidate and antiepilepsy drugs improves attention without any adverse effects on seizure threshold or EEG findings. We suggest that physicians give the combined medication to patients with ADHD and active seizures or abnormal EEG findings with close monitoring

Inclusion criteria

1. DSM‐III diagnosis of ADHD

2. Followed in a private clinic of 1 of the authors

Treatment compliance: not stated

Key conclusions of the study authors: the satisfactory and partial responses of methylphenidate treatment of ADHD observed in this study (79.1%) are in accordance with the literature, revealing therapeutic success in approximately 75% of the cases. We observed nausea and headache in 1 child, and only headache in another. Nausea can be controlled by lowering the dose; on the contrary, headache can be severe enough to result in cessation of treatment. Growth retardation is one of the possible side effects, which is of greater concern. Fortunately we did not observe this undesirable effect in our patients.

Inclusion criteria: no data

Treatment compliance: not stated

There was no central nervous system finding except irritability and agitation

Inclusion criteria

1. Definite ADHD diagnosis (DSM‐IV criteria)

2. ADHD symptoms for ≥ 6 months having caused clinically significant impairment in ≥ 2 settings

3. Informed consent by parents and patients

4. Age: 11‐18 years

5. Sufficient ability to read, write, communicate and understand the study procedures

1. Contraindications for methylphenidate

Treatment compliance: not stated

Serious adverse events

Non‐serious adverse events:

Key conclusions of the study authors: Ritalin LA improved CGI and quality of life in children with ADHD under routine practice conditions

Sociodemographics: not stated

Reintroduction of methylphenidate 7years later

Treatment compliance: not stated

Several days after initiation of treatment: visual hallucinations of rats, accompanied by some tactile hallucinations. Only present during the time the patient was under the influence of methylphenidate and disappeared thereafter. Discontinuation: immediate complete resolution Reintroduction of methylphenidate treatment. After 2 days: same complex visual hallucinations. Discontinuation: immediate complete resolution

Inclusion criteria

1. Adolescent outpatients between 12 to 17 years of age

2. Participants with the DSM‐IV diagnosis of ADHD, as manifested in the clinical evaluation and confirmed by structured interview, supplemented with structured diagnostic psychiatric interview using the Schedule for Affective Disorders and Schizophrenia for School Aged Children (KSADS‐E)

3. Participants with sufficient current ADHD symptoms to warrant treatment, as measured by a Clinical Global Impression Severity Scale (CGI‐S) score of greater than or equal to 4 (moderately ill); OR participants already on Concerta who are judged to be responders (CGI of 1‐2) and who tolerate treatment well

1. Any serious or unstable medical illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischaemic heart disease, hypertension), endocrinologic, neurologic, immunologic, or haematologic disease

2. Clinically significant abnormal baseline laboratory values

3. History of seizures

4. Active tic disorder

5. Pregnant or nursing females

6. Mental retardation (IQ < 75)

7. Organic brain disorder

8. Eating disorders, psychosis, current episode of bipolar disorder, current depression > mild (CGI‐S > 3), or current anxiety > mild (CGI‐S > 3)

9. Substance abuse or dependence within the past 2 months

10. Recent change in non‐monoamine oxidase inhibitor (MAOI) antidepressants (< 3 months)

11. Recent change in benzodiazepines (< 3 months)

12. Concerta non‐responder

13. History of cardiovascular disease, including structural cardiac abnormalities

Treatment compliance: not stated

Non‐serious adverse events

Key conclusions of the study authors: treatment with relatively high doses of OROS methylphenidate was associated with small but statistically significant mean increases in BP and HR, primarily during the first 6 weeks of treatment, without clinically meaningful changes in ECG. These observations are consistent with previous reports using lower doses

Inclusion criteria

1. Male or female. 12‐17 years of age

2. ADHD participants must meet the study criteria for the 'Prevention of Cigarette Smoking in ADHD Youth with CONCERTA Protocol'

3. Each participant and his/her authorised legal representative must understand the nature of this proposed study, and must sign informed consent and informed assent documents

4. Participant and parents must have a level of understanding sufficient to communicate intelligently with the investigator and study coordinator, and to cooperate with study procedures

1. Clinically significant chronic medical condition including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischaemic heart disease), endocrinologic, neurologic, immunologic, or haematologic disease

2. Organic brain disorders or mental retardation (IQ < 75)

3. Contraindication to MRI including presence of metal or surgical devices (plates, implants, braces or other items)

4. Pregnancy; women of child bearing potential must be using a medically approved method of birth control. Women of child bearing potential will receive a urinary pregnancy test prior to each MR scanning session

5. Severe phobia of being in small, enclosed spaces

6. Investigator and his/her immediate family; defined as the investigator's spouse, parent, child, grandparent, or grandchild will not be eligible to participate in the treatment arm of the study

7. Participants with active, clinically significant psychiatric comorbidity

8. Participants were dropped from the study if in the investigators' opinion there was lack of efficacy, intolerable adverse events and/or clinically significant laboratory values, pregnancy, clinical worsening, or noncompliance with the study protocol

Wash out period prior to study: prior medication for ADHD participants was discontinued 1‐4 weeks prior to the initial study scan

Key conclusions of the study authors: these preliminary findings suggest the presence of glutamatergic abnormalities in adolescents with ADHD, which may normalise with methylphenidate treatment. Documented clinical improvement and endpoint symptomatology by and ADHD‐specific rating scale

Inclusion criteria

1. Confirmed ADHD diagnosis

2. Patients who had received medical treatment during the period 2005‐2007

1. Children and adolescents without a confirmed ADHD diagnosis

2. Children and adolescents diagnosed with ADHD without medication or with medical treatment, which does not include the 2005‐2007 period

Treatment compliance: not stated

Non‐serious adverse events:

BMI: BMI values of children in this study were compared with age and gender reference values (Appendix, Table 2 and Table 3) based on a sample of over 34,000 German children and adolescents of all ages and sexes

Key conclusions of the study authors: the study shows that immediate‐release methylphenidate and the combination of immediate‐ with extended‐release methylphenidate should be first choice for ADHD drug treatment. For extended‐release methylphenidate as single treatment regimen and for atomoxetine and immediate‐release methylphenidate as combination treatment regimens, the benefit/risk ratio should be thoroughly weighed for each individual patient

Inclusion criteria

1. 6 to 14 years

2. DSM‐IV diagnosis of ADHD and comorbid ODD or CD treated for a minimum of 3 months with either methylphenidate or dexamphetamine

3. Attended psychiatric or paediatric clinics supervised by the authors

4. T‐scores for attention problems and aggressive behaviour on the Child Behavior Checklist of ≥ 70, placing them in the 'clinically significant' range

1. Obsessional symptoms, movement disorders, or psychosis

2. Mental retardation (IQ < 70)

3. History as determined by a physician of cardiac anomalies or other medical contraindications to the prescription of clonidine

Treatment compliance: not stated

Height and weight assessed at baseline and at week 6

Key conclusions of the study authors: the findings support the continued use of clonidine in combination with psychostimulant medication to reduce conduct symptoms associated with attention‐deficit/hyperactivity disorder. Treatment is well tolerated and unwanted effects are transient

Sociodemographics: not stated

Treatment compliance: not stated  

Supplemental information regarding diagnostic criteria, type of ADHD and intervention period received through personal correspondence with the author in August 2013 (Hechtman 2013 [pers comm])

Inclusion criteria

1. Meeting diagnostic criteria for ADHD according to DSM‐III (ADD with or without hyperactivity), DSM‐III‐R, or DSM‐IV (primarily inattentive, primarily hyperactive/impulsive, or combined subtypes)

2. Having received an EEG in the clinic

3. Follow‐up either by office visit or by telephone in 1999

Treatment compliance: not stated

Patient 4: episode 10 months after MPH initiation. He was heard to fall and was found unresponsive with upward eye deviation for approximately 2 minutes. EEG prior to stimulant treatment revealed focal epileptiform discharge

Key conclusions of the study authors: our data suggest that a normal EEG can be used to assign children to a category of 'minimal risk' for seizure. In contrast, an epileptiform EEG in neurologically normal children with ADHD predicts considerable risk for the eventual occurrence of seizure. The risk, however, is not necessarily attributable to stimulant use

Comedication: on both occasions, treatment with methylphenidate was temporally associated with a recent withdrawal of risperidone. Sociodemographics: parents separated before he was born. He has an older brother and 3 older half‐sisters, none of whom have had behaviour problems. His mother has fibromyalgia. There is no history of mental or movement disorders in the family

Trial 2: 18 mg, after a reducing course of risperidone over 4 weeks, with 6 risperidone‐free days before treatment

Trial 2: dyskinesia, increased aggression, difficulty sleeping within 8 hours of treatment

Supplemental information regarding diagnostic criteria received through personal email correspondence with the authors in October 2013 (Hollis 2013 [pers comm])

Sociodemographics: not stated

Treatment compliance: not stated

Growth impairment

Inclusion criteria

1. Children diagnosed with ADHD according to DSM‐IV criteria

2. Stimulant‐naïve

1. IQ < 70

2. Currently diagnosed with tic disorder, OCD, language disorder, learning disorder, convulsive disorder

3. Past and/or ongoing history of pervasive developmental disorder, schizophrenia, bipolar disorder, brain damage

Treatment compliance: 1 participant's parents were anxious about their child taking psychiatric medication, this participant discontinued prematurely

Non‐serious adverse events:

Key conclusions of the study authors: genetic determinants of methylphenidate response consist of both the dopaminergic and noradrenergic gene polymorphisms, and efforts to predict response to methylphenidate should cover these 2 catecholaminergic systems and their multifaceted aspects of their interactions as well

Inclusion criteria

1. ADHD diagnosis

2. Frequent, severe temper outbursts and chronic irritability

3. Medication‐free

4. Right‐handed

Treatment compliance: not stated

Headache: n = 1

Key conclusions of the study authors: we present preliminary data on corticolimbic functional connectivity (FC) abnormalities seen in highly irritable youth with ADHD. Open‐label methylphenidate was well tolerated and resulted in parent‐rated improvements in ER. Methylphenidate appears to impact FC between the amygdala, visual/insular cortices and pallidum

Inclusion criteria

1. Age between 7 and 15 years

2. ADHD based on DSM‐IV. Only symptoms rated as 'often' or 'very often' were counted toward the diagnosis

3. No history of intellectual disability, gross neurologic abnormality or Tourette syndrome

4. Patient decision to participate in a stimulant medication trial on clinical grounds

Treatment compliance: not stated

QTc was calculated with the use of Bazett's formula

Key conclusions of the study authors: this study reveals that methylphenidate reduces QT dispersion during the acute period, shortly after its administration. Data support the reliability of this drug in terms of early arrhythmia

Sociodemographics: not stated

Treatment compliance: not stated

Inclusion criteria

1. Pre‐pubertal children aged 6‐12 years old

2. ADHD DSM‐IV diagnosis

3. No previous methylphenidate treatment

4. No history or current co‐morbid psychiatric condition apart from ODD

5. Male

1. Intellectual disability or developmental delay

2. History of head injury

3. Any other neurological, metabolic or infectious disorder

4. Liver or kidney dysfunction

5. Routine use of any drugs

Treatment compliance: not stated

Height and weight were measured before and after treatment and BMI was calculated. The patients were instructed not to change diet or physical activity during the study

Key conclusions of the study authors: short‐acting methylphenidate does not affect leptin appetite at 0.6 mg/kg/day dose. Did not show significant difference between pre‐ and postleptin levels

Inclusion criteria

1. 6‐17 years old

2. DSM‐IV‐TR diagnostic criteria for ADHD confirmed by a child and adolescent psychiatrist

3. Total or subscale scores (or both) of ≥ 1.5 SDs above norms for patient's age and gender on Attention‐Deficit/Hyperactivity Disorder Rating Scale‐IV (ADHD‐RS‐IV) ‐ School Version

4. The children and their parents had to be willing to comply with all requirements of the trial

1. Psychiatric comorbidities (excluding oppositional defiant disorder)

2. High risk of suicide

3. Mental retardation (IQ < 70)

4. Clinically important chronic medical condition (such as epilepsy and organic brain disorders)

5. Drug abuse or dependence in the last 6 months

6. Hypertension or hypotension

7. History of allergy to bupropion or methylphenidate

8. Abnormal electrocardiogram

9. Psychotropic medication use in the last 14 days

Treatment compliance: not stated

Key conclusions of study authors: bupropion has a comparable safety and efficacy profile with methylphenidate in children and adolescents with ADHD

1. Medication Management (MGT)

2. Behavioural Treatment (BEH)

3. Combined Treatment (medication management + behavioural treatment) (COMB)

4. Community Care (the control group) (CC)

In our review we will compare combined treatment with behavioural treatment (RCT) according to our protocol, and look at the medication treatment group as a cohort (observational)

Main study (Jensen 1999):

10‐month follow‐up (MTA Group 2004)

3‐year follow‐up (Jensen 2007)

8‐year follow‐up (Molina 2008)

10‐year follow‐up, blood pressure (Vitiello 2012)

Growth studies: at 24 months assessment (Jensen 2004)

Growth studies: up to 36‐month assessment (Swanson 2007)

Inclusion criteria:

1. Boys and girls between ages of 7‐9.9 years

2. In grades 1 through 4

3. In residence with the same primary caretaker(s) for the last 6 months or longer

4. Meeting the DSM‐IV criteria for ADHD combined type

1. Child currently in hospital

2. Child currently in another study

3. Below 80 on all WISC‐III scales and on SIBBipolar disorder, psychosis, or personality disorder

4. Chronic serious tics or Tourette syndrome

5. OCD serious enough to require separate treatment

6. Neuroleptic medication in previous 6 months

7. Major neurological or medical illness

8. History of intolerance to MTA medications

9. Ongoing or previously unreported abuse

10. Missed 1/4 of school days in previous 2 months

11. Same classroom as child already in MTA study

12. Parental stimulant abuse in previous 2 years

13. Non‐English speaking primary caretaker

14. Another child in same household in MTA study

15. No telephone

16. Suicidal or homicidal

Main study (Jensen 1999)

10 months follow‐up (MTA Group 2004)

3‐year follow‐up (Jensen 2007)

8‐year follow‐up (Molina 2009)

10‐year follow‐up (Vitello 2012)

• CLAM (with inattention/overactive (I/O),

• Aggressive/defiant (A/D) and mixed (I/O + A/D) subscales). Sssessed daily by parents and teachers

• SKAMP (with attention and deportment subscales) rated daily by parents and teachers)

• SNAP Inattention and hyperactivity‐impulsivity subscale, both parent and teacher. Assessed at baseline, 3, 9, and 14 months

• SNAP oppositional‐defiant disorder subscale, both parent and teacher rated. Assessed at baseline, 3, 9, and 14 months

• Abikoff Classroom Observational System (ADHD and oppositional/aggressive symptoms), blind ratings by blind observer

• 6 of 11 reported severe side effects could have been due to non‐medication factors

• 3 deaths were recorded among the ADHD participants during the 10 years of observation: a suicide at age 14 (the patient was on MPH), a fatal car accident at age 17 (the patient was the driver and was on MPH), and a sudden unexplained death at age 17 (the patient was found dead in bed; no specific cause of death could be determined; he had been previously treated with MPH and had been off medication for more than 1 year when he died

• Pittsburgh Side Effects Rating Scale, monitored monthly, reviewed by the pharmacotherapist

• Internalising symptoms (anxiety and depression) were measured with an internalising subscale from parent‐ and teacher‐completed SSRS, measured at baseline, 3, 9, and 14 months

• Children's self‐ratings on the Multidimensional Anxiety Scale for Children (MASC). Assessed at baseline, 3, 9, and 14 months

• Pittsburgh Side Effect Rating Scale (10 adverse events commonly associated with MPH were rated)

• Substance abuse; substance use was assessed at 24 and 36 months using a child‐reported substance use questionnaire (Molina and Pelham, 2003) adapted for the MTA. The measure included items for lifetime and current (past 6 months) use of licit substances (alcohol, cigarettes, chewing tobacco) and illicit drugs (marijuana and other street drugs). Also included were items for inappropriate or non‐prescribed use of medications, including stimulants

• Delinquency; assessed by the Self‐Reported Antisocial Behavior Questionnaire through the 24‐month assessment and the

• Self‐reported delinquency questionnaire at the 36‐month assessment. Delinquency was coded along an ordinal scale based on the most serious act committed during the past 6 months: 0 = no delinquency; 1 = minor delinquency only at home (e.g. theft of less than USD 5 or vandalism); 2 = minor delinquency outside of the home (e.g. vandalism, cheating someone, shoplifting less than USD 5); 3 = moderately serious delinquency (e.g. vandalism, theft of ≥ USD 5, weapon carrying); 4 = serious delinquency (e.g. breaking and entering, drug selling, attacking someone with the intent to seriously hurt or kill, rape); and 5 = engagement in ≥ 2 different level 4 offenses. Because only a small number of MTA children were coded 5 (n = 14 at baseline, n = 4Y5 between 14 and 36 months), we grouped codes 4 and 5 for data analyses, making a 5‐level ordinal scale of 0 to 4

• Delinquent behaviour coded on a 5‐point ordinal scale using parent and youth report across several measures

• Number of contact with police and arrests using the Services for Children and Adolescents‐Parent Interview (SCAPI), parent reported

• Depression rated with the Children's Depression Inventory, self‐rated

• Anxiety rated with the Multidimensional Anxiety Scale for children, self‐rated

• Psychiatric hospitalisation by 8 year, parent reported

• Substance use: substance use was assessed with a child/adolescents‐reported questionnaire adapted for the MTA

10‐year follow‐up (Vitello 2012)

• Blood pressure and heart rate monitoring, measured after participants had been sitting for 5 minutes, adjusted for age and sex

• Height and weight

• Hospitalisation measured at each assessment point

• No symptomatic cardiovascular events leading to medical attention were reported during the period of observation, and no stimulant treatment discontinuation consequent to cardiovascular adverse effects occurred during the 10‐year period

• Height in cm and weight kg, assessed at baseline, 14 months, 24 months, and 36 months

Titration period (Greenhill 2001)

10‐month follow‐up (Group 2004)

3‐year follow‐up (Jensen 2007)

Vitiello 2001

Conners 2001

8‐year follow‐up (Molina 2008)

10‐year follow‐up, (Vitiello 2012)

Implications and applications for primary care providers (Jensen 2001)

Pelham 1999

Growth 24‐month outcomes (Jensen 2004)

Key conclusions of the study authors:

Vitiello 2001

Titration period (Greenhill 2001)

10‐month follow‐up (MTA Group 2004)

3‐year follow‐up (Jensen 2007)

24‐ and 36‐month assessment of delinquency and substance abuse (Molina 2007)

8‐year follow‐up (Molina 2009)

10‐year follow‐up blood pressure (Vitiello 2012)

Growth studies, 24‐month follow‐up (Jensen 2004)

Growth studies, 3‐year follow‐up (Swanson 2007)

Pelham 1999

1. Active medication for ADHD is better than withdrawn BT (on some but not most measures).

2. Combined treatment adds modestly to active medication but is superior to behaviour management alone.

3. Study treatments that include active medication are better than community treatments that include medication, while BT is comparable to medication as delivered in the community.

4. Concurrent BT results in ≥ 20% lower and non‐increasing medication dosages relative to treatment with medication alone.

Anxiety (March 2000)

Swanson 2007

Substance use (Molina 2012)

Pelham 2000

Comments from the review authors:

We sent several emails to the MTA group in order to get additional information and furthermore spoke orally to some of the authors. We did not get additional data

Inclusion criteria:

1. Between 4 and 15 years of age

2. Meet DSM‐IV criteria for ADHD

3. Be stimulant naïve

4. Be willing to provide a blood or saliva sample for genetic analysis

1. IQ < 70

2. Epilepsy, fragile X syndrome, fetal alcohol syndrome, maternal drug abuse during pregnancy, primary diagnosis of pervasive developmental disorder or bipolar disorder

3. Current treatment with non‐stimulant psychotropic medications

Treatment compliance: not stated

Key conclusions of the study authors: the study found an association between 2 CES1 SNP markers and sadness as a side effect of short‐acting methylphenidate

Inclusion criteria

1. ADHD combined subtype

2. Maternal report of development history consistent with ADHD

1. IQ below 70

2. Gross neurological, sensory or motor impairment as determined by paediatric examinations

3. Comorbid diagnosis as: seizure, psychosis, Tourette's syndrome, mental retardation, cardiovascular disorder, thyroid disorder, drug abuse history, intestinal obstruction

4. ADHD treatment drugs, herbs, antidepressants, antipsychotics within 1 month of the study

5. Taking OROS methylphenidate less than 2 days a week during study period

Treatment compliance: not stated

Key conclusions of the study authors: OROS methylphenidate improves performance on common tests of cognitive function. A further long‐term follow‐up study of these effects in ADHD is warranted

Inclusion criteria:

1. In a clinical sample

2. In a period of 6 months, all methylphenidate‐naïve patients with attention deficit hyperactivity disorder, whose parents accepted to participate in the study with an informed consent, were included

Treatment compliance: not stated

Key conclusions of the study authors: authors found significant decrease in appetite, and they suppose that some of the Barkley SES may represent both ADHD symptoms and methylphenidate adverse events

Sociodemographics: not stated

Treatment compliance: not stated

Discontinuation of OROS‐methylphenidate, 1 month: free of symptoms. Mean pulmonary arterial pressure of 28 mmHg

Sociodemographics: not stated

Treatment compliance: yes

Case 2

Sociodemographics: uneventful pregnancy and delivery history. Born from healthy, non‐consanguineous parents without any history of any psychiatric diseases, movement or muscle disorders

Case 2

Treatment compliance: yes

1. Osmotic release oral system methylphenidate

2. Atomoxetine

Inclusion criteria:

1. 6‐13 years old

2. ADHD, any subtype

3. DSM‐IV‐TR

4. Investigator‐rated ADHD‐RS score of at least 24 points and a Clinical Global Impression‐Severity of Illness scale (CGI‐S) rating as 'moderately ill' or worse at screening

5. ADHD medication treatment naïve or previously treated with ADHD medication with suboptimal response (judged by the clinician in conjunction with the parents)

1. Eating disorders

2. Substance use disorders

3. Comorbid psychiatric conditions other than oppositional defiant disorder

4. History of seizure, tic disorder, mental retardation, or severe developmental disorder

5. Personal or family history of Tourette syndrome

6. Previous diagnosis of hyperthyroidism or glaucoma

7. Use of medications contraindicated for coadministration with OROS methylphenidate or atomoxetine

8. Known non‐response to treatments indicated for ADHD

9. Occurrence of menarche in girls

Treatment compliance: 92% or higher

Spontaneously reported adverse effects by patients, parents or investigators

Key conclusions of the study authors: these results suggest greater ADHD symptom improvement with osmotic release oral system methylphenidate compared with atomoxetine

Inclusion criteria

No specific inclusion‐exclusion criteria regarding duration of methylphenidate treatment course, methylphenidate dose, and probable co‐administered medications for management of ADHD were used for patient selection

Treatment compliance: 63.1% received methylphenidate for ≥ 6 months; 2.8% less than a month

Serious adverse events:

Key conclusions of the study authors: our data suggested that although methylphenidate related adverse reactions were common in children with ADHD, they were mainly mild and non‐serious

1. Methylphenidate (Ritalin)

2. Methylphenidate (Stimdate)

Inclusion criteria:

1. 6‐16 years old

2. Meeting the DSM‐IV diagnostic criteria for ADHD

3. No psychological or medical treatment received in the last 4 weeks before the study

4. Having informed written consent signed by parents for participating in the study

5. Not having comorbid conditions including conduct disorder, pervasive developmental disorder, mood disorders, Tourette disorder, and psychotic disorders

6. The ability to comply with the study's visits schedule

1. The presence of clinically significant gastrointestinal problems, cardiovascular diseases, glaucoma, and seizure disorder

2. Suspicion or confirmation of substance abuse by patients or a family member

3. Presence of mental retardation according to educational history or, having an IQ score less than 70

4. Allergy to stimulants

5. Having to receive any psychiatric or somatic medication (except Ritalin or Stimdate) during the study

Treatment compliance: not stated

Key conclusions of the study authors: we recommend clinicians choose Ritalin or Stimdate according to the patient's preferences, sustained accessibility, primary response to treatment, and possible side effects encountered in course of treatment. This means that neither of these drugs has been proven to be superior to the other one

Inclusion criteria:

1. Age 6‐12 years

2. DSM‐IV diagnosis of ADHD

3. Clinical Global Impression‐Severity (CGI‐S) scale rating ≥ 4 ('moderately ill' or greater severity)

4. Normal medical history screening and physical examination

5. Patients and parents who were informed and voluntarily provided consent

1. Earlier exposure to a central nervous system stimulant within the previous 3 months.

2. Hypersensitivity to methylphenidate

3. IQ < 80 on the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children

4. Presence of comorbid psychiatric disorders except for oppositional defiant disorder (ODD).

5. Past and/or current history of developmental disorder, including autism spectrum disorder

6. Presence of seizure disorder

7. Presence of significant comorbid medical illness.

8. No medications that might influence clinical status or sleep characteristics were permitted

Treatment compliance: not stated

Apnea and hypopnea, scored according to the recommended criteria of the American Academy of Sleep Medicine at week 6. Apnea was defined as an absence of oronasal airflow with minimal interval of 2 respiratory cycles. Hypopnea was defined as 50% air flow reduction or more for ≥ 2 respiratory cycles resulting in EEG arousals or oxygen desaturation (Z3%)

Key conclusions of the study authors: these results suggest that OROS MPH in open‐label treatment does not appear to impair sleep on either qualitative measures of sleep or sleep architecture and may improve some aspects (including sleep quality)

Inclusion criteria:

1. ADHD based on the DSM‐IV criteria. Symptoms sufficiently severe to require medication with methylphenidate upon entry into the study

2. Been on a daily dose of MPH‐IR for ≥ 4 weeks and has been receiving a stable dose for ≥ 3 weeks before beginning the study

1. Presence of any medical condition that will contraindicate the use of stimulant medication

2. Presence of hypersensitivity to methylphenidate

3. IQ below 75 (determined by WISC)

4. Use of any additional medication (other than MPH) for ADHD

5. Use of any medication having CNS effects (monoamine oxidase inhibitors, clonidine, tricyclic antidepressants, SSRIs, theophylline, coumarin or anticonvulsants, and antipsychotics) or any investigational medications

6. Having reached menarche

7. Having a high risk of being pregnant

8. The presence of clinically significant gastrointestinal problems, cystic fibrosis, glaucoma, seizure disorders, Tourette syndrome, cardiovascular disease, hyperthyroidism, clinical depression, suicide risk, and substance abuse

Treatment compliance: 94.3% completed the 28 day study

No serious adverse events were reported during the study

Key conclusions of the study authors: the results of this study indicated that an IR‐MPH regimen can be successfully changed to a once‐daily OROS‐MPH regimen without any serious adverse effects. The changes in parent/caregiver IOWA Conners ratings suggested that OROS‐MPH improved the control of symptoms after school, a finding that is consistent with the 12‐h duration of action of this medication. Because the therapeutic effect of OROS‐MPH is sufficiently longer than that of a twice daily dose of IR‐MPH, OROS‐MPH had significant positive effects on oppositional/defiant behaviour in addition to its effects on the core symptoms of ADHD. No significant differences between the 2 drugs were noted related to appetite loss and sleep disturbances. Tic symptoms significantly decreased after switching from IR‐MPH to OROS‐MPH

Inclusion criteria

1. Between 5 and 14 years at the start of treatment

2. DSM‐IV diagnosis of ADHD

3. Receiving methylphenidate for ≥ 1 year

4. A baseline weight and height z score > −2.0 relative to the general Korean population

1. Prior exposure to a central nervous system stimulant or atomoxetine

2. Having initiated MPH treatment before the age of 5 years

3. IQ < 70 on the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children

4. Past and/or current history of developmental disorder, including autism spectrum disorder

5. Past and/or current history of schizophrenia, bipolar disorder, or other psychosis

6. Current seizure disorder

7. Mean compliance for the whole treatment period < 80%

8. Taking an adjunct medication that could affect growth

9. Past and/or current medical illness that could induce growth suppression

Treatment compliance: ≥ 80%

Key conclusions of the study authors: these results suggest that methylphenidate could be related to weight and height deficit in Korean children and adolescents, although the effects were minor, and disappeared after the 1st year

Inclusion criteria:

Treatment compliance: not stated

Key conclusions of the study authors: methylphenidate treatment for ADHD was associated with both symptom alleviation in children with ADHD and improvement in parental depressive mood and quality of life, suggesting that the effects of treatment could go beyond symptom improvement in ADHD

Inclusion criteria

1. Patients diagnosed at the Korea University Medical Centre between August 2007‐December 2010 attending outpatient clinic

2. Showing signs and symptoms of either inattention or hyperactivity‐impulsivity or both according to DSM‐IV‐TR criteria for ADHD

1. Medical problems requiring special attention such as cardiovascular disorders, learning disabilities and mental retardation

2. Other psychiatric comorbidities

Treatment compliance: 43% completed 12 week programme

Key conclusions of the study authors: HF and RMSSD suggested that parasympathetic dominance in ADHD can be changed by methylphenidate treatment

Inclusion criteria

1. ADHD diagnosis (any subtype) according to DSM‐IV

1. Patients with an IQ less than 70 (as assessed by the K‐Wechsler Intelligence Scale for Children, Third Edition)

2. Seizure disorders, brain injuries, psychotic disorders, pervasive developmental disorders, or serious medical or neurologic conditions

3. Children who were taking SSRIs or antipsychotics within 4 weeks prior to study

Treatment compliance: 12 patients dropped out because of medication non‐compliance

Key conclusions of the study authors: treatment with OROS‐MPH was associated with symptomatic functional changes that were moderately correlated; therefore, symptomatic functional outcomes appear to be partially overlapped but distinct domains. Consequently, functional measures should be incorporated as important outcome measures in future treatment studies; the importance of treatments targeting functional improvement should be emphasised in the treatment of children with ADHD

1. Methylphenidate alone (MPH)

2. Methylphenidate and multimodal psychosocial treatment (MPH + MPT)

3. Methylphenidate and attention control treatment (MPH + ACT)

Sociodemographics: 84 (81.2%) children lived with both parents, 13 (12.6%) with 1 parent (in all but one instance, the mother), and 6 (5.8%) with their mother and stepfather. Mean socioeconomic status was 2.5 SD 0.9 (range 1‐5) (Myers 1968). There were no significant difference in baseline demographics between the 2 groups

1. Children had to have a diagnosis of ADHD based on a parent interview with the Diagnostic Interview Schedule for Children (DISC‐P2) (Shaffer 1996) conducted by clinical psychologists confirmed by a child psychiatrist based on a comprehensive clinical interview with the child and parent and teacher reports

2. On 2 separate occasions, children had to receive a mean teacher rating of ≥ 1.5 on the Hyperactivity Factor or Hyperkinesis Index of the Conners Teachers Rating Scale (CTRS) (Goyette 1978)

3. Children had to be medication free for ≥ 2 weeks before evaluation

4. Normal IQs (i.e. WISC‐R ≥ 85)

5. Living with ≥ 1 parent

6. Have telephone access

7. Children had to derive meaningful benefit from the treatment without significant side effects

8. Methylphenidate treatment must not incur cognitive decrement in the children

1. Diagnosable neurological disorders

2. Psychosis

3. Significant medical illness

4. Current physical or sexual abuse

5. Chronic tic disorder or Tourette disorder

6. A DSM‐III‐R developmental reading or arithmetic disorder, defined as a standard score in reading or mathematics on the Kaufmann Test of Educational Achievement of 85 or less (i.e. ≥ 1 SD below the population mean) and ≥ 15 points (1 SD) below full‐scale IQ (Halperin 1984)

7. A diagnosis of conduct disorder

Treatment compliance: the percentage of positive Ritalin acid assays was 87%, without differences between groups. Medication compliance was addressed by counting returned pills

Before every visit, teachers were called to obtain information about the child's school performance. The sessions were used to assess vital signs (weight, height, pulse, blood pressure), side effects (reported by parent and child), and the child's overall condition

Key conclusions of the study authors: in stimulant‐responsive young children with ADHD without learning and conduct disorders, there is no support for academic assistance and psychotherapy to enhance academic achievement or emotional adjustment. Significant short‐term improvements were maintained over 2 years

Inclusion criteria

1. Confirmed diagnosis of ADHD (ICD‐10)

2. Medically indicated switch from IR MPH to OROS MPH due to insufficient efficacy and/or tolerability, and planned by treating physician

3. Age 6‐18 years old

Treatment compliance: 0.8% of ITT non compliant

Body weight: measured at baseline and after 3 months of treatment

Key conclusions of the study authors: in this naturalistic setting, transitioning from IR‐MPH to OROS‐MPH, in patients who showed previously insufficient response and/or poor tolerability, was successful. OROS methylphenidate was generally safe and well tolerated. Children/adolescents with ADHD who were switched from IR methylphenidate to OROS methylphenidate experienced clinically relevant improvements in symptoms, HRQoL and social functioning

1. Atomoxetine

2. Methylphenidate

Inclusion criteria

1. DSM‐IV diagnosis of ADHD

2. Severity score of ≥ 1.5 SD above age and gender norms on the ADHD‐IV Rating Scale‐Parent Version: investigator Administered (ADHD RS)

3. Age 7‐15

1. History of bipolar or psychotic disorders

2. Motor tics

3. Family history of Tourette syndrome

4. Substance abuse

5. Methylphenidate non‐responders (from a previous trial of methylphenidate of ≥ 2 weeks of treatment with at least 1.2 mg/kg per day)

6. Serious medical illness

Washout period prior to treatment ‐ duration not specified

Key conclusions of the study authors: the results of this study provide preliminary evidence that the magnitude and profile of symptom reduction associated with atomoxetine administration and its tolerability are comparable to that observed with methylphenidate

Inclusion criteria

1. Valid information on year of birth and sex

2. Age between 3 and 17 years in the respective year

3. Residence in Germany

Treatment compliance: not stated

Key conclusions of the study authors: children starting methylphenidate treatment had a high prevalence of pre‐existing psychiatric comorbidities which may affect methylphenidate prescribing. Cardiovascular and other comorbidities were generally rare, but require attention as they were more common among those who received methylphenidate than in the control group

Inclusion criteria

1. DSM‐IV diagnosis of ADHD

2. None on any other treatment

3. All treated with methylphenidate

1. No bone disease

2. No metabolic disease

Treatment compliance: not stated

• Serum calcium

• Serum phosphorous

• Bone mineral density measured by dual photon absorptiometry at the lumbar spine or femoral neck

• Bone turnover measured by serum bone‐specific alkaline phosphatase and urinary deoxypyridinoline excretion rate

Key conclusions of the study authors: in conclusion, our data do not support a significant effect of methylphenidate on bone mineral density turnover in children when used for 1‐2 years.

Inclusion criteria:

1. DSM‐TR‐IV diagnosis of ADHD

2. Currently or recently treated with methylphenidate sustained release

Treatment compliance: not stated

Key conclusions of the study authors: tics as a side effect of sustained‐release methylphenidate treatment in our patients was predominantly motor, of mild intensity and transient in nature, and did not require cessation of therapy

Inclusion criteria

1. Drug naïve ADHD outpatient

2. ADHD diagnosis according to DSM‐5 criteria

3. Attending the Unit of Child Neurology and Psychiatry of the University Polyclinic of Messina between September 2013 and March 2014

4. New user of immediate‐release methylphenidate

Treatment compliance: 100%

Key conclusions of the study authors: this study underlines the relative cardiac safety of IR‐MPH in childhood, even if stimulants may exert a cardiovascular effect on BP and HR. However, particular caution should be exercised by physicians in prescribing these drugs to patients with a genetic predisposition to arrhythmias. It might be useful to carry out an ECG examination in all patients starting methylphenidate therapy

Sociodemographics: not stated

Treatment compliance: not stated

Key conclusions of the study authors: the principal results support the study's hypothesis and show a significant baseline difference (P = 0.008) between the nocturnal movements of the ADHD children and those of the control children

Inclusion criteria

1. ADHD according to DSM‐V‐TR

2. Starting methylphenidate treatment

1. Any ocular abnormality other than disturbance of refractions

2. Any other medications

Treatment compliance: unknown

Key conclusions of the study authors: methylphenidate does not seem to affect refraction in most children with ADHD. After 9 months of treatment, however, there was a reduction in the anterior chamber depth, which has been described as a powerful predictor of angle closure glaucoma. Further investigation of the potential ocular side effects of methylphenidate is warranted

Inclusion criteria:

1. Full diagnosis based on DSM‐IV criteria

2. Moderate to severe level of impairment of ADHD symptoms

3. Drug naïve or not medicated ≥ 6 months before the initiation of the study

4. No abnormalities in baseline physical examination and routine laboratory tests

5. In addition only participants who were able to comply with the study visit schedule were included

1. Presence of clinically significant gastrointestinal problems, cardiovascular disease, glaucoma, seizure disorder, psychotic disorder, clinical depression or Tourette syndrome

2. Suspicion or confirmation of substance abuse

3. Receiving clonidine or other alpha‐2 adrenergic receptor agonists, tricyclic antidepressants, theophylline, coumarin or anticonvulsants

4. IQ < 70 as determined by the Korean Wechsler Intelligence Scale for children

Treatment compliance: 2 participants discontinued trial due to protocol non‐compliance

• 18‐item list of stimulant related AE symptoms (compiled by authors), self‐reported, days 7, 14 and 21

• Physical examination, general chemistry tests, blood pressure, pulse rate, ECG; observer, baseline and end of study

Key conclusions of the study authors: these data provide support for the benefit of the once daily methylphenidate preparation Concerta, in the treatment of Korean children with ADHD. Children were initiated safely in this short‐term trial, and its effectiveness was evident in the behavioural, as well as neuropsychological measurements

Exclusion criteria

1. Use of methylphenidate hydrochloride other than OROS‐MPH within the past 24 hours

2. Use of OROS‐MPH within the past 3 months

3. Use of psychotropic medication within the past 4 months (clonidine or other α‐adrenaline agonist, tricyclic antidepressant, selective serotonin reuptake inhibitor, theophylline, coumarin, or anticonvulsant, antipsychotics, benzodiazepine, modafinil)

4. History of hypersensitivity reaction to methylphenidate hydrochloride or another component of OROS methylphenidate

5. Other medical problems, such as gastrointestinal disorders, glaucoma, cardiovascular disease, or hyperthyroidism neurological illnesses, such as a seizure disorder

6. Comorbid psychiatric disorders, such as pervasive development disorder, psychotic disorder, or Tourette syndrome

7. IQ < 70, as assessed by the Korean Wechsler Intelligence Scale for Children (K‐WISC‐III)30

8. History of substance use or abuse

9. Possible pregnancy

Treatment compliance: not stated

Key conclusions of the study authors: high response time (RT) among Korean children with ADHD on a computerised continuous performance attention test RT variability may predict poor response to MPH treatment in children with ADHD

Inclusion criteria

1. 6‐12 year old elementary school children with a diagnosis of ADHD recruited from 3 university hospitals

2. Children whose ADHD accompanied by anxiety disorder, oppositional defiant disorder, or conduct disorder were included in the study

1. Patients with tic disorder, Tourette syndrome, schizophrenia, bipolar disorder, major depressive disorder, obsessive‐compulsive disorder or a pervasive development disorder

2. An IQ below 70, epilepsy or other neurological problems

3. Those who had been taking stimulants, antidepressants, antipsychotics, atomoxetine, clonidine, and antihistamine within 4 weeks of baseline

4. Sleep problems such as heavy snoring, sleep apnoea, sleep bruxism, narcolepsy, restless legs syndrome, and periodic limb movement disorder

5. Participants were dropped from the study if they violated the study protocol by failing to take the prescribed medicine more than twice a week, or if they presented with serious adverse effects such as seizures or hallucinations

Treatment compliance: the children and caregivers were visited weekly to review whether medication was taken as prescribed

• Daily sleep diaries were completed by caregivers (parents/guardians) at baseline and for 4 weeks after taking medication

• Adverse events (AEs) chart was completed weekly on the basis of direct questions, clinical observations and physical examinations by child psychiatrist

Key conclusions of the study authors: methylphenidate had negative impacts on sleep among young ADHD children, but different preparations and doses did not affect the result

Inclusion criteria:

Exclusion criteria: none stated

Treatment compliance: not stated

Key conclusions of the study authors: our findings highlight the high‐risk medications and the corresponding adverse events commonly reported in children and adolescents. Information from this analysis can be used to prioritise drugs and adverse events that might be investigated in future studies of drug safety in children

Sociodemographics: not stated

Treatment compliance: not stated

During methylphenidate treatment: ophthalmic examination every 6 months showed intraocular pressure consistently in the 16‐19 mmHg range bilaterally

1. Methylphenidate

2. Ningdong granule

Inclusion criteria

1. ADHD according to DSM‐IV

2. Teacher and Parent ADHD Rating Scale (Dupau, 1991) > 20

3. Patient from the outpatient department of integrative medicine in paediatrics, Provincial Hospital Affiliated to Shandong University and the department of Neurology, Tongji Hospital of Huazhong University of Science and Technology

1. Taken anti‐ADHD medication prior to study

2. Chronic medical condition including past history of cardiovascular disease, organic brain disorder, seizures

3. Current abuse or dependence on drugs within 6 months

Treatment compliance: not stated

• Side effects were systematically recorded and assessed using a checklist by the psychiatrist or parents anytime during the study

• No serious adverse effects were reported during the study

• Blood was collected at the beginning and end of the trial

• No abnormal findings were observed in the blood, urine and stool routine tests

Key conclusions of the study authors: compared to methylphenidate, Ningdong granule is effective and safe for ADHD children in the short term, increases the homovanillic acid concentration in sera to regulate dopamine metabolism, and promises to be an alternative medication, safely and effectively

1. DEX‐methylphenidate

2. No medication/no intervention

Inclusion criteria

1. Age 10‐17 years

2. DSM‐IV‐TR diagnosis of ADHD combined with either: Tourette Disorder or Chronic motor/vocal Tic Disorder

3. Baseline Yale Global Tic Severity Scale Total Tic Score ≥ 14 for TD or ≥ 10 for CTD

4. Exhibited 1 or more motor or vocal tics (or both) at a rate of ≥ 1 tic per minute averaged across a 10‐minute videotaped observation

5. Intellectual functioning was at least in the low‐average range or above as indicated by a score of greater than 75 on the Wechsler Abbreviated Scale of Intelligence (WASI)

6. No history of behavioural treatment for tics (greater than 3 weeks in duration) or other treatment in which suppression strategies were a primary component of the intervention

7. Current tic medication at the time of the study was allowed but no change of dose

8. Previous treatment with stimulants was allowed if the participant had not received stimulants for ≥ 48 hours prior to testing proceduresADHD symptoms must have been associated with impairment in at least one domain (home, school)

1. Participants with pervasive developmental disorder, schizophrenia, major depressive disorder, bipolar disorder, or substance abuse disorder

2. Participants currently receiving stimulant medication who could not temporarily discontinue it for study procedures

3. Participants with any medical condition that would contraindicate use of a stimulant, such as seizure disorder, previous hypersensitivity to methylphenidate, glaucoma, or a significant cardiac history, including fainting or dizziness, seizures, rheumatic fever, chest pain or shortness of breath with exercise, unexplained change in exercise tolerance, palpitations, increased heart rate, hypertension, heart murmur other than benign functional murmur, or current viral illness with chest pains or palpitations

4. Participants with a family history of sudden or unexplained death in someone less than 35 years of age, sudden death during exercise, cardiac arrhythmias, cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy or right ventricular cardiomyopathy, long QT syndrome, short QT syndrome or Brugada syndrome, Wolf‐Parkinson‐White syndrome or abnormal cardiac rhythms, event requiring resuscitation in family members under the age of 35, including syncope requiring resuscitation, or Marfan syndrome

5. Participants with abnormal electrocardiogram (ECG) at baseline, including prolongation of the QTc interval greater than 450 ms for males and 470 ms for females

6. Participants who meet full criteria for obsessive‐compulsive disorder or another anxiety disorder requiring pharmacological or behavioural treatment

Treatment compliance: not stated

Adverse events were generally mild. 7 (70%) participants experienced ≥ 1 minor adverse event during the study. The most common adverse events possibly related to study drug were drowsiness or sedation (20%) and stomach discomfort (20%)

Key conclusions from study authors: preliminary results suggest that dexmethylphenidate does not appear to enhance tic suppressibility in children with ADHD and TD. First, there was a clear tic‐reduction effect, and not exacerbation, with a 1‐time dose of dexmethylphenidate compared to no medication in these children. Second, youths with TD and ADHD appear to be able to suppress their tics with a behavioural reward comparable to youths with TD without ADHD

Inclusion criteria

1. Symptomatic for ≥ 9 months

2. Parents and children had to speak English or Spanish

3. Only children who were enrolled in an educational setting with ≥ 8 same‐age peers for at least 2 half days per week were eligible for the study. Participants had to have a CGI‐S score of ≥ 4 (moderately mentally ill) and a C‐GAS score ≥ 55. The Kaufman Brief Intelligence Test (K‐BIT) was administered to confirm an intelligence quotient (IQ) ≥70

1. History of intolerance or non‐response to stimulants

2. Current adjustment disorders, autism, psychosis, bipolar disorder, or suicidality

3. Children with a history of significant physical, sexual, or emotional abuse and medical abnormalities that would make use of B‐MPH clinically inappropriate were also excluded.

4. Concomitant treatments with antihypertensives, medication affecting blood pressure or heart rate, sedating antihistamines, antiseizure medications, diphenhydramine, and/or other psychotropic agents were not allowed during the study

Treatment compliance: not stated

These adverse events were resolved by the end of the study. 1 participant who terminated the study early experienced moderate levels of insomnia, vomiting, decreased appetite, and stomach pain, and another who also terminated early experienced moderate irritability

Key conclusions of the study authors: long‐acting methylphenidate was safe and effective for the treatment of ADHD in the 4‐ and 5‐year‐olds participating in this study. Rates of adverse events were higher than previously reported in methylphenidate trials of school‐aged children. 10‐mg/day doses failed to achieve response in the 5 children who could not tolerate higher doses

Inclusion criteria

1. ADHD diagnosis by community physician

2. Confirmed by T score ≥ 65 on CBCL Attentional Problems subscales

3. Conners' Parent Rating Scale ‐ 48 (CPRS 48) Impulsive‐Hyperactive Scale T score ≥ 65)

4. Taking methylphenidate for ≥ 1 year

1. Taking any other type of psychoactive medication

2. Exhibited any gross neurological, sensory, or motor impairment

3. A history of other significant learning or psychiatric problems

4. A known family history of diabetes (placebo contained sugar)

Treatment compliance: not stated

Key conclusions of the study authors: 3 of 5 participants reliably chose methylphenidate more often than placebo. Differences between the number of methylphenidate, placebo, and neither choices across participants were significant (P < 0.01)

Sociodemographics: her parents were first‐degree relatives. No family history of neurological disease

Duration of treatment: single dose

Inclusion criteria

1. ADHD diagnosis according to the DSM‐IV criteria

2. Clinical stability with MPH‐IR defined by scores below 1.5 on all Swanson, Nolan, and Pelham‐IV Questionnaire (SNAP‐IV) subscales (inattention, hyperactive/impulsive and opposition defiant) at last appointment

1. A clinically coexisting medical condition likely to impede the administration of MPH‐SODAS

2. Previous diagnosis of alcohol and/or drug abuse or dependence

3. Previous diagnosis of moderate mental retardation

4. Concomitant psychotherapy

Treatment compliance: the treatment adherence was checked by direct inquiring patients on compliance at week 4 and 8

Non‐serious adverse events:

Efficacy and side events were rechecked at week 4 and 8 using respectively the total, inattentive, hyperactive/impulsive scores of the SNAP‐IV and the total score of the SERS

Key conclusions of the study authors: results suggested that switching from immediate release methylphenidate to methylphenidate SODAS did not affect stabilisation of ADHD symptoms in most patients. Methylphenidate prescription in patients with previous cardiovascular conditions must be extremely careful

Inclusion criteria

1. Participants aged 6‐19 years

2. Received ≥ 1 prescription of methylphenidate

3. ≥ 1 trauma‐related ED admission during the study period (January 2001‐December 2013)

1. Patients with ≥ 1 prescription of atomoxetine

Treatment compliance: not stated

Key conclusions of the study authors: our study findings support the hypothesis that methylphenidate is associated with a reduced risk of trauma‐related ED admission in children and adolescents of both genders

Exclusion criteria

1. Children with ADHD but not hyperactivity

Key conclusions of the study authors: the results confirm and add to the research literature indicating that ADHD children who are of preschool age and/or who have co‐existing neurological disorders may benefit from methylphenidate

Inclusion criteria

1. 2‐21 years

2. ≥ 1 prescription for methylphenidate, dexamphetamine or atomoxetine

Treatment compliance: not stated

1. Patient aged 16‐21, cause of death: overdose. No active methylphenidate prescription. Comorbid anxiety/insomnia

2. Patient aged 16‐21, cause of death: unknown. No active methylphenidate prescription. Comorbid depression

3. Patient aged 16‐21, cause of death: stab wounds. No active methylphenidate prescription

4. Patient aged 8‐15, cause of death: suicide. Active methylphenidate prescription

5. Patient aged 8‐15, cause of death: suicide. Active methylphenidate prescription. Comorbid aggressive personality

Key conclusions of the study authors: in this study, it was not possible to demonstrate an increase in the risk of sudden death associated with methylphenidate, dexamphetamine or atomoxetine. Although it was not an initial aim of this study, an increase in the risk of suicide was observed, particularly in the younger teenager category

Inclusion criteria

1. Male or female aged 7‐14 years old

2. DSM‐IV ADHD (any subtype) diagnosed by semi‐structured diagnostic interview (Kiddie‐Schedule for affective disorders and schizophrenia‐PL and clinical interview)

3. Clinical Global Impression‐Severity (CGI‐S) scale score ≥ 4 for ADHD

1. Autistic disorder, any neurological disorder, chronic tic disorder, or structural heart defects

2. Current major depression, panic disorder, lifetime bipolar disorder or psychosis

3. Systolic or diastolic blood pressure > 95th or < 5th percentile for age and BMI

4. Medical condition contraindicating stimulants or alpha agonists

5. Need for chronic use of other central nervous system (CNS) medications

6. Full scale IQ < 80

Treatment compliance: not stated

Key conclusions of the study authors: combination medication treatment showed consistent evidence for clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and alpha2A agonists. Adverse events were generally mild to moderate, and combination treatment showed no differences in safety or tolerability

Sociodemographics: not stated

Treatment compliance: not stated

Intramuscular diphenhydramine at 50 mg was administered intramuscularly, and the patient could open his mouth within 30 minutes and with no further dystonia

Inclusion criteria

1. DSM‐IV diagnosis of ADHD

2. Taking anti‐ADHD medication including any form of dexamphetamine, any form of methylphenidate, atomoxetine

1. Treatment with any other medication including clonidine, Focalin, Metadate, guanfacine

2. Patients diagnosed and/or treated by a clinician "outside our group"

Treatment compliance: not stated

Key conclusions of the study authors: atomoxetine showed a significantly lower incidence of headaches than amphetamine/dextroamphetamine XR, amphetamine/dextroamphetamine or OROS‐methylphenidate

Sociodemographics: lives with parents and stepsister

Treatment compliance: not stated

Sociodemographics: not stated

Treatment compliance: not stated

1. Methylphenidate

2. Theophylline

Inclusion criteria

1. 6‐14 years

2. ADHD according to DSM‐IV diagnostic criteria

3. Newly diagnosed

1. Previously diagnosed with a psychiatric disorder or mental retardation (IQ < 70)

2. A clinically significant chronic medical condition, including a past history of cardiovascular disease, organic brain disorder, seizures, current abuse or dependence on drugs within 6 months and current treatment with psychotropic medications

3. Parents and children had to be willing to comply with all requirements of the study

Treatment compliance: not stated

Key conclusions of the study authors: the results suggest that theophylline may be a useful for the treatment of ADHD. In addition, a tolerable side‐effect profile is one of the advantages of theophylline in the treatment of ADHD

Inclusion criteria

1. ADHD DSM‐IV‐TR

2. 6‐15 years old

3. IQ > 70

1. Current diagnosis of any other axis I psychiatric disorders

2. Substance abuse or dependency

3. A history of seizures or any other serious medical disorders and use of any psychotropic drugs in the 6 weeks prior to the study

Treatment compliance: not stated

Key conclusions of the study authors: based on the results of this study, no significant difference was observed between the 2 medications, and it seems both drugs behave in a similar way. In addition, Stimdate appears to be effective and well tolerated for ADHD in children and adolescents in Iran

1. Methylphenidate

2. Amantadine

Inclusion criteria

1. 6‐14 years old

2. DSM‐IV‐TR diagnosis of ADHD

3. Total or subscale scores (or both) on ADHD‐RS‐IV School Version of ≥ 1.5 SD above norms for patient's age and gender

4. Parents and children had to be willing to comply with all requirements of the study

1. A history or current diagnosis of pervasive developmental disorders, schizophrenia or other psychiatric disorders (DSM‐IV axis I)

2. Any current psychiatric comorbidity that required pharmacotherapy

3. Any evidence of suicide risk and mental retardation (IQ < 70)

4. A clinically significant chronic medical condition, including organic brain disorder, seizures and, current abuse or dependence on drugs the last 6 months, hypertension or hypotension

Treatment compliance: not stated

Haematology tests were collected at baseline and weeks 2, 4 and 6; serum chemistry and urinalysis were evaluated at baseline and week 6

Key conclusions of the study authors: the results of this study indicate that amantadine significantly improved symptoms of ADHD and was well tolerated and it may be beneficial in the treatment of children with ADHD. Nevertheless, the present results do not constitute proof of efficacy

1. Methylphenidate + placebo

2. Methylphenidate + melatonin

Methylphenidate + placebo group

Inclusion criteria:

1. 7‐12 years old

2. Newly diagnosed with ADHD, ICD‐10 combined type

3. Clinical need to be treated with methylphenidate

4. Parental and child consent

1. Use of any confounding drugs or dietary supplements

2. History of major prenatal complications such as prematurity

3. Low birthweight (reported by parents)

4. Any past or present psychosis, comorbid Tourette syndrome, celiac, phenylketonuria, autism, or other persistent developmental disorders

5. Narcotics use

6. Any confounding comorbidities

Treatment compliance: not stated

Stimulant drug side effects questionnaires were completed by mothers at week 8 (methylphenidate + placebo, n = 18)

Key conclusions of study authors: melatonin with methylphenidate can partially improve symptoms of sleep disturbance by circadian cycle modification. However, it did not seem to reduce the attention deficiency and hyperactivity behaviour of ADHD children

Inclusion criteria:

1. Met the DSM‐IV‐TR diagnostic criteria for ADHD

2. Total or subscale scores (or both) on ADHD‐RS‐IV School Version of ≥ 1.5 SD above norms for patient's age and gender

3. Parents and children had to be willing to comply with all requirements of the study

4. Written informed consent was obtained from each patient's parent or guardian

1. History or current diagnosis of pervasive developmental disorders, schizophrenia or other psychiatric disorders (DSM‐IV axis I)

2. Any current psychiatric comorbidity that required pharmacotherapy

3. Any evidence of suicide risk

4. Mental retardation (IQ below 70)

5. A clinically significant chronic medical condition, including organic brain disorder, seizures

6. Current abuse or dependence on drugs the last 6 months

7. Hypertension or hypotension

Treatment compliance: not stated

Key conclusions of the study authors: the results of this study suggest that administration of buspirone has no comparable efficacy in comparison with methylphenidate in the treatment of ADHD. Nevertheless, in our study, those in the buspirone group experienced fewer adverse events than the methylphenidate group in particular regarding decreased appetite, headache and insomnia

Inclusion criteria:

1. 10‐16 years old

2. Admitted to a child psychiatric consultation

3. Not candidate for atomoxetine (sufficient response to stimulant treatment)

4. Not candidate for immediate‐release methylphenidate because of prior poor tolerance (but at least with a partial response to Concerta or Medikinet)

5. Not candidate for a short‐acting methylphenidate (4 hours)

6. Candidate for taking methylphenidate with effect from 8 am to 9 pm defined as: patients attending school from 8 am to 3 pm or 8 am to 5 pm and needing supplemental support of stimulant treatment, and furthermore, also studying in the afternoon (at school or at home) (60%), or having challenging conduct problems and needing an extended effect until at least 9 pm (20%) or both situations

7. Either moderate or severe in symptomatology according to the 20 items Conners Scale for teachers (above 45) and Clinical global impression scale (above or equal to a severity of 5 to 7) when off medication

8. IQ above 70

Treatment compliance: not stated

Key conclusions of the study authors: at week 8, 63% of the participants reached complete remission, and 27.5% reached partial remission. Scores in all subscales of Eyberg, Conners (parents and teachers) were reduced till the level of normal population (except for the conduct subscale of the teacher rated) in a statistical significant level. Due to insomnia, 2 patients reduced the afternoon dose of 50/50‐ER/IR‐MPH from 20 mg to 10 mg and 3 patients changed the 20 mg 50/50‐ER/IR‐MPH afternoon dose to 10 mg IR‐MPH

1. Methylphenidate

2. Parent training

Inclusion criteria:

1. DSM‐IV diagnosis of ADHD

2. A score of 1.5 SD above the mean for the subscales of inattention, hyperactivity‐impulsivity, and DSM‐IV total in either Conners' Parent Rating Scale‐Revised or Conners' Teacher Rating Scale‐Revised

3. IQ of or above 70

4. Symptoms severe enough to interfere and impair daily functioning

5. No prior stimulant or psychological treatment

1. Meeting diagnostic criteria for a developmental disorder, mental impairment, or any sensory disturbance at the time of screening

Treatment compliance: not stated

Key conclusions of the study authors: to our knowledge this is the first article describing the effectiveness of methylphenidate and parent training in Venezuelan children diagnosed with ADHD. It should be considered as a preliminary study, that supports the thesis of positive effects of psychosocial and psychopharmacological interventions in children with ADHD. There was no difference in the effectiveness of the 2 types of treatment

Inclusion criteria:

1. Age 6 years and above

2. Start short‐acting methylphenidate medication at any time between 1 January 2000 to 31 31 December 2007

3. Continued medicine ≥ 1 year

1. ADHD children who received other medications continuing more than 3 months

2. Concomitant genetic or neurological disorders

Treatment compliance: not stated

Key conclusions of the study authors: prolonged medication with short‐acting methylphenidate showed minimal impact on growth only at the first 6 months; however, growth could catch up in the adolescent period

Sociodemographics: not stated

Treatment compliance: yes

Supplemental information regarding IQ and comedication received through personal email correspondence with the authors in April 2016 (Munk 2016 [pers comm]). Not possible to retrieve information regarding ADHD subtype

Inclusion criteria

1. DSM‐IV criteria for ADHD and considered to require medication therapy

2. Participants that agreed to observe visit schedules and willingly complete the evaluation defined by participant (possibly to be completed by parents/guardians) during the treatment period

3. Participants and parents/guardians that are able to understand the participation procedures of the research and spontaneously request the discontinuation therein at any time

4. Participants that offered spontaneous consent for participation

5. Participants whose guardian/legal representative provided spontaneous written consent

6. 12‐18 years of age

1. Hypersensitivity to methylphenidate HCL

2. Participants diagnosed with major depression or anxiety disorders according to DSM‐IV diagnostic criteria and who requires drug therapy

3. Significant suicidal ideation

4. Learning disabilities or mental retardation, any history of bipolar disorder, psychotic disorder, or substance use disorder

5. Diagnosed with a pervasive developmental disorder, organic brain disease, seizure disorder, and movement disorder requiring pharmacological treatment

6. Family history of Tourette syndrome

7. Previously taken OROS methylphenidate within 6 months before screening

8. Severe general medical conditions (e.g. glaucoma, severe cardiovascular, hepatic, or renal illnesses), or clinically significant gastrointestinal problems, and

9. Taking a‐2 adrenergic receptor agonists, theophylline, coumarin, antidepressants, antipsychotics, benzodiazepines, modafinil, anticonvulsants, or health supplements that may influence activity of the central nervous system at the time of screening

10. Abnormalities in baseline physical examination or routine laboratory tests

Treatment compliance: not stated, but participants were required to take ≥ 70% of the study medication during the study period

The study‐specific adverse events checklist consisted of 61 methylphenidate‐specific questions (Items from the Symptom Rating Scale (Barkley 1990) and the Pittsburg Side‐Effects Rating Scale (Pelham 1993) were included)

Key conclusions of the study authors: OROS methylphenidate was effective in enhancing learning skills in adolescents with ADHD. Furthermore, clinicians should supplement the subjective report on adverse events 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 patterns of adverse events reported by patients and their parents, it is generally recommended that clinicians obtain information from both parties when possible

Sociodemographics: not stated

Treatment compliance: not stated

Dosage‐reduction to 10 mg/day: improved the depressed mood

Supplemental information regarding ADHD type received through personal email correspondence with author in July 2013 (Niederhofer 2013 [pers comm])

Cases with aggression (n = 1) and emotional instability (n = 1)

Sociodemographics: not stated

Cases with aggression and emotional instability

Treatment compliance: not stated

Supplemental information regarding ADHD subtype and duration of intervention received through personal email correspondence with author in July 2013 (Niederhofer 2013b [pers comm])

Sociodemographics: not stated

Treatment compliance: not stated

Inclusion criteria:

1. DSM‐IV‐TR diagnosis of ADHD

2. Aged 6‐12 years

3. ≥ moderate symptom severity on the Clinical Global Impression‐Severity (CGI‐S) scale and severe enough to warrant treatment with medication

4. No previous exposure to psychostimulants

1. Other mental disorders, except for transient tic disorder, oppositional defiant disorder, mild anxiety disorder, and enuresis

2. Current or previous brain damage or convulsive disorder

3. Mental retardation, autism, language difficulties, or developmental problems, including learning disabilities

Treatment compliance: not stated

Key conclusions of the study authors: ADHD participants with the A/a genotype at the NTF3 rs6332 polymorphism showed the highest 'proneness to crying' and 'nail biting' item scores, followed by those with the G/a genotype and those with the G/G genotype (P = 0.047 and P = 0.017, respectively). These data provide preliminary evidence that genetic variation in the NTF3 gene is related to susceptibility to emotional side effects in response to methylphenidate treatment in Korean children with ADHD

Inclusion criteria:

Exclusion criteria:

1. Children with ADHD found to be unsuitable for treatment with methylphenidate

2. Under 4 years of age

3. IQ < 90

4. Or for any other reason

Treatment compliance: data used for this article is confined to those children who consistently attended clinics and completed 6 months of treatment

Key conclusions of the study authors: close involvement of parents in monitoring outcome of treatment of ADHD helps to focus on aspects of care relevant to them

Inclusion criteria

Exclusion criteria

Treatment compliance: not stated

Key conclusions of the study authors: Child Behavior Checklist‐Dysregulation Profile (CBCL‐DP) was associated neither with poorer response to methylphenidate nor with more side effects. There were no differences in cognitive performance between participants with and without CBCL‐DP

Children

Adolescents

Inclusion criteria

1. Aged 6‐17 years

2. Primary diagnosis of ADHD according to DSM‐IV

3. Have blood pressure measurements within the 95th percentile for age, sex, and height

4. Normal laboratory parameters and vital signs, including ECG results

1. Comorbid psychiatric diagnosis (except oppositional defiant disorder)

2. History of seizures or tic disorders; suicidal ideation; serious cardiac problems; substance abuse or dependence disorder (excluding nicotine dependence); skin disorder (e.g. skin cancer, skin manifestations of allergies, dermatitis, eczema, psoriasis, signs of skin irritation)

3. Known intolerance to psychostimulants in general, and to MPH in particular

4. Any illness that might jeopardise safety or compromise the study assessments

5. Female participants must not have been pregnant or lactating

6. Participants must not have consumed food or beverages containing alcohol, caffeine, or xanthine 48 hours before check‐in; ingested nicotine 48 hours before check‐in; taken investigational medications, hepatic or cytochrome P450 enzyme‐altering agents, or medications with central nervous effects within 30 days before screening; or taken prescription medication or over‐the‐counter medications within 7 days before check‐in

7. Participants must not have donated plasma of 500 mL or more within 56 days before screening

Treatment compliance: not stated

• Safety was monitored throughout the study by measuring adverse events and reviewing results of physical examinations, ECGs, vital signs, and standard clinical laboratory evaluations

• All clinically significant changes (determined by the investigator) were recorded as AEs and were characterised as to intensity and relationship to the study treatment

• AEs were coded using the Medical Dictionary for Regulatory Activities, version 7.0

• Application Site Skin Evaluation

• Participants receiving MTS treatment underwent skin evaluations at the application site to identify irritation and discomfort and determine the degree of patch adhesion, using the dermal response scale (DRS; 0 (no erythema) to 7 (strong reaction beyond the application site)

• The experience of discomfort and pruritus was used to evaluate the overall level of discomfort at the patch application site

Key conclusions of the study authors: overall, after single and multiple fixed or escalating doses of MTS or OROS methylphenidate, systemic exposure to the predominantly active d‐methylphenidate was greater in children compared with adolescents. As a result of drug accumulation on repeated dosing, systemic exposure to d‐methylphenidate in children after multiple escalating doses was 1.4‐ to 1.6‐fold higher for MTS compared with OROS; however, in adolescents, systemic exposure was similar for both formulations. Plasma concentrations of l‐MPH were approximately half those of d‐MPH across both age groups after single and multiple doses of MTS. In contrast, plasma concentrations of l‐MPH were negligible after single and multiple doses of OROS MPH. Reported AEs included those that are typical for oral methylphenidate treatment, with the exception of generally mild application site irritations associated with transdermal delivery of methylphenidate

Inclusion criteria:

1. ADHD diagnosis according to DSM‐IV criteria (children who fulfilled all criteria except for age of onset of impairment (i.e. before 7 years) were included)

2. Age between 4 and 17 years,

3. European‐Brazilian race/ethnicity

4. Drug naïve for methylphenidate

5. Prescribed daily dosage of methylphenidate hydrochloride of ≥ 0.3 mg/kg

6. Data on response to methylphenidate was available for at least the first month of treatment

Treatment compliance: data were excluded from 2 children because of irregular use of methylphenidate

Key conclusions of the study authors: the study documented the effect of the G allele at the ADRA2A ‐1291 C > G polymorphism on the improvement of inattentive symptoms with methylphenidate treatment in children and adolescents with ADHD. Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylphenidate action

Sociodemographics: mother presented with affective seasonal disorder and binge eating disorder

Treatment compliance: not stated

24 months follow‐up period: no further hallucinations occurred

Supplemental information regarding IQ received through personal email correspondence with the authors in October 2013 (Curatolo 2013 [pers comm])

Inclusion criteria

1. ADHD diagnosis according to DSM‐IV

2. Patients from a single private practice in Penrith prescribed methylphenidate in 1999

1. Methylphenidate for less than 6 months

2. Previous experience with stimulant treatment

Treatment compliance: many patients were taking less than the prescribed dose of stimulant medication, ceasing or reducing medication at weekends or during school holidays, but precise details were not available

• Height ‐ measured to the nearest 1 mm by the same observer using a wall‐mounted stadiometer, measured every 6th month or more frequently if clinically indicated

• Weight ‐ measured to the nearest 0.5 kg using electronic scales, measured every 6th month or more frequently if clinically indicated

Key conclusions of the study authors: stimulant medication is associated with a decrease in height and weight SD scores during the first 6‐30 months with a characteristic pattern on the growth chart

Inclusion criteria

1. ADHD according to DSM criteria

2. Aged < 9 years old

3. Newly diagnosed

4. Clinical indication for starting treatment with stimulant medication

1. Previous treated with psychotropic medication

2. Medical conditions likely to impact on growth

Treatment compliance: not stated

BMI were corrected for age and sex by conversion to z scores based on Centers for Disease Control and Prevention (CDC) reference data

Key conclusions of the study authors: stimulant medication was associated with early fat loss and reduced bone turnover. Lean tissue including bone increased more slowly over 3 years of continuous treatment than would be expected for growth in height. There was long‐term improvement in the proportion of central fat for height. This study shows that relatively minor reductions in weight on stimulant medication can be associated with long‐term changes in body composition. Further study is required to determine the effects of these changes on adults

Supplemental information regarding data received through personal email correspondence with the authors in October 2013 (Poulton 2013b [pers comm])

Sociodemographics: family history was unremarkable

Treatment compliance: not stated

Supplemental information regarding ADHD diagnosis and type, comorbidity and comedication received through personal email correspondence with the authors in April 2016 (Pranav 2016 [pers comm])

Sociodemographics: working single mother, sporadic contact with father. Patient and his siblings were intermittently exposed to domestic violence

Treatment compliance: not stated

While taking extended release methylphenidate (Concerta): nausea and vomiting

Supplemental information regarding ADHD diagnosis and IQ received through personal email correspondence with the authors in November 2013 (Rappaport 2013 [pers comm])

Sociodemographics: low socioeconomic status

Treatment compliance: not stated

1. 1 girl experienced moderate to severe stomach discomfort approximately 60 minutes post‐ingestion of her scheduled 15 mg dose. This was attributed to her failure to eat lunch earlier (reported by parent). Decrease of distress followed ingestion of a sandwich after 30 minutes

Sociodemographics: history of several foster placements, now adopted

Follow‐up 1 year later: no unexplained somatic complaints

Key conclusions of the study authors: here we describe a case of a 10‐year‐old boy with ADHD with a chronic pattern of somatisation, which evolved into overt somatic hallucinations with an increase in the methylphenidate dose. This pattern of somatisation was retrospectively recognised as partial somatic hallucinations