Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non‐randomised studies

Ole Jakob Storebø; Nadia Pedersen; Erica Ramstad; Maja Lærke Kielsholm; Signe Sofie Nielsen; Helle B Krogh; Carlos R Moreira‐Maia; Frederik L Magnusson; Mathilde Holmskov; Trine Gerner; Maria Skoog; Susanne Rosendal; Camilla Groth; Donna Gillies; Kirsten Buch Rasmussen; Dorothy Gauci; Morris Zwi; Richard Kirubakaran; Sasja J Håkonsen; Lise Aagaard; Erik Simonsen; Christian Gluud

doi:10.1002/14651858.CD012069.pub2

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Figure 1

Study flow diagram

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Figure 2

Proportion of participants on methylphenidate with any serious adverse events

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Figure 3

Proportion of participants withdrawn from methylphenidate due to serious adverse events

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Figure 4

Proportion of participants withdrawn from methylphenidate due to adverse events of unknown severity

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Figure 5

Proportion of participants on methylphenidate with any non‐serious adverse event

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Figure 6

Proportion of participants withdrawn from methylphenidate due to non‐serious adverse events

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Figure 7

Proportion of participants withdrawn from methylphenidate for unknown reasons

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Analysis 1.1

Comparison 1 Comparative studies: number of serious adverse events, Outcome 1 Any serious adverse events.

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Analysis 1.2

Comparison 1 Comparative studies: number of serious adverse events, Outcome 2 Central nervous system.

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Study
Arrhythmias
Shin 2016	RR 1.61 (95% CI 1.48 to 1.74)
Hypertension
Shin 2016	RR 1.07 (95% CI 0.94 to 1.22)
Myocardial infarction
Shin 2016	RR 1.33 (95% CI 0.90 to 1.98)
Ischaemic stroke
Shin 2016	RR 0.70 (95% CI 0.49 to 1.01)
Heart failure
Shin 2016	RR 0.54 (95% CI 0.30 to 0.96)

Analysis 1.3

Comparison 1 Comparative studies: number of serious adverse events, Outcome 3 Cardiovascular and respiratory system.

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Analysis 2.1

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 1 Central nervous system: sleep‐related adverse events.

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Analysis 2.2

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 2 Central nervous system: other specific sleep‐related adverse events.

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Analysis 2.3

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 3 Central nervous system: other specific adverse events.

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Analysis 2.4

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 4 Cardiovascular and respiratory system.

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Analysis 2.5

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 5 Gastrointestinal system.

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Analysis 2.6

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 6 Musculoskeletal system.

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Analysis 2.7

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 7 Musculoskeletal system: body mass index (BMI).

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Analysis 2.8

Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 8 Musculoskeletal system: z scores.

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Analysis 3.1

Comparison 3 Comparative studies: number of participants withdrawn from methylphenidate treatment, Outcome 1 Proportion of participants withdrawn from methylphenidate for unknown reasons.

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Study	Symptoms	Adverse events/total number of participants
Altin 2013	No patients experienced any serious adverse events	0/221
Arabgol 2015	Severe anorexia	1/18
Ardic 2014	Serious adverse events	0/101
Arnold 2004	Serious adverse events	3/89
Arnold 2010	Acute depression and suicide attempt	1/150
Ashkenasi 2011	Hallucinations	1/26
Berek 2011	Serious adverse events	4/822
Cherland 1999	Serious adverse events	13/98
Chou 2012b	Serious adverse events	0/230
Cortese 2015	Serious adverse events	64/1426
Davari‐Ashtiani 2010	Serious adverse events	0/16
Dittmann 2014	Serious adverse events	0/247
Döpfner 2011a, OBSEER	Serious adverse events	21/777
Döpfner 2011b	Serious adverse events	38/822
Findling 2009	Serious adverse events	3/157
Germinario 2013	Serious adverse events	7/1098
Gerwe 2009	Serious adverse events	2/263
Haertling 2015	Serious adverse events	3/239
Hammerness 2009	Participants affected or at risk	5/57
Hammerness 2012	Serious adverse events	0/10
Hulvershorn 2012	Serious adverse events	0/25
Jafarinia 2012	Serious adverse events	0/20
Jensen 1999 (MTA)	Serious adverse events	1/245
Kemner 2005 (FOCUS)	Sudden death	0/850
Kim 2011	Serious adverse events	0/97
Lakic 2012	Strong depressive symptoms	1/68
Lee 2014	Serious adverse events	542/4055
Li 2011	Serious adverse events	0/36
Maayan 2009	Serious adverse events	0/8
McCarthy 2009	Sudden death	5/5351
McCracken 2016	Serious adverse events	0/61
Mohammadi 2004	Serious adverse events	3/116
Pierce 2010	Serious adverse events	0/71
Remschmidt 2005	Serious adverse events	4/89
Schmidt 2002	Generalized tonic‐clonic seizure	1/124
Schulz 2010	Serious adverse events	0/145
Shin 2016	Serious adverse events	1224/123,636
Sobanski 2013	Serious adverse events	8/347
Steele 2006	Serious adverse events	0/73
Su 2015	Serious adverse events	0/239
Valdizán Usón 2013	Serious adverse events	0/689
Warshaw 2010	Serious adverse events	0/260
Weiss 2007	Serious adverse events	0/79
Wigal 2011	Serious adverse events	0/31
Wigal 2013	Serious adverse events	0/39
Wigal 2015	Serious adverse events	1/200
Wilens 2006	Serious adverse events	1/87
Wilens 2008	Serious adverse events	0/127
Winterstein 2009	Serious adverse events	171/18,238
Zheng 2015	Serious adverse events	0/149

Analysis 4.1

Comparison 4 Non‐comparative studies: proportion of participants with serious adverse events, Outcome 1 Any serious adverse event.

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Study	Symptom	Adverse events/total number of participants
Sudden death
Kemner 2005 (FOCUS)	Sudden death	0/850
Lee 2014	Sudden death	7/100
McCarthy 2009	Sudden death	1/5351
Suicide
Jensen 1999 (MTA)	Suicide	1/245
McCarthy 2009	Suicide	4/5351
Suicide attempt
Arnold 2010	Acute depression and suicide attempt	1/150
Lee 2014	Suicide attempt	6/100
Remschmidt 2005	Suicide attempt	1/89
Suicide thoughts
Remschmidt 2005	Depressive, suicidal thoughts	1/89
Wilens 2006	Serious adverse events were reported in only 1 participant during the open‐label, dose‐titration phase of the study	1/87
Psychotic symptoms
Cherland 1999	Psychotic symptoms	7/96
Cortese 2015	Hallucinations	2/1426
Findling 2009	Paranoid behavior disorder	3/157
Green 2011	Hallucinations	0/22
Mohammadi 2004	Hallucinations	0/11
Na 2013	Hallucinations	0/55
Remschmidt 2005	Delusions	1/89
Shyu 2015	Psychotic disorders	856/52,646
Su 2015	Hallucinations	1/239
Wilens 2005	Hallucinations	0/369
Seizure
Cortese 2015	Seizures	3/1426
Schmidt 2002	Generalized tonic‐clonic seizure	1/124
Syncope
Findling 2009	Syncope	1/327
Germinario 2013	Vasovagal syncope	1/1098
Tremor
Arnold 2004	Tremor	1/89
Gerwe 2009	Tremor	1/306
Psychiatric problems
Arnold 2004	Rambling speech	1/89
Cortese 2015	Psychiatric disorder	5/1426
Germinario 2013	Psychiatric problems	5/1098
Severe depression
Cherland 1999	Severe depression	1/98
Lakic 2012	Strong depressive symptoms	1/68
Overdose
Lee 2014	Overdose	6/100
Eating disorder
Cortese 2015	Eating disorder	1/1426
Aphasia
Cortese 2015	Aphasia	1/1426
Headache
Cortese 2015	Headache	3/1426
Neurological disorder
Cortese 2015	Neurologicaol disorder	2/1426
Sleep disorder
Cortese 2015	Sleep disorder	1/1426
Mood disorder
Cortese 2015	Mood disorder	1/1426
Loss of consciousness
Gerwe 2009	Short loss of consciousness	1/306
Family stress
Gerwe 2009	Family stress	1/306
Impotence
Germinario 2013	Impotence	1/1098
Severe aggression
Remschmidt 2005	Severe aggression	1/89
Severe anorexia
Arabgol 2015	Severe anorexia	1/18
Amphetamine intoxication
Cherland 1999	Amphetamine intoxication	3/98

Analysis 4.2

Comparison 4 Non‐comparative studies: proportion of participants with serious adverse events, Outcome 2 Central nervous system.

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Study	Symptom	Adverse events/total number of participants
Respiratory, thoracic and mediastinal disorders
Germinario 2013	Aortic embolism	1/1098
Hammerness 2009	Spontaneous pneumothorax	1/57
Cardiac problems
Arman 2013	Cardiac rhythm abnormalities	0/15
Germinario 2013	Cardiovascular problems	2/1098
Winterstein 2009	Serious cardiac problems	171/18,238
Tachycardia
Cortese 2015	Tachycardia	2/1426
Germinario 2013	Tachycardia	2/1098
Severe hypertension
Cortese 2015	Severe hypertension	2/1426
Epistaxsis
Cortese 2015	Epistaxsis	1/1426
Viral illness
Hammerness 2009	Participants affected by viral illness	1/57

Analysis 4.3

Comparison 4 Non‐comparative studies: proportion of participants with serious adverse events, Outcome 3 Cardiovascular and respiratory system.

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Study	Symptom	Adverse events/total number of participants
Gastrointestinal disease
Cortese 2015	Gastrointestinal disease	6/1426
Liver disease
Cortese 2015	Hyperbilrubinemia	1/1426

Analysis 4.4

Comparison 4 Non‐comparative studies: proportion of participants with serious adverse events, Outcome 4 Gastrointestinal system.

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Study	Symptom	Adverse events/total number of participants
Findling 2009	Ankle fracture	1/327
Hammerness 2009	Leg fracture	2/57

Analysis 4.5

Comparison 4 Non‐comparative studies: proportion of participants with serious adverse events, Outcome 5 Musculoskeletal system: fractures.

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Study	Symptom	Adverse events/total number of participants
Cortese 2015	Autoimmune disease	1/1426

Analysis 4.6

Comparison 4 Non‐comparative studies: proportion of participants with serious adverse events, Outcome 6 Immune system: autoimmune disease.

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Study
Serious adverse events
Arabgol 2015	1/18
Arnold 2010	1/171
Ashkenasi 2011	1/26
Faraone 2007a	3/268
Findling 2010	2/162
Na 2013	1/121
Wilens 2005	1/407
Hallucinations
Ashkenasi 2011	1/26
Na 2013	1/121
Wilens 2005	1/407
Severe anorexia
Arabgol 2015	1/18
Suicide attempt
Arnold 2010	1/171

Analysis 5.1

Comparison 5 Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to serious adverse events, Outcome 1 Proportion of participants withdrawn from methylphenidate treatment due to serious adverse events.

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Study
Altin 2013	4/204
Arnold 2004	4/89
Arnold 2010	4/171
Atzori 2009	17/189
Chou 2012b	15/296
Dodangi 2011	2/15
Döpfner 2011a, OBSEER	26/822
Findling 2009	51/326
Kim 2015b	8/143
Kordon 2011	53/598
Kratochvil 2002	5/44
Lee 2009	28/144
Lee 2012	1/93
Maia 2008	3/39
Mayes 1994	2/69
McCracken 2016	1/69
Mohammadi 2009	6/30
Remschmidt 2005	16/89
Steele 2006	6/73
Yang 2004	2/25
Yang 2012	15/130
Yildiz 2010	3/50

Analysis 5.2

Comparison 5 Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to serious adverse events, Outcome 2 Proportion of participants withdrawn from methylphenidate treatment due to adverse events of unknown severity.

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Study	Symptom	Adverse events/total number of participants
Barbaresi 2006	Adverse events of unknown seriousness	63/251

Analysis 6.1

Comparison 6 Non‐comparative studies: proportion of participants with adverse events of unknown severity, Outcome 1 Proportion of participants with adverse events of unknown severity.

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Study	Symptom	Adverse events/total number of participants
Altin 2013	Total adverse events	21/142
Ardic 2014	Any adverse event (with OROS (osmotic controlled release oral delivery system) methylphenidate)	52/122
Arnold 2004	Any adverse event	76/76
Atzori 2009	Total number of patients who experience adverse events	54/134
Barrickman 1995	Total adverse events	5/15
Berek 2011	Total adverse events	195/762
Chou 2012b	Total adverse events	95/230
Cortese 2015	Total adverse events	369/1426
Dirksen 2002	Total adverse events	78/287
Dittmann 2014	Total adverse events	25/195
Döpfner 2011a, OBSEER	Total adverse events	209/822
Döpfner 2011b	Total adverse events	40/106
Findling 2010	Total adverse events	68/88
Garg 2014	Total adverse events	18/27
Gau 2008	Total adverse events	180/607
Gerwe 2009	Total adverse events	160/263
Goez 2012	Total adverse events	7/28
Green 2011	Total adverse events	14/14
Greenberg 1987	Total adverse events	8/49
Greenhill 1983	Total adverse events	5/7
Gucuyener 2003	Total adverse events	26/119
Haertling 2015	Total adverse events	27/239
Hammerness 2009	Total adverse events	45/57
Hammerness 2012	Total adverse events	0/27
Haubold 2010	Total adverse events	32/103
Jensen 1999 (MTA)	Total adverse events	150/245
Karabekiroglu 2008	Total adverse events	28/90
Khajehpiri 2014	At least one adverse drug reaction	71/71
Kim 2015b	Total adverse events	8/116
Kordon 2011	Total adverse events	172/541
Lee 2014	Total adverse events	3513/4055
Lyon 2010	Total adverse events	7/10
Mayes 1994	Total adverse events	35/63
McCracken 2016	Total adverse events	58/60
Na 2013	Total number of patients who experienced adverse events	98/103
Remschmidt 2005	Total adverse events	76/89
Schulz 2010	Total adverse events	36/145
Sobanski 2013	Total adverse events	26/347
Song 2012	Total adverse events	116/116
Su 2015	Total adverse events	101/205
Tasdelen 2015	Total adverse events	12/17
Valdizán Usón 2013	Total adverse events	177/689
Warshaw 2010	Total adverse events	242/260
Weiss 2007	Total adverse events	64/79
Wigal 2013	Total adverse events	42/45
Wilens 2005	Total adverse events	344/407
Wilens 2006	Total adverse events	96/135
Yatsuga 2014	Total adverse events	7/50
Zheng 2015	Total adverse events	24/123

Analysis 7.1

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 1 Non‐serious adverse events.

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Study	Symptom	Adverse events/total number of participants
Affect lability
Sahin 2014	Moodiness	10/30
Wigal 2013	Affect lability	12/44
Aggression
Barrickman 1995	Anger	1/15
Berek 2011	Aggressive reaction	13/762
Davari‐Ashtiani 2010	Aggression	1/16
Dittmann 2014	Aggression	0/195
Döpfner 2011a, OBSEER	Aggression	31/777
Döpfner 2011b	Aggression	2/113
Haertling 2015	Aggression	3/239
Kemner 2005 (FOCUS)	Aggression	10/850
Kordon 2011	Aggression	10/541
Lee 2014	Aggression	7/100
Mayes 1994	Aggression	1/69
Na 2013	Anger	6/103
Remschmidt 2005	Aggression	1/105
Wilens 2005	Hostility	8/407
Anorexia
Arabgol 2015	Anorexia	8/15
Arnold 2004	Anorexia	16/76
Arnold 2010	Anorexia	6/150
Berek 2011	Anorexia	35/762
Cortese 2015	Anorexia	9/1426
Döpfner 2011a, OBSEER	Anorexia	9/777
Döpfner 2011b	Anorexia	0/113
Gerwe 2009	Anorexia	20/263
Greenhill 1983	Anorexia	5/7
Haertling 2015	Anorexia	11/239
Khajehpiri 2014	Anorexia	45/71
Kordon 2011	Anorexia	23/541
Kratochvil 2002	Anorexia	6/25
Lee 2007	Anorexia	29/110
Na 2013	Anorexia	66/103
Song 2012	Anorexia	104/116
Wang 2007	Anorexia	42/166
Warshaw 2010	Anorexia	9/260
Weiss 2007	Anorexia	16/79
Wilens 2006	Anorexia	22/220
Yildiz 2011	Anorexia	9/11
Zelnik 2015	Anorexia	36/128
Çetin 2015	Anorexia	12/61
Anxiety
Abbasi 2011	Anxiety	9/20
Akhondzadeh 2003	Anxiety	3/10
Akhondzadeh 2004	Anxiety	3/20
Amiri 2008	Anxiety, nervousness	4/27
Barrickman 1995	Anxiety	1/15
Blader 2010	Anxiety or nervousness	12/65
Davari‐Ashtiani 2010	Phobia & anxiety	2/16
Efron 1997	Anxiousness	76/123
El‐Fiky 2014	Anxious	2/31
Gau 2006	Anxious	10/32
Ghanizadeh 2012	Anxiety	1/12
Green 2011	Anxiousness	4/14
Hammerness 2009	Anxiety	2/57
Hazell 2003	Anxious	6/10
Jafarinia 2012	Anxiety	5/20
Maia 2008	Anxious	12/31
Mohammadi 2004	Anxiety	0/11
Mohammadi 2010	Anxiety	9/19
Na 2013	Anxiety	9/103
Song 2012	Anxiety	12/116
Wilens 2005	Anxiety	9/407
Zelnik 2015	Anxiety	21/128
Fingernail biting
Blader 2010	Bites fingernails	9/65
Efron 1997	Biting fingernails	56/123
El‐Fiky 2014	Bites fingers	0/31
Gau 2006	Biting fingernails	8/32
Green 2011	Biting fingernails	3/14
Hazell 2003	Biting fingernails	2/10
Maia 2008	Bites fingernails	3/31
Sahin 2014	Nail biting	3/30
Shang 2015	Nail biting	1/66
Daydreams
Efron 1997	Daydreams	77/123
Gau 2006	Daydreams	10/32
Green 2011	Daydreams	3/14
Sahin 2014	Daydreams	7/30
Difficulty falling asleep
Akhondzadeh 2003	Difficulty falling asleep	4/10
Akhondzadeh 2004	Difficulty falling asleep	6/20
Altin 2013	Insomnia	5/71
Amiri 2008	Difficulty falling asleep	8/30
Ardic 2014	Insomnia	19/101
Arnold 2004	Insomnia	16/76
Arnold 2010	Insomnia	9/171
Atzori 2009	Insomnia	3/129
Barrickman 1995	Insomnia	1/15
Berek 2011	Insomnia	59/762
Blader 2010	Insomnia	21/65
Chou 2012b	Insomnia	25/230
Cortese 2015	Insomnia	31/1426
Coşkun 2010	Sleep problems	4/7
Davari‐Ashtiani 2010	Sleep problems	7/16
Döpfner 2011a, OBSEER	Initial insomnia	11/777
Döpfner 2011b	Initial insomnia	3/113
Efron 1997	Trouble sleeping	79/123
El‐Fiky 2014	Insomnia	2/31
Famularo 1987	Later sleep onset	1/10
Garg 2014	Insomnia	1/27
Gau 2006	Insomnia or trouble sleeping	15/32
Germinario 2013	Insomnia	1/9
Gerwe 2009	Difficulty falling asleep	73/263
Grcevich 2001	Sleep problems	7/75
Green 2011	Trouble sleeping	7/34
Greenhill 1983	Insomnia	2/7
Gucuyener 2003	Difficulty falling asleep	19/119
Haertling 2015	Insomnia	3/239
Hazell 2003	Sleep problems	7/10
Işeri 2007	Sleep problems	5/20
Jafarinia 2012	Insomnia	10/20
Jensen 1999 (MTA)	Insomnia	12/245
Johnson 2013	Insomnia (new onset)	12/45
Jung 2007	Insomnia	16/83
Kemner 2005 (FOCUS)	Insomnia	53/850
Khajehpiri 2014	Insomnia	44/71
Kim 2010	Insomnia	6/24
Kordon 2011	Insomnia	46/541
Kratochvil 2002	Insomnia	7/25
Lee 2007	Insomnia	24110
Li 2011	Difficulty falling asleep	9/34
Maayan 2009	Trouble sleeping	3/8
Maia 2008	Insomnia	5/31
Mayes 1994	Insomnia	9/63
McCracken 2016	Insomnia	20/61
Miller‐Horn 2008	Insomnia	2/23
Mohammadi 2004	Difficulty falling asleep	4/11
Mohammadi 2010	Trouble sleeping	9/19
Mohammadi 2012a	Difficulty falling asleep	8/23
Mohammadi 2012b	Insomnia	9/20
Montañés‐Rada 2012	Insomnia	5/40
Na 2013	Trouble sleeping	37/103
Peyre 2012a	Insomnia	21/121
Remschmidt 2005	Insomnia	3/89
Sahin 2014	Difficulty falling asleep	16/30
Sangal 2006	Insomnia	21/79
Shang 2015	Insomnia	12/66
Song 2012	Insomnia	44/116
Steele 2006	Insomnia	12/60
Su 2015	Insomnia	20/205
Tasdelen 2015	Insomnia	1/17
Thorell 2009	Difficulties falling asleep	15/79
Tomás Vila 2010b	Difficulty falling asleep	45/114
Valdizán Usón 2004	Initial insomnia	11/155
Wang 2007	Insomnia	9/166
Warshaw 2010	Difficulty falling asleep	25/260
Weiss 2007	Insomnia	13/79
Wigal 2013	Insomnia	9/39
Wigal 2015	Insomnia	24/200
Wilens 2005	Insomnia	81/229
Wilens 2006	Insomnia	16/220
Wilens 2008	Insomnia	25/127
Yatsuga 2014	Insomnia	4/50
Yildiz 2010	Difficulty sleeping	15/47
Yildiz 2011	Insomnia	7/11
Zarinara 2010	Insomnia	10/18
Zelnik 2015	Insomnia	31/128
Zeni 2007	Insomnia	21/106
Zheng 2011	Insomnia	145/1154
Zheng 2015	Insomnia	3/123
Çetin 2015	Insomnia	5/61
Depression
Atzori 2009	Vegetative symptoms	4/134
Cherland 1999	Mood symptoms or mood‐congruent psychotic symptoms	11/98
Döpfner 2011a, OBSEER	Depressed mood	13/777
Grcevich 2001	Depression	1/75
Haertling 2015	Depression	1/262
Kratochvil 2002	Depression	2/25
Na 2013	Depression	9/103
Song 2012	Depression	5/116
Valdizán Usón 2013	Depressive symptoms	7/689
Weiss 2007	Depression	5/79
Wilens 2005	Depression	6/407
Yildiz 2010	Depressive symptoms	4/47
Yildiz 2011	Depression	3/11
Disturbed sleep
Abbas 2006	Sleeping problems	4/90
Abbasi 2011	Trouble sleeping	10/20
Arabgol 2015	Disturbed sleep	4/15
Arnold 2010	Insomnia	9/150
Blader 2010	Early waking	6/65
Efron 1997	Trouble sleeping	79/123
Findling 2009	Insomnia	29/157
Galland 2010	Restless sleep	14/27
Gau 2008	Poor sleep quality	37/607
Haertling 2015	Sleep disorder	1/239
Hammerness 2009	Insomnia	7/57
Hazell 2003	Nightmares	8/10
Işeri 2007	Sleep problems	5/20
Kim 2010	Insomnia	6/27
Kim 2011	Poor sleep	8/97
Mohammadi 2004	Disturbed sleep	4/11
Montañés‐Rada 2012	Insomnia	5/40
Perera 2010	Poor sleep	13/102
Remschmidt 2005	Delayed sleep	1/105
Steele 2006	Sleep disorder	3/60
Su 2015	Poor quality sleep	1/205
Valdizán Usón 2013	Sleep disorder	33/689
Yildiz 2011	Insomnia	7/11
Zheng 2015	Poor sleep quality	3/149
Dizziness
Abbasi 2011	Dizziness	8/20
Blader 2010	Dizzy	1/65
Chou 2012b	Dizziness	9/230
Cortese 2015	Dizziness	5/1426
Davari‐Ashtiani 2010	Dizziness	0/16
Döpfner 2011b	Dizziness	1/113
Efron 1997	Dizziness	15/123
El‐Fiky 2014	Dizziness	0/31
Green 2011	Dizziness	3/14
Haertling 2015	Dizziness	1/239
Hammerness 2009	Dizziness	4/57
Hazell 2003	Dizziness	7/9
Jafarinia 2012	Dizziness	1/20
Kemner 2005 (FOCUS)	Dizziness	7/850
Kim 2010	Dizziness	2/27
Lee 2007	Dizziness	5/110
Li 2011	Dizziness	4/34
Maia 2008	Dizziness	3/39
McCracken 2016	Dizziness	6/61
Mohammadi 2004	Dizziness	2/11
Mohammadi 2012b	Dizziness	2/20
Na 2013	Dizziness	11/103
Pierce 2010	Dizziness	2/71
Sahin 2014	Dizziness	6/30
Shang 2015	Dizziness	1/66
Song 2012	Dizziness	15/116
Wang 2007	Dizziness	12/166
Wilens 2005	Dizziness	7/407
Yildiz 2010	Dizziness	2/47
Drowsiness
Barrickman 1995	Drowsiness	1/15
Efron 1997	Drowsiness	22/123
El‐Fiky 2014	Drowsiness	2/31
Garg 2014	Drowsiness	1/27
Gau 2006	Drowsiness	6/32
Germinario 2013	Drowsiness	1/9
Ghanizadeh 2012	Drowsiness	2/12
Green 2011	Drowsiness	2/14
Hazell 2003	Drowsiness	7/10
Kratochvil 2002	Somnolens	0/40
Lyon 2010	Drowsiness	2/10
Maia 2008	Drowsiness	1/39
Sahin 2014	Drowsiness	8/30
Song 2012	Somnolence	6/116
Wilens 2005	Somnolence	10/407
Wilens 2006	Somnolence	3/220
Yildiz 2011	Somnolence	1/11
Dysthymia
Haertling 2015	Dysphemia	1/239
Mohammadi 2004	Dysphemia	0/16
Emotional lability
Ardic 2014	Emotional change	22/101
Davari‐Ashtiani 2010	Emotional lability	0/16
Findling 2009	Emotional lability	5/157
Hammerness 2009	Moody	2/57
Kemner 2005 (FOCUS)	Emotional disturbance	5/850
Kordon 2011	Emotional lability	8/598
Kratochvil 2002	Emotional lability	2/25
Maayan 2009	Emotional lability	2/8
McCracken 2016	Affect lability	14/61
Silva 2004	Emotional lability	4/22
Steele 2006	Emotional lability	9/60
Warshaw 2010	Affect lability	18/260
Weiss 2007	Emotional lability	3/79
Wigal 2013	Affect lability	10/39
Wilens 2005	Emotional lability	1/229
Yildiz 2010	Emotional lability	12/47
Euphoria/hypomania
Blader 2010	Unusually happy	12/65
El‐Fiky 2014	Euphoria	0/31
Gau 2006	Euphoric	3/32
Grcevich 2001	Agitation	2/75
Green 2011	Unusually happy	0/14
Kim 2010	Euphoria	1/27
Maia 2008	Euphoric	2/39
Mohammadi 2004	Euphoria or hypomania	0/16
Sahin 2014	Ecstasy	8/30
Asthenia and fatigue
Abbasi 2011	Fatigue	13/20
Arnold 2004	Asthenia	7/76
Blader 2010	Tired + low energy	4/65
Davari‐Ashtiani 2010	Tiredness	0/16
Dittmann 2014	Fatigue	0/195
Döpfner 2011b	Fatigue	0/113
Galland 2010	Daytime sleepiness	2/27
Garg 2014	Fatigue	2/27
Haertling 2015	Asthenia	1/239
Kemner 2005 (FOCUS)	Fatigue	3/850
Lee 2007	Fatigue	5/110
McCracken 2016	Fatigue	5/61
Mohammadi 2010	Fatigue	4/19
Na 2013	Fatigue	13/103
Pierce 2010	Fatigue	3/71
Sangal 2006	Fatigue	3/79
Steele 2006	Fatigue	7/60
Wang 2007	Fatigue	5/166
Wigal 2015	Fatigue	10/200
Headache
Abbas 2006	Headache	2/90
Abbasi 2011	Headache	12/20
Akhondzadeh 2003	Headache	6/10
Akhondzadeh 2004	Headache	9/20
Altin 2013	Headache	3/25
Amiri 2008	Headache	7/27
Ardic 2014	Headache	16/101
Arnold 2004	Headache	24/76
Arnold 2010	Headache	12/150
Atzori 2009	Headache	6/129
Barrickman 1995	Headache	1/15
Berek 2011	Headache	15/762
Blader 2010	Headache	1/65
Chou 2012b	Headache	7/230
Cortese 2015	Headache	62/1426
Dirksen 2002	Headache	17/287
Dittmann 2014	Headache	1/195
Döpfner 2011a, OBSEER	Headache	9/777
Döpfner 2011b	Headache	8/113
Efron 1997	Headache	30/123
El‐Fiky 2014	Headache	4/31
Findling 2009	Headache	54/157
Galland 2010	Morning headache	3/27
Garg 2014	Headache	4/27
Gau 2006	Headache	11/32
Gau 2008	Headache	21/607
Gerwe 2009	Headache	15/263
Goez 2012	Headache	4/28
Golubchik 2011	Headache	2/9
Green 2011	Headache	8/14
Greenberg 1987	Headache	1/49
Greenhill 1983	Headache	2/7
Gucuyener 2003	Headache	14/119
Guerreiro 1996	Headache	2/22
Haertling 2015	Headache	2/239
Hammerness 2009	Headache	14/57
Hazell 2003	Headache	8/10
Hulvershorn 2012	Headache	1/25
Işeri 2007	Headache	5/20
Jafarinia 2012	Headache	10/20
Jung 2007	Headache	8/83
Kemner 2005 (FOCUS)	Headache	33/850
Khajehpiri 2014	Headache	7/71
Kim 2010	Headache	3/27
Kordon 2011	Headache	14/541
Kratochvil 2002	Headache	13/25
Lee 2007	Headache	16/110
Lee 2014	Headache	6/100
Li 2011	Headache	3/34
Maayan 2009	Headache	1/11
Maia 2008	Headaches	4/39
Mayes 1994	Headache	3/63
McCracken 2016	Headache	23/61
Miller‐Horn 2008	Headache	1/23
Mohammadi 2004	Headache	7/11
Mohammadi 2010	Headache	15/19
Mohammadi 2012a	Headache	4/23
Mohammadi 2012b	Headache	9/20
Na 2013	Headache	32/103
Perera 2010	Headache	13/102
Peyre 2012a	Headache	43/121
Pierce 2010	Headache	6/71
Remschmidt 2005	Headache	2/105
Sahin 2014	Headache	14/30
Sangal 2006	Headache	12/79
Schulz 2010	Headache	9/145
Shang 2015	Headache	14/66
Silva 2004	Headache	4/22
Song 2012	Headache	30/116
Steele 2006	Headache	14/60
Su 2015	Headache	4/205
Tasdelen 2015	Headache	1/17
Thorell 2009	Headache	6/79
Valdizán Usón 2004	Headache	2/155
Valdizán Usón 2013	Headache	11/689
Wang 2007	Headache	16/166
Warshaw 2010	Headache	23/260
Weiss 2007	Headache	10/79
Wigal 2013	Headache	7/39
Wigal 2015	Headache	35/200
Wilens 2005	Headache	123/229
Wilens 2006	Headache	25/220
Wilens 2008	Headache	27/127
Yatsuga 2014	Headache	7/50
Yildiz 2010	Headache	27/47
Yildiz 2011	Headache	3/11
Zarinara 2010	Headache	11/18
Zelnik 2015	Headache	107/128
Zheng 2011	Headache	143/1154
Çetin 2015	Headache	2/61
Increased need to sleep
Blader 2010	Trouble waking	1/65
Galland 2010	Hard to wake + difficult to wake	14/27
Mohammadi 2004	Increased need to sleep	5/11
Mohammadi 2012a	Sleepiness	4/23
Na 2013	Somnolence	8/103
Pierce 2010	Somnolence	2/71
Wang 2007	Somnolence	6/166
Zarinara 2010	Somnolence	3/19
Involuntary movements
Balázs 2011	Involuntary movements after methylphenidate treatment	9/34
Berek 2011	Muscle contractions, involuntary	34/762
Blader 2010	Shaking + tremor	4/65
Galland 2010	Restless legs	2/27
Kordon 2011	Muscle contraction, involuntary	13/541
Kratochvil 2002	Hyperkinesia	2/25
Lee 2014	Convulsion	4/100
Irritability
Abbasi 2011	Irritability	18/20
Amiri 2008	Irritability	6/27
Ardic 2014	Irritability	30/101
Atzori 2009	Irritability	9/129
Barrickman 1995	Irritability	1/15
Blader 2010	Irritability	16/65
Cortese 2015	Irritabillity	67/1426
Efron 1997	Irritable	100/123
El‐Fiky 2014	Irritable	6/31
Findling 2009	Irritability	20/157
Garg 2014	Irritability	2/27
Gau 2006	Irritable	7/32
Green 2011	Irritability	2/14
Greenhill 1983	Irritability	4/7
Hazell 2003	Irritability	3/10
Işeri 2007	Irritability	3/20
Jensen 1999 (MTA)	Irritability	10/245
Johnson 2013	Irritability	23/45
Kemner 2005 (FOCUS)	Irritability	7/850
Khajehpiri 2014	Irritability	25/71
Maayan 2009	Irritability	1/8
Maia 2008	Irritability	10/39
Mayes 1994	Irritability	18/63
McCracken 2016	Irritability	12/61
Mohammadi 2012a	Irritability	10/23
Na 2013	Irritable	16/121
Sangal 2006	Irritability	12/79
Silva 2004	Irritability	3/22
Song 2012	Irritability	9/116
Tasdelen 2015	Irritability	5/17
Valdizán Usón 2004	Irritability	4/155
Wang 2007	Irritability	10/166
Warshaw 2010	Irritability	15/260
Wigal 2015	Irritability	11/200
Yildiz 2010	Irritability	16/47
Nervousness
Arabgol 2015	Nervousness	5/15
Berek 2011	Nervousness	17/762
Jafarinia 2012	Nervousness	5/20
Kordon 2011	Nervousness	13/541
Kratochvil 2002	Nervousness	4/25
Lee 2007	Nervousness	2/110
Mohammadi 2010	Nervousness	14/19
Na 2013	Nervousness	7/103
Song 2012	Nervousness	9/116
Steele 2006	Nervousness	9/60
Weiss 2007	Nervousness	14/79
Wilens 2006	Nervousness	6/220
Yildiz 2011	Nervousness	9/11
Çetin 2015	Nervousness	2/61
Nightmares
Blader 2010	Nightmares	2/65
El‐Fiky 2014	Nightmares	1/31
Gau 2006	Nightmares	8/32
Green 2011	Nightmares	1/14
Khajehpiri 2014	Nightmares	3/71
Kim 2010	Nightmares	1/27
Maia 2008	Nightmares	1/31
Sahin 2014	Nightmares	4/30
Silva 2004	Nightmares	1/22
Song 2012	Nightmares	10/116
Tomás Vila 2010b	Nightmares	12/114
Restlessness and agitation
Blader 2010	Restlessness	3/65
Davari‐Ashtiani 2010	Restlessness	4/16
Dittmann 2014	Agitation	1/195
Döpfner 2011b	Restlessness	1/113
Grcevich 2001	Agitation	2/75
Haertling 2015	Agitation	2/239
Khajehpiri 2014	Agitation	16/71
Lee 2014	Agitation	6/100
Mohammadi 2010	Restlessness	8/19
Perera 2010	Restlessness	5/102
Sahin 2014	Restlessness	9/30
Steele 2006	Agitation	8/60
Valdizán Usón 2013	Physical activity modifications	16/689
Zarinara 2010	Restlessness	5/19
Sadness
Abbasi 2011	Sadness	9/20
Amiri 2008	Sadness	6/27
Barrickman 1995	Low mood	1/15
Blader 2010	Crying + sadness	17/65
Davari‐Ashtiani 2010	Sadness	3/16
Efron 1997	Sadness or unhappiness	69/123
El‐Fiky 2014	Sad	3/31
Garg 2014	Sadness	0/27
Gau 2006	Sadness	14/32
Green 2011	Sadness	7/14
Hammerness 2009	Sad	1/57
Hazell 2003	Sad	5/10
Işeri 2007	Sadness	2/20
Jensen 1999 (MTA)	Tearfulness	6/245
Johnson 2013	Sadness	18/45
Kemner 2005 (FOCUS)	Crying	13/850
Maia 2008	Sad	4/31
Mohammadi 2010	Sadness	4/19
Mohammadi 2012a	Sadness	2/23
Perera 2010	Sadness	13/102
Sahin 2014	Sadness	9/30
Stares
Blader 2010	Stares into space	3/65
El‐Fiky 2014	Stares a lot	8/31
Hazell 2003	Stares	6/10
Maia 2008	Stares a lot or daydreams	7/31
Excessive talking
Blader 2010	Overly talkative	8/65
Hazell 2003	Talks too much	5/10
Khajehpiri 2014	Speaking more	6/71
Taciturnity ('talking too little')
Blader 2010	Less talkative	4/65
El‐Fiky 2014	Talk less	2/31
Green 2011	Talking little	6/14
Maia 2008	Talk less	9/31
Tics
Ardic 2014	Tics	3/101
Atzori 2009	Tics	2/129
Blader 2010	Tics	3/65
Cortese 2015	Tics	27/1426
Davari‐Ashtiani 2010	Tics	1/16
Döpfner 2011a, OBSEER	Tics	100/777
Döpfner 2011b	Tics	1/113
Efron 1997	Tics	35/123
El‐Fiky 2014	Tics or involuntary movements	0/31
Findling 2009	Tics	0/157
Gau 2006	Tics	6/32
Germinario 2013	Tics	1/9
Golubchik 2011	Motor tics exacerbation	1/9
Grcevich 2001	Motor tics	1/75
Green 2011	Tics	0/14
Gucuyener 2003	Motor tics	2/119
Işeri 2007	Tics	3/20
Johnson 2013	Tics (new onset)	1/45
Khajehpiri 2014	Tics	18/71
Kim 2010	Tics	3/27
Kim 2011	Tics	19/97
Lakic 2012	Tics	3/61
Lee 2007	Tics	6/110
Miller‐Horn 2008	Tics	2/23
Mohammadi 2004	Tics	0/11
Mohammadi 2012a	Tics	1/23
Mohammadi 2012b	Tics	4/20
Remschmidt 2005	Tics	7/89
Sahin 2014	Tics	2/30
Shang 2015	Tics	1/66
Song 2012	Tics	7/116
Su 2015	Tourette disorder	6/205
Tasdelen 2015	Tics	1/17
Valdizán Usón 2004	Tics	1/155
Varley 2001	Tics	31/374
Wilens 2005	Twitching	40/229
Yildiz 2010	Tics	1/47
Yildiz 2011	Tics	2/11
Çetin 2015	Tics	1/16
Isolation and lack of interest in others
Blader 2010	Lack of interest	6/65
Efron 1997	Uninterested in others	39/123
El‐Fiky 2014	Uninterested in others	2/31
Green 2011	Uninterested	4/14
Hazell 2003	Uninterested	6/10
Khajehpiri 2014	Isolation	6/71
Maia 2008	Uninterested others	6/31
Perera 2010	Social withdrawal	6/102
Sahin 2014	Being in own world	5/30
Yildiz 2010	Introversion (maybe isolation)	5/47
'Zombie like' demeanour
Davari‐Ashtiani 2010	Zombie like	3/16
Jensen 1999 (MTA)	Zombie like	18/245
Wilens 2005	Apathy	4/407
Somnolence
Chou 2012b	Somnolence	1/230
Khajehpiri 2014	Somnolence	5/71
McCracken 2016	Somnolence	3/61
Na 2013	Somnolence	8/103
Shang 2015	Somnolence	1/66
Wang 2007	Somnolence	6/166
Weiss 2007	Somnolence	7/79
Wilens 2005	Somnolence	1/229
Yildiz 2011	Somnolence	1/11
Obsession
Cortese 2015	Obsessive behaviour	6/1426
Khajehpiri 2014	Obsession	1/71
Çetin 2015	Obsession	2/32
Mood disorder
Cortese 2015	Mood disorder	49/1426
Haertling 2015	Emotional disorder of childhood	1/239
Confusional state
Haertling 2015	Confusional state	1/262
Zelnik 2015	Sense of dopiness	13/128
Sleep disorder
Dittmann 2014	Sleep disorder	6/195
Döpfner 2011a, OBSEER	Sleep disorder	9/777
Su 2015	Sleep disorder	26/239
Propensity to cry
El‐Fiky 2014	Prone to cry	4/31
Sahin 2014	Sudden crying	12/30
Sedation
McCracken 2016	Sedation	4/61
Mohammadi 2010	Sedation	4/19
Daytime sleepiness
Galland 2010	Daytime sleepiness	2/27
Tomás Vila 2010b	Datime sleepiness	2/114
Dysphoria
Atzori 2009	Dysphoria	2/134
Logorrhoea
Atzori 2009	Loggorrhoea	1/129
Impaired concentration
Berek 2011	Impaired concentration	14/822
Difficulty waking up
Galland 2010	Difficult to wake up	7/28
Urinary incontinence
Garg 2014	Urinary incontinence	1/32
Paralysis
Haertling 2015	Paralysis	1/239
Affective disorder
Haertling 2015	Affective disorder	1/239
Jumbled thoughts
Hammerness 2009	Jumbled thoughts	1/154
Bulimia
Khajehpiri 2014	Bulimia	5/71
Sleep late
Khajehpiri 2014	Sleeping late	22/71
Tooth grinding
Khajehpiri 2014	Tooth grinding	3/71
Tremor
Khajehpiri 2014	Tremor	2/71
Stuttering
Khajehpiri 2014	Stuttering	4/71
Flushing
Khajehpiri 2014	Flushing	9/71
Apathy
Kordon 2011	Apathy	6/541
Abnormal behaviour
Lee 2014	Abnormal behaviour	5/100
Stereotypies
Mohammadi 2004	Stereotypies	0/16
Quietness
Sahin 2014	Quietness	6/30
EEG changes
Schmidt 2002	Pathologic	25/124
Did not like themselves
Thorell 2009	Does not like him‐ or herself	10/79
Sleep walking
Tomás Vila 2010b	Sleep walking	2/114
Personality and behaviour disorders
Valdizán Usón 2013	Personality and behavior disorders	14/633
Vertigo
Yildiz 2011	Vertigo	3/11

Analysis 7.2

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 2 Central nervous system.

Ir a la figura de la revisión


Study	Symptom	Adverse events/total number of participants
Cough
Arnold 2004	Cough increased	7/76
Arnold 2010	Cough	5/150
Findling 2009	Cough	38/157
Kratochvil 2002	Cough increased	2/25
Pierce 2010	Cough	2/71
Sangal 2006	Cough	7/79
Wang 2007	Cough	10/166
Pharyngolaryngeal pain
Arnold 2010	Pharyngolaryngeal pain	5/150
Findling 2009	Pharyngolaryngeal pain	19/326
Pierce 2010	Pharyngolaryngeal pain	3/71
Upper respiratory tract infection
Findling 2009	Upper respiratory tract infection	40/157
Pierce 2010	Upper respiratory tract infection	2/71
Wang 2007	Upper respiratory tract infection	11/166
Wigal 2015	Upper respiratory tract infection	13/200
Wiguna 2012	Upper respiratory tract infection	5/20
Tachycardia
Blader 2010	Heart races	2/65
Cortese 2015	Tachycardia	24/1426
Findling 2009	Tachycardia	3/326
Jafarinia 2012	Tachycardia	1/20
Kratochvil 2002	Tachycardia	2/25
Su 2015	Tachycardia	8/239
Abnormal ECG
Findling 2009	Abnormal ECG	1/326
Findling 2010	Abnormal ECG	30/162
Nasal congestion
Findling 2009	Nasal congestion	18/157
Maayan 2009	Nasal congestion	1/11
Sangal 2006	Nasal congestion	10/79
Palpitation
Mohammadi 2004	Palpation	3/11
Na 2013	Palpitations	8/103
Shang 2015	Palpation	1/66
Systolic blood pressure
Cho 2012	No difference	Non‐significant increase following methylphenidate
Döpfner 2011b	No difference	‐
Findling 2009	Increased	The proportion of participants with a systolic blood pressure above the upper limit of normal (> 123 mmHg) ranged from 1% to 10%, whereas 1.5% had an above normal systolic blood pressure at baseline
Gadow 1995	Increased	‐
Germinario 2013	No difference	100.6 mmHg (SD = 12.3)
Gerwe 2009	No difference	Mean change from baseline: 0.1 mmHg (SD = 10.8)
Hazell 2003	Decreased	Drop in systolic blood pressure in 8/10 participants
Kim 2010	Decreased	113.8 mmHg (SD = 10.2)
Kratochvil 2002	Increased	102.2 mmHg (SD = 9.89)
Lamberti 2015	Increased	105.4 mmHg (SD = 10.3)
Maayan 2009	No difference	96.2 mmHg (SD = 14.0)
McCracken 2016	Increased	‐
Na 2013	Increased	‐
Song 2012	Increased	105.3 mmHg (SD = 12.6)
Wilens 2005	Increased	104.7 mmHg (SD = 8.10)
Winsberg 1982	Increased	103.1 mmHg (SD = no information)
Yildiz 2011	Decreased	97 mmHg (SD = 10.8)
Zheng 2011	No difference	96.6 mmHg (SD = 10.6)
Zheng 2015	No difference	No changes
Diastolic blood pressure
Cho 2012	No difference	Non‐significant, marginal increase after methylphenidate
Döpfner 2011b	Increased	69 mmHg (SD = 1.00)
Findling 2009	Decreased	‐
Germinario 2013	Decreased	63.2 mmHg (SD = 10.9)
Gerwe 2009	‐	‐
Hazell 2003	Decreased	Drop in diastolic blood pressure in 9/10 participants
Kim 2010	Decreased	75.2 mmHg (SD = 12.0)
Kratochvil 2002	Increased	63.5 mmHg (SD = 7.90)
Lamberti 2015	Increased	59.2 mmHg (SD = 7.10)
Maayan 2009	No difference	61.4 mmHg (SD = 13.7)
McCracken 2016	Increased	‐
Na 2013	Increased	‐
Song 2012	Increased	66.9 mmHg (SD = 10.1)
Yildiz 2011	Decreased	63.5 mmHg (SD = 12.0)
Zheng 2011	Increased	64.6 mmHg (SD = 7.51)
Zheng 2015	No change	‐
Pulse rate
Cho 2012	Increased	‐
Döpfner 2011b	No difference	79 beats/min (SD = 1.00)
Germinario 2013	Decreased	79.9 beats/min (SD = 12.9)
Ilgenli 2007	No difference	88 beats/min (SD = 13.80)
Kim 2010	No difference	87.5 beats/min (SD = 6.10)
Kim 2015a	Increased	86.4 beats/min (SD = 11.2)
Kratochvil 2002	Increased	80.4 beats/min (SD = 9.70)
Lamberti 2015	Increased	80.5 beats/min (SD = 15.5)
Maayan 2009	Decreased	95.5 beats/min (SD = 16.0)
McCracken 2016	Increased	‐
Na 2013	Increased	75.57 beats/min (SD = 7.33)
Yildiz 2011	Increased	80.8 beats/min (SD = 9.80)
Zheng 2011	No difference	82.5 beats/min (SD = 7.81)
Zheng 2015	No difference	82.5 beats/min (SD = 7.81)
Özcan 2004	Decreased	148.2 beats/min (SD = 29.70)
ECG‐QT
Cho 2012	Non‐significant change in QT and QRS	‐
Germinario 2013	‐	After 24 months, out of 77 patients treated with methylphenidate: 8 (10.4%) with altered ECG (electrocardiogram) at 24 months 11 (29.0%) with sinus bradycardia 12 (31.6%) with sinus tachycardia 6 (15.8%) with lengthened QTc
Ilgenli 2007	Minimum QT of 317.00 (23.3) Maximum QT of 373.7 (21.8)	After 2 hours: Minimum QT of 322.3 (21.6) Maximum QT of 361.8 (29.0)
Lamberti 2015	QTc of 407.6 (12.4)	After 2 hours: QTc of 409.8 (12.0)
Cold fingers
Khajehpiri 2014	Cold fingers	13/71
Sweating
Khajehpiri 2014	Sweating	6/71
Hypertension
Cortese 2015	Hypertension	8/1426
Hypotension
Cortese 2015	Hypotension	3/1426
Respiratory, thoracic and mediastinal disorders
Haertling 2015	Respiratory, thoracic, and mediastinal disorders	1/239
Proportion of patients with micro‐nucleated (Mn) peripheral lymphocytes
Walitza 2009	(MN‐Cells/1000 Cells mean)	Baseline: 4.90 (SD = 4.00) 6 months: 4.50 (SD = 3.50)

Analysis 7.3

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 3 Cardiovascular and respiratory system.

Ir a la figura de la revisión


Study	Symptom	Adverse events/total number of participants
Abdominal pain
Abbasi 2011	Abdominal pain	8/20
Akhondzadeh 2003	Abdominal pain	3/10
Akhondzadeh 2004	Abdominal pain	4/20
Amiri 2008	Abdominal pain	7/27
Ardic 2014	Stomach ache	16/101
Arnold 2004	Abdominal pain	15/89
Arnold 2010	Abdominal pain	7/150
Atzori 2009	Stomach pain	3/129
Barrickman 1995	Stomach ache	1/15
Berek 2011	Abdominal pain	12/762
Blader 2010	Abdominal pain	6/65
Chou 2012b	Abdominal pain	12/230
Cortese 2015	Abdominal pain	22/1426
Davari‐Ashtiani 2010	Abdominal pain	1/16
Dirksen 2002	Stomach ache	14/287
Dittmann 2014	Upper abdominal pain	4/195
Döpfner 2011a, OBSEER	Gastrointestinal pain	9/777
Döpfner 2011b	Gastrointestinal pain	6/113
Efron 1997	Stomach aches	40/123
El‐Fiky 2014	Stomach aches	9/31
Findling 2009	Abdominal pain	27/157
Garg 2014	Abdominal pain	3/27
Gau 2006	Stomach aches	8/32
Gerwe 2009	Abdominal pain	10/306
Golubchik 2011	Abdominal pain	1/9
Grcevich 2001	Stomach ache	2/75
Green 2011	Stomach aches	9/34
Greenhill 1983	Stomach aches	4/7
Gucuyener 2003	Stomach ache	14/119
Haertling 2015	Abdominal pain	4/239
Hammerness 2009	Stomach ache	2/57
Hazell 2003	Stomach pain	6/10
Işeri 2007	Abdominal pain	3/20
Jafarinia 2012	Abdominal pain	6/20
Kemner 2005 (FOCUS)	Abdominal pain	33/850
Khajehpiri 2014	Abdominal pain	9/71
Kim 2010	Abdominal pain	1/27
Kordon 2011	Abdominal pain	11/541
Kratochvil 2002	Abdominal pain	7/25
Lee 2007	Abdominal pain	6/110
Li 2011	Abdominal pain	12/34
Lyon 2010	Stomach discomfort	2/10
Maayan 2009	Gastrointestinal pain	2/8
Maia 2008	Stomach ache	2/31
McCracken 2016	Abdominal pain	28/61
Mohammadi 2004	Abdominal pain	0/11
Mohammadi 2010	Abdominal pain	8/19
Mohammadi 2012a	Stomach ache	5/23
Mohammadi 2012b	Abdominal pain	5/20
Na 2013	Stomach ache (abdominal pain)	19/103
Perera 2010	Abdominal pain	15/102
Peyre 2012a	Abdominal pain	7/121
Pierce 2010	Abdominal pain	3/71
Remschmidt 2005	Abdominal pain	3/89
Sahin 2014	Abdominal pain	7/30
Sangal 2006	Abdominal pain	4/79
Schulz 2010	Abdominal pain	9/145
Shang 2015	Abdominal pain	4/66
Silva 2004	Stomach ache	3/22
Song 2012	Abdominal pain	20/116
Steele 2006	Abdominal pain	10/72
Su 2015	Abdominal pain	10/205
Tasdelen 2015	Abdominal pain	4/17
Thorell 2009	Stomach aches	2/79
Valdizán Usón 2004	Abdominal pain	1/155
Wang 2007	Abdominal pain	15/166
Warshaw 2010	Abdominal pain	9/260
Weiss 2007	Abdominal pain	5/79
Wigal 2013	Abdominal pain	17/39
Wigal 2015	Abdominal pain	29/200
Wilens 2005	Abdominal pain	45/229
Wilens 2006	Abdominal pain	9/220
Wilens 2008	Abdominal pain	15/127
Yildiz 2010	Stomach ache	6/47
Yildiz 2011	Abdominal pain	3/11
Zarinara 2010	Abdominal pain	3/18
Zelnik 2015	Abdominal pain	36/128
Zheng 2011	Stomach ache	140/1154
Çetin 2015	Stomach ache	3/61
Constipation
Ardic 2014	Constipation	10/101
Khajehpiri 2014	Constipation	4/71
Mohammadi 2004	Constipation	2/11
Shang 2015	Constipation	1/66
Decreased appetite
Abbas 2006	Loss of appetite	2/90
Abbasi 2011	Loss of appetite	12/20
Akhondzadeh 2003	Decreased appetite	5/10
Akhondzadeh 2004	Decreased appetite	8/20
Altin 2013	Decreased appetite	27/221
Amiri 2008	Decreased appetite	26/27
Ardic 2014	Decreased appetite	47/101
Arnold 2010	Loss of appetite	11/150
Atzori 2009	Decreased appetite	27/129
Blader 2010	Decreased appetite	13/65
Chazan 2011	Decreased appetite	118/205
Chou 2012b	Decreased appetite	95/230
Cortese 2015	Decreased appetite	213/1426
Coşkun 2010	Decreased appetite	3/7
Davari‐Ashtiani 2010	Loss of appetite	11/16
Dirksen 2002	Decreased appetite	8/287
Dittmann 2014	Lack of appetite	5/195
Döpfner 2011a, OBSEER	Decreased appetite	8/777
Döpfner 2011b	Decreased appetite	3/113
Efron 1997	Poor appetite	69/123
El‐Fiky 2014	Decreased appetite	12/31
Famularo 1987	Decreased appetite	1/10
Findling 2009	Loss of appetite	81/157
Garg 2014	Decreased appetite	14/27
Gau 2006	Decreased appetite	19/32
Gau 2008	Loss of appetite	128/607
Germinario 2013	Decreased appetite	5/9
Gerwe 2009	Loss of appetite	83/263
Ghanizadeh 2013	Decreased appetite	1/26
Golubchik 2011	Decrease in appetite	4/9
Grcevich 2001	Appetite suppression	5/75
Green 2011	Poor appetite	13/14
Gucuyener 2003	Loss of appetite	23/119
Hammerness 2009	Decreased appetite	19/57
Hazell 2003	Appetite suppression	7/10
Hulvershorn 2012	Decreased appetite	6/25
Işeri 2007	Loss of appetite	3/20
Jafarinia 2012	Decreased appetite	11/20
Johnson 2013	Reduced appetite	26/45
Jung 2007	Appetite loss	16/83
Kemner 2005 (FOCUS)	Decreased appetite	49/850
Kim 2010	Decreased appetite	9/27
Kim 2011	Poor appetite	22/97
Kratochvil 2002	Anorexia	6/25
Lakic 2012	Loss of appetite	68/68
Lee 2007	Decreased appetite	31/110
Li 2011	Decreased appetite	13/34
Maayan 2009	Decreased appetite	7/11
Maia 2008	Barkley decreased appetite	19/31
Mayes 1994	Decreased appetite	14/63
McCracken 2016	Decreased appetite	31/61
Miller‐Horn 2008	Decreased appetite	2/23
Mohammadi 2004	Loss of appetite	4/11
Mohammadi 2010	Decreased appetite	17/19
Mohammadi 2012a	Loss of appetite	11/23
Mohammadi 2012b	Decreased appetite	9/20
Na 2013	Decreased appetite	66/103
Perera 2010	Loss of appetite	51/102
Peyre 2012a	Reduced appetite	9/121
Pierce 2010	Decreased appetite	7/71
Poulton 2003	Decreased appetite	12/13
Sahin 2014	Loss of appetite	21/30
Sangal 2006	Decreased appetite	19/79
Shang 2015	Decreased appetite	36/66
Silva 2004	Decreased appetite	7/22
Steele 2006	Decreased appetite	17/60
Su 2015	Decreased appetite	72/205
Tasdelen 2015	Loss of appetite	9/17
Thorell 2009	Loss of appetite	21/79
Valdizán Usón 2004	Loss of appetite	9/155
Valdizán Usón 2013	Appetite and nutrition disorders	68/689
Wang 2007	Decreased appetite	32/166
Warshaw 2010	Decreased appetite	77/260
Wigal 2013	Decreased appetite	21/39
Wigal 2015	Decreased appetite	38/200
Wilens 2005	Appetite suppression	55/229
Wilens 2008	Decreased appetite	35/127
Yalcin 2014	Decreased appetite	28/40
Yatsuga 2014	Decreased appetite	3/50
Yildiz 2010	Loss of appetite	27/47
Zarinara 2010	Decreased appetite	7/18
Zeni 2007	Decreased appetite	53/106
Zheng 2011	Loss of appetite	552/1154
Zheng 2015	Loss of appetite	16/123
Decreased weight
Abbas 2006	Weight loss	2/90
Abbasi 2011	Weight loss	6/20
Amiri 2008	Weight loss	7/27
Ardic 2014	Weight loss	25/101
Arnold 2004	Weight loss	3/76
Arnold 2010	Decreased weight	5/171
Berek 2011	Weight decrease	10/762
Cortese 2015	Weight loss	37/1426
Davari‐Ashtiani 2010	Weight loss	4/16
Dittmann 2014	Weight decrease	3/195
Döpfner 2011b	Weight loss	0/113
Findling 2009	Decreased weight	33/157
Grcevich 2001	Weight loss	3/75
Haertling 2015	Weight decreased	3/239
Işeri 2007	Weight loss	2/20
Johnson 2013	Weight loss	9/45
Kordon 2011	Weight decrease	8/541
Kratochvil 2002	Weight loss	2/25
Lakic 2012	Moderate loss of body weight	68/68
Mohammadi 2012a	Weight loss	9/23
Remschmidt 2005	Weight decrease	1/105
Sahin 2014	Weight loss	20/30
Song 2012	Weight loss	4/116
Warshaw 2010	Decreased weight	9/260
Wilens 2005	Weight loss	8/407
Yildiz 2010	Weight loss	12/47
Yildiz 2011	Weight loss	5/11
Çetin 2015	Weight loss	1/16
Diarrhoea
Abbasi 2011	Diarrhoea	5/20
Blader 2010	Diarrhoea	2/65
Hammerness 2009	Diarrhoea	3/57
Khajehpiri 2014	Diarrhoea	3/71
Kordon 2011	Diarrhoea	7/541
Kratochvil 2002	Diarrhoea	1/25
Mohammadi 2004	Diarrhoea	0/11
Mohammadi 2010	Diarrhoea	1/19
Dry mouth
Abbasi 2011	Dry mouth	8/20
Amiri 2008	Dry mouth	10/27
Blader 2010	Dry mouth	2/65
Davari‐Ashtiani 2010	Dry mouth	0/16
Işeri 2007	Dry mouth	1/20
Mohammadi 2004	Dry mouth	3/11
Mohammadi 2010	Dry mouth	6/19
Mohammadi 2012a	Dry mouth	3/23
Mohammadi 2012b	Dry mouth	3/20
Gastrointestinal adverse events
Dittmann 2014	Gastrointestinal disorders	6/247
Gau 2008	Gastrointestinal upset	36/607
Valdizán Usón 2013	Gastrointestinal symptomatology	9/633
Nausea
Abbasi 2011	Nausea	5/20
Akhondzadeh 2003	Nausea	2/14
Akhondzadeh 2004	Nausea	3/20
Amiri 2008	Nausea	4/27
Ardic 2014	Nausea	14/101
Arnold 2004	Nausea	7/76
Barrickman 1995	Nausea	1/18
Chou 2012b	Nausea	15/230
Dittmann 2014	Nausea	2/195
Döpfner 2011a, OBSEER	Nausea	9/777
Döpfner 2011b	Nausea	1/113
Findling 2009	Nausea	20/157
Garg 2014	Nausea	1/27
Ghanizadeh 2013	Nausea + vomiting	1/26
Gucuyener 2003	Nausea	11/119
Guerreiro 1996	Nausea	1/22
Haertling 2015	Nausea	4/239
Hammerness 2009	Nausea	4/57
Işeri 2007	Nausea	1/20
Kemner 2005 (FOCUS)	Nausea	9/850
Khajehpiri 2014	Nausea	4/71
Kim 2010	Nausea	1/27
Kordon 2011	Nausea	10/541
Kratochvil 2002	Vomiting + nausea + dyspepsia	4/25
Lee 2007	Nausea	5/110
Lee 2014	Nausea	5/100
Li 2011	Nausea	16/34
Mohammadi 2004	Nausea	0/11
Mohammadi 2010	Nausea	4/19
Na 2013	Nausea	32/103
Pierce 2010	Nausea	3/71
Schulz 2010	Nausea	8/145
Song 2012	Nausea	9/116
Su 2015	Nausea	11/205
Tasdelen 2015	Nausea	1/17
Wang 2007	Nausea	17/166
Warshaw 2010	Nausea	13/260
Wilens 2005	Nausea	7/407
Yildiz 2010	Nausea	9/47
Yildiz 2011	Nausea	5/11
Zarinara 2010	Nausea	5/18
Upset stomach
Arnold 2004	Dyspepsia	6/89
Hulvershorn 2012	Upset stomach	4/25
Na 2013	Dyspepsia	13/103
Vomiting
Arnold 2004	Vomiting	3/76
Dittmann 2014	Vomiting	1/195
Findling 2009	Vomiting	23/157
Jafarinia 2012	Vomiting	3/20
Kemner 2005 (FOCUS)	Vomiting	11/850
Lee 2007	Vomiting	8/110
Lee 2014	Vomiting	5/100
Maayan 2009	Vomiting	1/8
Mohammadi 2010	Vomiting	2/19
Mohammadi 2012a	Vomiting	3/23
Mohammadi 2012b	Vomiting	2/20
Na 2013	Vomiting	7/103
Shang 2015	Vomiting	5/66
Silva 2004	Vomiting	6/22
Su 2015	Vomiting	9/205
Valdizán Usón 2004	Vomiting	2/155
Wang 2007	Vomiting	6/166
Wilens 2005	Vomiting	6/407
Yildiz 2011	Vomiting	1/11
Zarinara 2010	Vomiting	4/18
Dyspepsia
Arnold 2004	Dyspepsia	6/76
Cortese 2015	Dyspepsia	9/1426
Gastroenteritis
Arnold 2004	Gastroenteritis	0/76
Wigal 2015	Gastroenteritis	4/200
Increased appetite
Blader 2010	Increased appetite	1/65
Xerostomia
Khajehpiri 2014	Xerostomia	12/71

Analysis 7.4

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 4 Gastrointestinal system.

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Study	Symptom	Adverse events/total number of participants
Chest pain
Arnold 2004	Chest pain	0/76
Hammerness 2009	Chest pain	2/57
Shang 2015	Chest pain	1/66
Height
Jensen 1999 (MTA)	No difference	‐
Kim 2010	Increased from baseline	128.7 cm (SD = 9.10)
Mohammadi 2012a	Increased from baseline	133.8 cm (SD = 14.81)
Vincent 1990	No difference	158.7 cm (SD = 10.2)
Wiguna 2012	Increased from baseline	0.55 cm (SD = no information)
Yalcin 2014	Increased from baseline	134.6 cm (SD = 12.32)
Weight
Davari‐Ashtiani 2010	Increased from baseline	Weight gain in 1/16 participants
Germinario 2013	Increased from baseline	38.4 kg (SD = 11.3)
Kim 2010	No difference	28.5 kg (SD = 6.40)
Kratochvil 2002	No difference	40.7 kg (SD = 17.2)
Mohammadi 2012a	Increased from baseline	32.7 kg (SD = 14.7)
Vincent 1990	No difference	Observed weight: 47.9 kg (SD = 10.3) Expected weight: 48.1 kg (SD = 10.6)
Wiguna 2012	Decreased from baseline	36.2 kg (SD = 11.9)
Yalcin 2014	Increased from baseline	Weight gain in 15/33 participants
BMI
Gerwe 2009	No difference	Mean change from baseline: −0.3 kg/m² (SD = 0.70)
Mohammadi 2012a	No difference	18.2 kg/m² (SD = 4.74)
Yalcin 2014	No difference	Methylphenidate group: 18.1 kg/m² (SD = 2.76) Untreated group: 17.8k kg/m² (SD = 2.71)
Height z score
Bereket 2005	Decreased from baseline	‐
Germinario 2013	Decreased from baseline	Z score = 0.36 (SD = 1.21)
Moungnoi 2011	Decreased from baseline	Z score = 0.09 (SD = no information)
Poulton 2003	Decreased from baseline	Z score = 0.26 (SD = 0.82)
Poulton 2012	Decreased from baseline	Z score = 0.34 (SD = 0.81)
Schertz 1996	Decreased from baseline	Z score = ‐0.1(SD = no information)
Spencer 1992	Decreased from baseline	Z score = ‐0.23 (SD = 0.42)
Weight z score
Bereket 2005	Decreased from baseline	0.2 (SD = 1.04)
Gerwe 2009	Decreased from baseline	0.26 kg (SD = 1.40)
Moungnoi 2011	Decreased from baseline	Z score = 0.01 (SD = no information)
Poulton 2003	Decreased from baseline	Z score = 0.44 (SD = 0.97)
Schertz 1996	Decreased from baseline	‐
BMI z score
Bereket 2005	No difference	After 14 months: Age‐adjusted SD = 0.71 Sex‐adjusted SD = 0.65
Dubnov‐Raz 2011	No difference	‐
Poulton 2012	No difference	‐
Increased mobility
Ardic 2014	Increased mobility	22/122
Bone mineral density
Lahat 2000	Quote: "There was no significant difference between serum calcium, phosphorus or bone‐specific alkaline phosphatase, urinary deoxypyridinoline, or bone mineral density in the two groups of children. No child deviated from his height percentile during the treatment period."	NA

Analysis 7.5

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 5 Musculoskeletal system.

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Study	Symptom	Adverse events/total number of participants
Nasopharyngitis
Arnold 2004	Rhinitis	5/76
Arnold 2010	Rhinitis	6/150
Döpfner 2011b	Rhinitis	2/113
Findling 2009	Rhinitis	24/157
Kratochvil 2002	Rhinitis	8/25
Pyrexia
Arnold 2004	Fever	7/89
Findling 2009	Fever	33/157
Wang 2007	Pyrexia	17/166
Allergies
Hammerness 2009	Allergies	3/154
Pierce 2010	Pruritis	2/71
Cold symptoms
Hammerness 2009	Cold symptoms	2/57
Kratochvil 2002	Fever + flu syndrome	8/25
Steele 2006	Flu‐like symptoms	7/72
Pharyngitis
Arnold 2004	Pharyngitis	10/76
Döpfner 2011b	Pharyngitis	2/113
Kordon 2011	Pharyngitis	6/541
Kratochvil 2002	Pharyngitis	3/25
Sangal 2006	Pharyngitis	7/79
Viral infection
Arnold 2004	Viral infection	18/76
Kordon 2011	Viral infection	8/598
Rash
Arnold 2004	Rash	6/76
Garg 2014	Rash	1/27
Lee 2007	Rash	4/110
Rhinitis
Arnold 2004	Rhinitis	5/76
Kordon 2011	Rhinitis	8/541
Ear disorders
Hammerness 2009	Ear pain	3/57
Fever
Kordon 2011	Fever	9/541
Infections
Valdizán Usón 2013	Nonspecific pathogen	13/689

Analysis 7.6

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 6 Immune system.

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Study	Symptom	Adverse events/total number of participants
Blader 2010	Enuresis	2/65
Galland 2010	Enuresis	3/27
Tomás Vila 2010b	Enuresis	16/114

Analysis 7.7

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 7 Urogenital system: enuresis.

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Study	Description	Adverse events/total number of participants
Hair loss
Abbas 2006	Hair loss	1/90
Khajehpiri 2014	Hair loss	3/71
Skin problems
Haertling 2015	Skin disorder	1/239
Khajehpiri 2014	Acne	2/71
Pierce 2010	Application site erythema	2/71
Shang 2015	Skin eruption	1/66
Accidental injury
Arnold 2004	Accidental injury	10/76
Voice frequency
Congologlu 2009	In conclusion, this clinical trial is the only study that has examined the effects of stimulant medication on vocal acoustic parameters in children with ADHD (attention deficit hyperactivity disorder), 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	NA
Hypersalivation
Garg 2014	Hypersalivation	1/27
Nasal bleeding
Ghanizadeh 2013	Nasal bleeding	1/26
Chromosomal aberration
Witt 2008	% of cells with chromosomal abberations	Before: 0.48% (0.09). After: 0.46% (0.09) Study population: 25

Analysis 7.8

Comparison 7 Non‐comparative studies: proportion of participants with non‐serious adverse events, Outcome 8 Other body systems.

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Study
Arabgol 2015	2/18
Arnold 2010	1/171
Berek 2011	60/822
Chou 2012a	26/521
Dirksen 2002	10/310
Döpfner 2011b	4/113
Efron 1997	1/125
Faraone 2007a	45/268
Findling 2010	13/162
Garg 2014	7/33
Gerwe 2009	43/306
Greenberg 1987	1/50
Guerreiro 1996	1/24
Hammerness 2009	19/152
Hong 2012	3/112
Karabekiroglu 2008	8/90
Khodadust 2012	1/15
Kim 2014b	3/57
Lee 2007	2/119
Maayan 2009	3/11
Na 2013	7/121
Shang 2015	3/80
Sobanski 2013	5/381
Song 2012	8/143
Su 2015	16/239
Tasdelen 2015	3/22
Wang 2007	6/166
Wang 2011	3/50
Warshaw 2010	21/305
Weber 2003	4/57
Weiss 2007	4/90
Wigal 2013	2/45
Wilens 2005	38/407
Winsberg 1982	5/25
Yildiz 2011	1/12
Zheng 2011	34/1447
Çetin 2015	5/73

Analysis 8.1

Comparison 8 Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to non‐serious adverse events, Outcome 1 Proportion of participants withdrawn from methylphenidate treatment due to non‐serious adverse events.

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Study
Akhondzadeh 2003	4/14
Akhondzadeh 2004	2/22
Altin 2013	30/204
Amiri 2008	3/30
Ardic 2014	21/122
Balázs 2011	3/37
Barbaresi 2006	84/379
Bereket 2005	58/72
Chou 2012b	34/296
Dirksen 2002	13/310
Dittmann 2014	52/247
El‐Zein 2005	6/18
Findling 2009	109/326
Findling 2010	54/162
Gadow 1995	7/34
Galland 2010	2/30
Gau 2008	13/137
Germinario 2013	161/351
Guerreiro 1996	2/24
Haertling 2015	16/262
Hammerness 2009	97/152
Hong 2012	5/112
Jensen 1999 (MTA)	29/144
Kim 2011	5/102
Kim 2014b	12/75
Kim 2015a	49/86
Klein 2004	9/129
Lee 2009	6/144
Lee 2012	22/93
Li 2011	2/36
McCracken 2016	6/69
Mohammadi 2004	5/16
Mohammadi 2012a	8/32
Mohammadi 2012b	3/23
Peyre 2012a	37/173
Poulton 2003	6/19
Remschmidt 2005	26/89
Shang 2015	11/80
Sobanski 2013	29/381
Steele 2006	4/73
Tasdelen 2015	2/22
Walitza 2009	15/26
Wang 2007	7/166
Wang 2011	17/50
Warshaw 2010	28/305
Weber 2003	8/57
Weiss 2007	3/90
Wigal 2013	3/45
Wilens 2005	140/407
Wilens 2006	36/171
Witt 2008	9/34
Yalcin 2014	2/40
Yang 2012	12/130
Zarinara 2010	1/19
Zheng 2011	202/1447
Zheng 2015	25/153
Çetin 2015	7/73

Analysis 8.2

Comparison 8 Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to non‐serious adverse events, Outcome 2 Proportion of participants withdrawn from methylphenidate for unknown reasons.

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Study
Psychotic conditions
Abali 2007	A 14‐year‐old girl with diagnoses of ADHD (attention deficit hyperactivity disorder), major depression and conduct disorder. During her treatment with methylphenidate of 20 mg/day and fluoxetine of 20 mg/day, she developed visual and auditory hallucinations. It may be concluded that it is possible that methylphenidate may cause hallucinations in patients treated simultaneously with fluoxetine
Aguilera‐Albesa 2010	2 case reports of the appearance of hallucinations a few hours after methylphenidate ingestion in an 8‐year‐old boy (extended‐release methylphenidate of 18 mg/day, given once daily for 2 days) and a 6‐year‐old girl (extended‐release methylphenidate of 10 mg/day for 3 days and 20 mg/day for 1 day, given once a day). Both diagnosed with ADHD according to criteria in the DSM‐IV (Diagnostic and Statistical Manual, Fourth Edition) and with IQs (intelligence quotients) > 85. These case reports suggest an individual susceptibility to psychotic symptoms after taking methylphenidate. This adverse event is considered idiosyncratic, extraordinary and unpredictable
Coşkun 2008	A paediatric patient who developed tactile and visual hallucinations with the combination of osmotic release oral system (OROS) methylphenidate and fluoxetine. Comments from the study authors: In conclusion, we think that the causative agent was the combination of both medications rather than either medication alone. However, in either situation, it is important to note that this distressing side effect may occur even in the absence of underlying psychotic or substance‐related disorders, and clinicians' awareness is important in this issue, particularly in cases where polypharmacy is considered
Goetz 2011	A case report of nocturnal visual hallucinations during methylphenidate treatment. A girl with ADHD and ODD (oppositional defiant disorder) experienced a 3‐hour episode of nocturnal complex bizarre visual hallucinations when treated with 18 mg of OROS methylphenidate. Nocturnal polysomnography performed 2 weeks later revealed REM (rapid eye movement) sleep reduction (17%) and fragmentation. 2 episodes of confusional arousals were recorded. This finding is typical of parasomnia associated with NREM sleep – disorder of arousal. It is hypothesized that this pre‐existing sleep impairment represents a factor of vulnerability to methylphenidate sleep side effects
Gross‐Tsur 2004	3 children with ADHD, who were treated with low doses of methylphenidate and who developed complex visual and haptic hallucinations Comments from the study authors: The causal role of methylphenidate in the development of hallucinations was based on their appearance after ingestion of the drug, resolving after its withdrawal, and the absence of psychiatric comorbidity that could explain such phenomena. In 1 patient, the hallucinations reappeared after an inadvertent re‐challenge. Because methylphenidate is a widely used, well‐studied, and safe pharmacologic agent, physicians who prescribe methylphenidate should be aware of even rare adverse manifestations occurring at therapeutic doses
Halevy 2009	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; immediate complete resolution upon discontinuation of the drug. Reintroduction of metyhlphenidate treatment after 2 days resulted in same complex visual hallucinations, with immediate complete resolution upon discontinuation of the drug Key conclusions of the study authors: In our case, the occurrence of hallucinations after a very low dose of methylphenidate on 2 occasions may suggest an idiosyncratic reaction. The phenomenon might also be explained by a drug‐induced dysfunction of the monoamine transmitters. Given the wide use of methylphenidate, clinicians should be aware of this possible side effect
Irmak 2014	A case report of phobias and visual hallucinations during methylphenidate treatment in a 9‐year‐old boy. OROS methylphenidate gradually titrated up to 1 mg/kg. Methylphenidate prescribed at initial ADHD diagnosis and then withdrawn following the onset of phobias and visual hallucinations, as well as lack of improvement in attention problems
Mino 1999	A case report on methylphenidate‐induced psychosis in an adolescent with hyperkinetic disorder; use of methylphenidate for 1 month. Three weeks after starting methylphenidate (10 mg/day), the mother reported by telephone that the patient seemed depressed. Dose of methylphenidate was reduced to 5 mg/day. A week later the patient visited the clinic. The therapist diagnosed her condition as a depressive state and discontinued methylphenidate. Six weeks after discontinuation of methylphenidate she was diagnosed with a schizophrenic‐like psychotic state, due to symptoms of delusions of reference and persecution, delusional mood, silly smile and thought block. There was no evident hallucination. The patient took antipsychotic medication for 2 months and her psychotic symptoms disappeared
Porfirio 2011	3 years after start of methylphenidate treatment: An episode of complex visual hallucinations (dramatic scenes appearing before going to sleep, sometimes during the day after ingestion of methylphenidate
Rashid 2007	A case report of intensified somatic hallucinations during dose increase of methylphenidate treatment in a 10‐year‐old boy with a chronic pattern of somatization, which evolved into overt somatic hallucinations with an increase in methylphenidate dosage. This pattern of somatization was retrospectively recognized as partial somatic hallucinations
Shibib 2009	A report of four cases of psychosis during methylphenidate treatment Key conclusion of the study authors: Psychosis is an important, unpredictable side effect of stimulant medication. Symptoms resolve with discontinuation of treatment. Reemergence of ADHD symptoms are rapid and re‐challenge is often indicated. It would be advisable for all professionals involved in the care and treatment of patients with ADHD to receive mental health training to aid the early recognition and appropriate management of such side effects
Tomás Vila 2010a	After two weeks of 50% immediate‐release and 50% extended‐release methylphenidate: visual hallucinations (insects on hands, feet, abdomen and thorax), with associated itching, initiated two hours after ingestion and ceased five hours after. Discontinuation of methylphenidate and initiation of risperidone resulted in no visual hallucinations. No re‐administration of methylphenidate due to ethical reasons Key conclusions of the study authors: This is the first case report of visual hallucinations caused by 50% immediate‐release and 50% extended‐release methylphenidate, which is not surprising considering the relative recent appearance of this preparation on the market
Seizures
Feeney 1997	First‐reported seizure in a patient being treated with methylphenidate and sertraline combined
Hemmer 2001	Reported seizures in a boy aged six, and two girls aged six and seven, receiving 0.3 to 1 mg/kg/day of methylphenidate for six weeks, 10 and three months, respectively
Cerebral arteritis
Trugman 1988	Key conclusions of the study authors: Cerebral arteritis and infarction were caused by chronic use of oral methylphenidate. The Cerebrospinal fluid (CSF) profile and angiogram support the diagnosis of inflammatory arteritis, yet laboratory evaluation revealed no identifiable cause. In the six years since the stroke, while not on methylphenidate, there has been no evidence of active central nervous system or systemic vasculitis
Self‐harm and suicidal behaviour
Arun 2014	2 case reports with 2 children having suicidal ideation
Gökce 2015	Reported a 12‐year‐old boy who made a suicide attempt after switching from 27 mg to 36 mg of OROS methylphenidate: The patient reported irritable mood when he took the first dose of 36 mg of long‐acting methylphenidate. This might be the cause of the suicide attempt. He had a full recovery after withdrawal from methylphenidate
Strandell 2007	Reported concerns about suicidal behaviour, including suicide, based on information retrieved from the WHO Collaborating Centre for International Drug Monitoring (Uppsala, Sweden). A total of 116 reports of methylphenidate related to "suicide attempts", although this term was not explicitly defined. The data included reports of methylphenidate and atomoxetine
Death
Tølløfsrud 2006	A case report of death caused by heart failure (acute dilated cardiomyopathy) during methylphenidate treatment
Dyskinesia
Yilmaz 2013	Involuntary movements started about 5 hours after taking MPH. Lip‐licking, lip‐smacking and tongue‐rolling movements. Dyskinetic tongue movements inside and outside the mouth and involuntary bilateral arm swinging while sitting and standing. Opening and closing his fingers without complete extension. Occasional repetitive movements of the feet, such as beating them against each other while sitting. About 15 hours after MPH intake both hand‐mouth movements and excessive mobility had significantly resolved. Dyskinetic symptoms had completely disappeared on the second day of hospitalization, and the patient was discharged Key conclusions of the study authors: This case is reported to emphasize the potential side effects of methylphenidate, individual differences in drug sensitivities, and drug‐receptor interactions via different mechanisms

Analysis 9.1

Comparison 9 Patient reports/series: number of participants with serious adverse events, Outcome 1 Central nervous system.

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Study
Cardiovascular events
Munk 2015	The present case demonstrates that myocardial infarction can occur due to methylphenidate exposure in a healthy 11‐year‐old boy, without other known cardiovascular risk factors. 54 mg methylphenidate/day. Treatment duration was 2 years. Cardiac arrest followed exercise without prior complaints of chest pain/discomfort or shortness of breath. A week before the event, he had a short episode of tachycardia. Clinical examination showed that the myocardial infarct was not acute but had occurred weeks prior to the cardiac arrest. It was thought to be due to thinning of the myocardium and an adversely remodelled left ventricle. A pacemaker was inserted and methylphenidate treatment was discontinued. The only apparent cause, after extensive assessment, appeared to be the high‐dose methylphenidate treatment (maximum recommended) over an extended period
Nymark 2008	A case report of serious cardiomyopathy during MPH treatment. Serious cardiovascular adverse effects (hypoxia and dyspnoea requiring hospitalisation) after 11 months of MPH treatment. Clinical examination showed signs of liver failure, renal failure and heart failure Comments of the study authors (Nymark et al): With a BMI of 40 our patient had extreme obesity. The hyperdynamic circulation, with increased cardiac output, was thought to be a compensatory adaptation to increased adipose tissue. This may have led to non‐ischaemic dilated cardiomyopathy at the expense of left ventricular hypertrophy and remodeling as may occur in severely obese subjects (McGavock et al 2006). This is, however, unlikely as the only cause in our young patient. Human obesity is also characterized by sympathetic nervous system activation (Eikelis and Esler 2005). A possible obesity‐linked susceptibility to the toxic effect of methylphenidate could therefore play a role in the development of DCM in our patient, especially with regards to the short treatment time of one year
Hypertension
Saieh 2004	A case report of hospitalisation due to hypertension during MPH treatment Serious adverse events 72‐hour hospitalisation, emergency unit Abdominal pain for four days prior to hospitalisation, intermittent accentuation (hours), no other symptoms Secondary hypertension: Persistent hypertension (158/88‐170/105, pulse: 78‐98 bpm). Normal physical examination. Normal eye fundus and normal cardiological examination Discontinuation of MPH: Hypertensive treatment only necessary for 24 hours Normal blood pressure after one week

Analysis 9.2

Comparison 9 Patient reports/series: number of participants with serious adverse events, Outcome 2 Cardiovascular and respiratory system.

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Study

Bernhard 2009

A hepatotoxic reaction

Liver enzymes were elevated prior to therapy. Vomiting starting 5 weeks after onset of methylphenidate therapy and increased within the next 3 days. Abdominal pain increased in intensity. Liver transaminases elevated over 30 times of the normal level, CK level also increased

Analysis 9.3

Comparison 9 Patient reports/series: number of participants with serious adverse events, Outcome 3 Gastrointestinal system: hepatoxicity.

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Study
Cakin‐Memik 2010	A case report of a 14‐year‐old male with attention deficit hyperactivity disorder (ADHD) who presented with priapism after administration of immediate‐release methylphenidate. When the usage of immediate‐release methylphenidate was terminated, priapism spontaneously disappeared
Schwartz 2004	A case report of a 15‐year‐old white male with ADHD (inattention subtype) who experienced painful erections two weeks after beginning sustained release (OROS) MPH and repeated painful erections that increased with increased doses (during withdrawal). MPH use for more than 2 months. It is likely that withdrawal from OROS methylphenidate was the cause of this adolescent boy's priapism. He was embarrassed to disclose the problem to an adult until it became quite severe. It is possible that this adverse event is under‐reported due to sensitivity and embarrassment of young people

Analysis 9.4

Comparison 9 Patient reports/series: number of participants with serious adverse events, Outcome 4 Urogenital system: priapism.

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Study
Tics
Adrian 2001	A case report of a boy aged 10 years referred to a tertiary neurodevelopmental assessment clinic for a second opinion on the management of his ADHD. He started with 20 mg/day of methylphenidate at 7 years of age and gradually increased to 40 mg/day, for 2 to 3 years. Both motor and vocal tics started at 40 mg/day of methylphenidate and subsided spontaneously after a year of treatment Authors' conclusion: The clinically explosive outbursts of tics were coincident with a period of treatment with methylphenidate for the treatment of ADHD (attention deficit hyperactivity disorder) and should not be mistaken for a symptom of the disorder
Chandler 1989	Reported non‐serious adverse events. After a month, the child's mother reported motor and phonic tics again. He was treated first with methylphenidate and then with nortriptyline. With both drugs he manifested severe facial grimacing and phonic tics; apparently, the tics had only occurred in the past when the child was treated with methylphenidate. It is, however, very difficult to attribute the tics to methylphenidate with any certainty because of the common co‐occurrence of tics in children and young people with ADHD Key conclusions of the study authors: Side effects, such as hypomania, hyperreflexia and diaphoresis, have been reported in patients being treated with a combination of a monoamine oxidase inhibitor and tryptophan. By itself, L‐tryptophan may be mildly sedating. In light of such a favourable side‐effect profile, combined with no evidence for adverse interaction with stimulants, and at least some rationale from preclinical research, it should be investigated further as a means of alleviating some of the harsh consequences of psychostimulant treatment in ADHD
Involuntary movements or dyskinesia
Hollis 2007	A case report of acute and transient dyskinesia occurring within hours of taking modified‐release methylphenidate (Concerta XL) in a stimulant‐naïve 7‐year‐old boy who had recently stopped taking risperidone Key conclusions of the study authors: This report is the first of a dyskinesia occurring after a single first dose of methylphenidate in a previously stimulant‐naïve patient after neuroleptic withdrawal. It is also the first to link this effect with modified‐release methylphenidate. The dyskinesia described here consisted of both brief tic‐like movements
Machado 2010	Choreoathetoid movements of orofacial muscles, arms and legs, with transient dystonic postures of the right arm induced by a single dose of extended‐release methylphenidate. Author believes that the immediate response ensuing chlorpromazine prescription argues in favour of a specific role for dopamine receptor antagonists in methylphenidate‐induced chorea
McLaren 2010	The patient experienced spasmodic muscular contractions of his jaw. The staff noticed a forceful jaw closure, contraction and tension, and the patient had difficulties opening his mouth. 50 mg of diphenhydramine was administered intramuscularly and the patient could open his mouth within 30 minutes and with no further dystonia

Analysis 10.1

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 1 Central nervous system: movement‐related outcomes.

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Study
Depression and disturbed mood
Hechtman 2011	A case report about a 5‐year‐old boy. MPH use for around a year. Reported non‐serious adverse events. In late afternoon and early evening, he became very emotional, with frequent crying, marked irritability and many tantrums. The emotional side effects subsided after he discontinued methylphenidate treatment
Mino 1999	3 weeks after starting on 10 mg/day of methylphenidate, the mother reported by telephone that the patient seemed depressed. The dose of methylphenidate was reduced to 5 mg/day. A week later the patient visited the clinic. The therapist diagnosed her condition as a depressive state and discontinued methylphenidate. 6 weeks after discontinuation of methylphenidate, she was diagnosed with a schizophrenic‐like psychotic state, due to symptoms of delusions of reference and persecution, delusional mood, silly smile and thought block. There was no evident hallucination. The patient took antipsychotic medication for 2 months and her psychotic symptoms disappeared
Niederhofer 2009	An 11‐year‐old boy received 20 mg/day of methylphenidate for 2 months, which led to depressed mood and appetite loss
Irritability
Hechtman 2011	A case report about a boy, who became very emotional, with frequent crying episodes, marked irritability and many tantrums when treated with methylphenidate; methylphenidate was used for around a year
Sabuncuoglu 2007	3 case reports of hyperactivity and irritability during switch from risperidone to methylphenidate Case 1: Methylphenidate introduced 2 days after abrupt discontinuation of 1 mg/day of risperidone (8 months), and produced agitation, irritability, vigilance, and violent behavior. No dyskinetic movements. Methylphenidate was discontinued and the adverse events disappeared. After a 6‐week long, drug‐free period, methylphenidate was reintroduced at 15 mg/day. No adverse events were observed Case 2: Methylphenidate introduced after discontinuation of 1 mg/day of risperidone (2 years), and produced a near manic state, irritability, agitation, racing thoughts, and distractibility. No dyskinetic movements. Methylphenidate was discontinued and the adverse events disappeared. After a couple of months, methylphenidate was reintroduced at 15 mg/day and was well‐tolerated Case 3: Methylphenidate introduced after a 1‐week medication‐free interval after treatment with 1 mg of risperidone, and produced irritability, agitation and discomfort. Methylphenidate was discontinued and the adverse events disappeared. The patient did not retry the medication Key conclusions of the study authors: This report of 3 patients draws attention to a unique condition that arises in switching from an atypical antipsychotic to stimulant medication. A drug‐free interval is recommended in switching from risperidone to methylphenidate
Aggression
Coignoux 2009	A case report of a 14‐year‐old boy receiving methylphenidate for 2 years who developed gestural stereotypies and verbal aggressiveness towards his parents whilst on methylphenidate treatment
Niederhofer 2011	A case series describing adverse effects (xerostomia, aggression and emotional instability) among children taking methylphenidate
Mania/euphoria
Corrigall 1996	A case report of methylphenidate euphoria in an 11‐year‐old boy diagnosed with hyperkinetic disorder Key conclusions of the study authors: Methylphenidate euphoria can occur in young prepubertal children and this may lead to abuse of medication
Ghanizadeh 2009	Mother and nursery teacher complained about increased hyper‐talkativity starting about 45 minutes after taking medication. The increased hyper‐talkativity continued for about 3–4 hours. They scored the hyper‐talking as 7–9 on a 1–10 visual analogue scale. Re‐challenge was conducted many times (more than 20 times) and hyper‐talking reoccurred after every time he took the medication

Analysis 10.2

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 2 Central nervous system: mood disorders.

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Study
Disturbed sleep
Langevin 2012	A controlled before‐and‐after study. Methylphenidate used to treat ADHD (attention deficit hyperactivity disorder), from December (time 1) to June (time 2) 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 children with ADHD and those of children in the control group
Other sleep problems
Arun 2014	A case report of a child whose sleep was impaired for 1 night after receiving methylphenidate
Coşkun 2010	A case series of 7 children who experience side effects during methylphenidate treatment: Sleep problems: n = 4 Worsening of pre‐existing sleep problems: n = 2 No worsening of pre‐existing sleep problems: n = 1

Analysis 10.3

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 3 Central nervous system: sleep problems.

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Study
Voice problems
Yalcin 2012	Teacher and family observed disturbance of voice quality, hoarseness, bifurcation‐strain and over vibration of voice. The symptoms began on the first day of treatment with methylphenidate. Hoarseness and reduction in the voice amplitude was evident during the first visit to a psychiatric out‐hospital clinic. No symptoms were observed by parents or during the psychiatric control on drug‐free days. Experienced hoarseness when methylphenidate administered in the clinic. Voice quality returned to normal three hours after ingestion. Laryngitis or other organic conditions causing hoarseness were not observed in physical and endoscopic examination. There were no important side effects with discontinuation of methylphenidate and administration of atomoxetine
Stuttering
Alpaslan 2015	A case report of a 7‐year‐old boy who developed stuttering associated with the use of methylphenidate; received 10 mg/daily of short‐acting methylphenidate. 10 days after beginning treatment with short‐acting methylphenidate, the client began to stutter. Treatment was stopped. 1 week later, the patient's speech was back to normal. 4 weeks later atomoxetine treatment was started with no recurrence of stuttering

Analysis 10.4

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 4 Central nervous system: voice and speech disorders.

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Study
Anorexia
Findling 1996	A case report about an 11‐year‐old girl who experienced transient side effects after receiving methylphenidate: mild and transient anorexia, transient weight loss of 2 kg observed in the initiation of methylphenidate therapy
Obsessive compulsive disorder (OCD) symptoms
Coşkun 2011	A case report of OCD symptoms during methylphenidate treatment. Decreased appetite and initial headache with 18 mg/day of osmotic‐controlled release oral delivery system (OROS) methylphenidate, and obsessive‐compulsive symptoms, decreased appetite, facial grimace, and nail picking/biting with 27 mg/day of OROS methylphenidate. Gradual disappearance of symptoms, although still subsyndromal obsessive‐compulsive symptoms, with discontinuation of medication. Mild facial grimace and similar obsessive‐compulsive symptoms with re‐administration of 27 mg/day of OROS methylphenidate. After three weeks, total score of 21 on Children's Yale‐Brown Obsessive‐Compulsive Scale (CY‐BOCS)
Woolley 2003	Obsessions and compulsions with anxiety. DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edtion) diagnosis of OCD. Washing hands excessively, which was accompanied by checking rituals, reassurance seeking, and emetophobia. When methylphenidate was withdrawn, OCD symptoms decreased rapidly but increased when methylphenidate was reintroduced
Headache
Mize 2004	A case report of headache and mild depression during methylphenidate treatment
EEG changes
Dupuy 2008	A controlled before‐and‐after study investigating the effects of stimulants on EEG (electroencephaolography) coherence in 9 girls with ADHD (attention deficit hyperactivity disorder); intrahemispheric and interhemispheric coherences in girls with ADHD who were treated with stimulant medication. Girls had elevated frontal coherence in all frequency bands

Analysis 10.5

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 5 Central nervous system: other specific adverse events.

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Study
Vasculopathy
Yu 2010	These case reports raise the concern that adverse effects in the peripheral vascular system of children and adolescents may be associated with psychostimulant treatment Patient 1: Tachycardia at age 11 while taking Concerta, 54 mg/d. Vasculopathy at age 16. His hands and feet were a continuous blue colour on his hands and fingers, which increased in frequency in cold weather. He was diagnosed with "decreased circulation but not Raynaud's syndrome". Occured when the Concerta dose was increased from 54 mg/d to 90 mg/d in 3 months with the same Focalin (dexmethylphenidate) dose (10mg/d) Patient 2: Vasculopathy. First diagnosed with Raynaud's syndrome with finger pain and colour changes during a neurology consultation at age 10 years. At age 12 years had diffuse erythema of both earlobes, the fingers of both hands, and the toes of his left foot. Tics at age 10 years but not clear if these were present prior to treatment for ADHD Patient 4: Vasculopathy. After taking Focalin for a year, he developed persistent curling of the toes of both feet. In addition, he had reddish and purple colour changes in his hands and feet with cold exposure that lasted for 20 minutes. No associated pain and only rare paraesthesia. At age 10 years, toes 2, 3 and 4 of both feet were held in a flexed position ("curled toes"), and there was skin discolouration and excoriation
Cardiovascular problems
Karaman 2010	A case report of a 15‐year old boy with ADHD who developed pulmonary arterial hypertension (PAH) during OROS MPH treatment Fourth day of treatment: The patient began to experience occasional episodes of slightly shortness of breath. Continued over several months. Not associated with either exercise or anxiety At 18th month of treatment: Fainting. Normal weight. No sign of allergy, hypersensitivity, or sleep apnoea. Mean pulmonary arterial pressure of 40 mmHg at rest, otherwise no pathological findings from extensive testing (Examination: clear lungs, no murmurs, rubs, or gallops, and otherwise unremarkable. Laboratory tests, including C‐reactive protein, thyroid and liver function tests, electrolytes. Blood gases, antinuclear antibodies, D‐dimers, chest X‐ray, ventilation–perfusion scintigraphy, electrocardiography, respiratory function tests. Echography. Transthoracic echocardiogram: normal except for the mean pulmonary arterial pressure). No use of any other drug. No history of alcohol and substance use and no symptoms or signs of MPH misuse (intravenous injection). The personal and familial histories were also negative for pulmonary or cardiovascular diseases Discontinuation of OROS‐MPH, one month: free of symptoms After the fourth week of discontinuation: Mean pulmonary arterial pressure of 28 mmHg
Bleeding
Grossman 1985	A case report of a 7‐year‐old girl on methylphenidate treatment who developed idiopathic trombocytopenic purpura (ITP). Physical examination at the paediatric outpatient department found countless petechiae over the entire dermal surface. Numerous areas of purpura were noted, especially over her buttocks and extremities. Multiple areas of buccal mucosal and gingival bleeding with a large hematoma presented on the left lateral surface of her tongue. Clotted blood was seen in her nostrils and ear canals bilaterally. Bone marrow aspiration showed normal to increased megakaryocytes with normal red and white cell precursors. MPH was stopped and the patient was admitted. After one week of treatment for the condition, her petechia had begun to fade. She did not start on MPH again. There has been no recurrence of petechiae or bruising one year later. MPH use for seven months prior to presentation of ITP
Tachycardia
Gracious 1999	A case report of atrioventricular (AV) nodal re‐entrant tachycardia during stimulant treatment Key conclusions of the study authors: Stimulant medication may evoke onset of AV nodal tachyarrhythmias in patients who have the potential to develop them, possibly in combination with a selective serotonergic reuptake inhibitor Comments from the study authors: The cardiologist consulted believed this patient had a structural vulnerability of genetic etiology for the arrhythmia which was then precipitated by the stimulant

Analysis 10.6

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 6 Cardiovascular and respiratory system.

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Study
Loss of appetite
Agarwal 2008	A case report of the combination of atomoxetine and methylphenidate treatment of ADHD. Non‐serious adverse events: decreased appetite and delayed onset in sleep
Coşkun 2009a	IR MPH, 10–20 mg/day, co‐medication: valproate 400 mg/day. Decreased appetite, no weight decrease
Ghanizadeh 2008a	A case report of decrease in appetite during treatment with MPH
Rappaport 2004	A case report of side effects during MPH treatment in a 14‐year‐old boy with ADHD and a number of other co‐morbid conditions (whilst taking immediate‐release MPH)
Yalcin 2012	Significant appetite loss, drowsiness, disturbance of voice and hoarseness Disturbance of voice and hoarseness occurred on everyday since the first day of the medication. The symptoms started short after the single morning dose and decreased gradually to dinner time and disappeared before bedtime. Drug‐free days: no symptoms. Otolaryngology consultation: no organic pathology was detected with respect to clinical and endoscopic observation. Discontinuation of MPH and prescription of atomoxetine: no symptom of hoarseness and disturbance of voice quality
Nausea and vomiting
Rappaport 2004	A case report of side effects during MPH treatment in a 14‐year‐old boy with ADHD and a number of other co‐morbid conditions (whilst taking extended‐release MPH: Concerta)

Analysis 10.7

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 7 Gastrointestinal system.

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Study

Holtkamp 2002

A case report of growth impairment during MPH treatment

Key conclusions of the study authors: One may conclude that some children are at risk of serious growth decrement when treated with MPH. The growth of children should thus be monitored carefully, even if there are no alarming gastrointestinal side effects from MPH. We found that the determination of growth velocity was a sensitive marker for the evaluation of growth impairment in our patient

Analysis 10.8

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 8 Musculoskeletal system: growth.

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Study
Confino‐Cohen 2005	A case report of pruritic maculopapular skin rash developing during MPH treatment. The rash improved with antihistamines and re‐challenge at a lower dose caused the reappearance, though less severe, of the rash. Desensitisation through graded exposure of MPH in incremental doses prevented further rash development
Vashi 2011	After 8 months of using an MPH patch the patient presented with pruritic dermatitis. She had itchy, burning, red lesions. Symptoms began on her hip at the area of patch placement, then progressively spread to her arms, legs, abdomen, and back. MPH discontinued: Symptoms lasted for 2 months. First and second patch test. Re‐tested with MPH patch: Nine days after the first test the patient presented with recall reaction, characterized by a return of the original pruritic dermatitis to her entire back, similar to the eruption that had occurred months previously after therapeutical use of MPH patch. Avoidance of MPH patches: symptom‐free

Analysis 10.9

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 9 Immune system: allergic reactions.

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Study
Testicular failure
Ramasamy 2014	A case report of testicular failure possibly associated with chronic use of Methylphendiate. The patient was 20 years old with treatment duration of approximately 17 years with voluntary cessation a few years ago. Dosage varied with age. The patient's complaint was initially delayed puberty. He complained of high‐pitched voice, lack of libido, low energy level, chronic fatigue and poor erectile function. The patient was advised to begin testosterone supplementation. The patient described in the case study seemed to exhibit characteristics related to the effects of chronic use of methylphenidate on development of human reproductive function. The unknown effects of methylphenidate are currently being studied, but as can be seen, one should exercise caution and patients should be followed closely when prescribing methylphenidate. However, because the developmental changes that occurred in the human participant occurred over a number of years of treatment with methylphenidate, there is very little information about the patient's condition and how it developed during that period of time
Sexual adverse events
Coşkun 2009b	Case 1: Treated with 10‐30 mg/day of immediate‐release methylphenidate and experienced initial headache and nausea. Treated with 18 mg/day osmotic‐controlled release oral delivery system (OROS) methylphenidate and experienced emotional side effects (sense of nervousness in the chest, occasional emotional numbing), multiple daily erections (unrelated to sexual stimuli, painless and without ejaculations), occurring a few hours after ingesting methylphenidate and lasting 5‐10 minutes. No erections unrelated to sexual stimuli during a 1‐week medication‐free period. With re‐administration of 35 mg/day OROS methylphenidate for 3 weeks, experienced re‐emergence of erections of a longer duration compared with 18 mg/day of OROS methylphenidate, headache, nausea, and the same emotional side effects. No erections on drug‐free days, and no erections with discontinuation of medication. Case 2: Treated with 18 mg/day of OROS methylphenidate and experienced loss of appetite, headache, abdominal pain, sleep problems, and conjunctival injection. Headache and abdominal pain almost disappeared after 1 week. Also experienced hypersexual behaviours, with morning erections lasting 1 hour before ingestion of methylphenidate, and a weight loss of 1.5 kg within 2 months. On drug‐free days had almost no hypersexual behaviour during the day and no erection the following morning. When treated with 10‐20 mg/day of immediate‐release methylphenidate, morning erections and hypersexual behaviours decreased dramatically, sleep and appetite problems improved mildly, and there was no conjunctival injection (after three weeks). There were, however, possible withdrawal symptoms (increased irritability and hyperactivity, getting tearful easily), several hours after each dosage. Had no morning erections or hypersexual behaviours with discontinuation of OROS methylphenidate
Incontinence
Tang 2010	Side effects reported by the mother: IR‐MPH, 10 mg, no side effects. OROS‐MPH, 18 mg/d, no side effects. OROS‐MPH, 36 mg/d, double incontinence; stool incontinence (every day, frequent during daytime) and urinary incontinence (almost every day). The double incontinence completely resolved rapidly after the discontinuation of OROS methylphenidate 36 mg
Enuresis
Ghanizadeh 2008b	A case report of nocturnal enuresis during MPH treatment Non‐serious adverse events MPH, titrated to 20 mg/day: Nocturnal enuresis Discontinuation of MPH: enuresis stopped immediately MPH, when titrated to 20 mg/day: Immediate re‐occurence of nocturnal enuresis Discontinuation of MPH: enuresis stopped immediately MPH, when titrated to 20 mg/day: Immediate re‐occurence of nocturnal enuresis Discontinuation of MPH: enuresis stopped immediately
Williamson 2011	Two case reports showing resolution of enuresis when treated with MPH

Analysis 10.10

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 10 Urogenitial system.

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Study
Skin reactions
Cohen 1992	Case 1: 5 days of MPH treatment: hospitalisation due to two days of severe swelling and redness of the scrotum The skin eruption resolved spontaneously four days after MPH was discontinued. Two weeks later, 18 hour after MPH retrial, the same skin eruption of the scrotum was documented. Discontinued once again, and followed by a complete resolution of the rash in four days Case 2: 7 days of MPH treatment: Six hours of severe swelling and redness of the scrotum. Discontinuation of MPH was followed by a complete resolution of rash in three days.Rechallenge with MPH two months later was followed by the same skin eruption of the scrotum within two days. Complete resolution was seen after drug withdrawal
Coşkun 2009a	OROS‐MPH 18 mg/day, co‐medication: valproate 400 mg/day. Maculopapular pruritic skin eruptions on the patient's neck, arms, and legs, one week after starting OROS MPH treatment Re‐administering of OROS‐MPH 18 mg/day, comedication: gabapentine 300 mg/day. Same skin eruptions with same severity, nine days after starting OROS‐MPH treatment again Discontinuation of medication: skin lesions abated within the next several weeks Restart of IR‐MPH, 10–20 mg/day, co‐medication gabapentine 300 mg/day, four months: no skin eruptions
Problems with sedation
Ririe 1997	A case report (6‐year‐old boy) on unexpected interaction of methylphenidate (Ritalin) with anaesthetic agents: There could be a potential risk of unwanted interactions between methylphenidate and anaesthetic agents. Based on the observations from the case report, a more detailed and systematic investigation of methylphenidate in patients undergoing anaesthesia or sedation is warranted
Eye problems
Ghanizadeh 2008c	Photophobia, occurring a few days after initiation of MPH treatment Discontinuation of MPH at least three times: no symptoms of photophobia Re‐administration of MPH: immediate reoccurrence of photophobia
Lewis 2012	This report concluded stimulant medication (MPH) should not be withheld in patients with glaucoma as long as intraocular pressure (IOP) remains well controlled

Analysis 10.11

Comparison 10 Patient reports/series: number of participants with non‐serious adverse events, Outcome 11 Other body systems.

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Summary of findings for the main comparison. Methylphenidate for children and adolescents aged 18 years and under with attention deficit hyperactivity disorder (ADHD): adverse events

Methylphenidate for children and adolescents aged 18 and under with attention deficit hyperactivity disorder (ADHD): adverse events
Patient or population: children and adolescents aged 18 years and under diagnosed with ADHD Settings: outpatient clinic, inpatient hospital ward and register data Intervention: methylphenidate Comparision: control or no control
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies) at follow‐up	Quality of the evidence (GRADE)
	Risk with control or no control	Risk difference with Methylphenidate
*Comparative studies*
Serious adverse events Measured by: proportion of serious adverse events (total) Average study duration (range): not stated	12 per 1000	4 more per 1000 (2 more to 7 more)	RR 1.36 (1.17 to 1.57)	72,005 (2 studies)	⊕⊝⊝⊝ Very low^a
*Non‐comparative studies*
Serious adverse events Measured by: proportion of any serious adverse events Average study duration (range): 4.7 months (14 days to 21 months)	1.20% (0.70% to 2.00%)		—	162,422 (51 studies)	⊕⊝⊝⊝ Very low^b
Withdrawal of methylphenidate due to serious adverse events (non‐comparative cohort studies) Measured by: proportion of participants withdrawn from treatment Average study duration (range): 7.9 months (1 month to 37 months)	1.20% (0.60% to 2.30%)		—	1173 (7 studies)	⊕⊝⊝⊝ Very low^b
Withdrawal of methylphenidate due to adverse events of unknown severity Measured by: proportion of participants withdrawn from treatment Average study duration (range): 4.6 months (21 days to 36 months)	7.30% (5.30% to 10.0%)		—	3708 (22 studies)	⊕⊝⊝⊝ Very low^b
Non‐serious adverse events Measured by: proportion of any non‐serious adverse events Average study duration (range): 5.99 months (1 day to 41 months)	51.2% (41.2% to 61.1%)		—	13,978 (49 studies)	⊕⊝⊝⊝ Very low^b
Withdrawal of methylphenidate due to non‐serious adverse events Measured by: proportion of participants withdrawn from treatment Average study duration (range): 5.60 months (0.6 months to 41 months)	6.20% (4.80% to 7.90%)		—	7142 (37 studies)	⊕⊝⊝⊝ Very low^b
Withdrawal of methylphenidate for unknown reasons Measure by: proportion of participants withdrawn from treatment Average study duration (range): 6.13 months (1 day to 36 months)	16.2% (13.0% to 19.9%)		—	8340 (57 studies)	⊕⊝⊝⊝ Very low^b
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ROBINS‐I: Risk Of Bias In Non‐randomised Studies ‐ of Interventions; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aOutcome assessed at critical risk of bias using the ROBINS‐I. Consequently, we downgraded the quality of the evidence by 3 levels due to study limitations. ^bOutcome not critically assessed with ROBINS‐I due to lack of control group. However, due to the nature of the studies and the risk of confounding, we considered the studies to be at critical risk of bias. Consequently, we downgraded the quality of the evidence by 3 levels due to study limitations.

Summary of findings for the main comparison. Methylphenidate for children and adolescents aged 18 years and under with attention deficit hyperactivity disorder (ADHD): adverse events

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Table 1. Study design

Study design	Description
Cohort study	An observational study in which a defined group with ≥ 1 samples of people (the cohort) is followed over time. The outcomes of people in subsets of this cohort might be compared, to examine people who were exposed or not exposed (or exposed at different levels) to a particular intervention or other factor of interest. A prospective cohort study assembles participants and follows them into the future. A retrospective (or historical) cohort study identifies participants from past records and follows them from the time of those records to the present. Because participants are not allocated by the investigator to different interventions or other exposures, adjusted analysis is usually required to minimise the influence of other factors (confounders).
Patient‐control study	A study that compares people with a specific disease or outcome of interest (cases) to people from the same population without that disease or outcome (controls), and which seeks to find associations between the outcome and prior exposure to particular risk factors. This design is particularly useful when the outcome is rare and when past exposure can be reliably measured. Patient‐control studies are usually but not always retrospective.
Cross‐sectional study	Studies in which the presence or absence of disease or other health‐related variables are determined for each member of the study population or in a representative sample at one particular time. This contrasts with cohort studies, which are followed over a period of time.
Taken from the Cochrane Glossary.

Table 1. Study design

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Table 2. Data on adverse events from published systematic review on methylphenidate versus placebo or no intervention (Storebø 2015), National Summary of Product Characteristics, and from the present review

Adverse event	Randomised clinical trials: methylphenidate group (from Storebø 2015)	Randomised clinical trials: placebo or no intervention group (from Storebø 2015)	National Summary of Product Characteristics (UK, USA, DK)	Non‐comparative cohort studies and cohort studies from randomised trials (present review)	Non‐comparative cohort studies (present review)	Non‐comparative cohort studies from randomised trials (present review)
Serious adverse events	1.90% (95% CI 1.10% to 3.20%; 9 studies, 919 participants)	2.80% (95% CI 1.70% to 4.80%; 9 studies, 613 participants)	No information	1.20% (95% CI 0.70% to 2.00%; 51 studies, 162,434 participants)	1.10% (95% CI 0.60% to 2.00%; 32 studies, 159,761 participants)	1.60% (95% CI 1.00% to 2.30%; 18 studies, 2661 participants)
Non‐serious adverse events	51.4% (95% CI 41.9% to 60.9%; 21 studies, 1861 participants)	38.3% (95% CI 30.3% to 47.0%; 21 studies, 1271 participants)	No information	51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants)	47.1% (95% CI 35.6% to 58.9%; 36 studies, 13,035 participants)	62.1% (95% CI 44.4% to 77.1%; 13 studies, 943 participants)
Headache	11.6% (95% CI 8.80% to 13.3%; 17 studies, 1642 participants)	9.40% (95% CI 7.10% to 12.4%; 17 studies, 1082 participants)	1% to 10%	14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants)^a	9.90% (95% CI 7.00% to 13.9%; 57 studies, 10,929 participants	24.3% (95% CI 18.0% to 32.1%; 33 studies, 2540 participants)
Anxiety	6.50% (95% CI 1.20% to 29.2%; 3 studies, 356 participants)	12.4% (95% CI 8.30% to 18.0%; 3 studies, 240 participants)	1% to 10% (UK and DK); no information (USA)	18.4% (95% CI 11.3% to 28.7%; 22 studies, 1287 participants)^a	10.2% (95% CI 5.30% to 18.9%; 8 studies, 938 participants	27.9% (95% CI 17.8% to 40.8%; 14 studies, 349 participants
Sleep difficulty	8.00% (95% CI 5.80% to 11.1%; 13 studies, 1417 participants)	8.30% (95% CI 6.40% to 10.7%; 13 studies, 999 participants)	1% to 10%	17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants)^a	14.3% (95% CI 11.2% to 18.2%; 51 studies, 9073 participants	25.4% (95% CI 18.2% to 34.4%, 31 studies, 2434 participants)
Irritability	6.40% (95% CI 3.70% to 10.8%; 11 studies, 1038 participants)	3.50% (95% CI 1.40% to 8.60%; 11 studies, 778 participants)	1% to 10%	17.2% (95% CI 11.5% to 25%; 35 studies, 4792 participants)^a	15.5% (95% CI 10.2% to 22.7%; 21 studies, 3298 participants	20.6% (95% CI 7.90% to 44.1%; 14 studies, 1494 participants)
Tics	2.30% (95% CI 1.00% to 5.20%; 7 studies, 684 participants)	5.50% (95% CI 3.70% to 8.10%; 7 studies, 476 participants)	No information	6.40% (95% CI 4.50% to 8.90%; 39 studies, 1980 participants)^a	5.60% (95% CI 3.80% to 8.10%; 29 studies, 1601 participants)	10.6% (95% CI 5.30% to 19.9%; 10 studies, 379 participants)
Drowsiness	7.30% (95% CI 2.40% to 20.2%; 4 studies, 510 participants)	6.70% (95% CI 2.60% to 16.2%; 4 studies, 310 participants)	1% to 10%	9.50% (95% CI 5.20% to 16.6%; 17 studies, 1146 participants)^a	7.50% (95% CI 3.10% to 17.2%; 7 studies, 644 participants)	11.3% (95% CI 5.00% to 23.3%; 10 studies, 502 participants)
Sadness	5.70% (95% CI 1.30% to 21.9%; 4 studies, 382 participants)	4.20% (95% CI 0.90% to 16.9%; 4 studies, 318 participants)	No information	16.8% (95% CI 9.40% to 28.3%; 21 studies, 1802 participants)^a	13.1% (95% CI 6.60% to 24.1%; 9 studies, 626 participants)	20.6% (95% CI 8.10% to 43.1%; 12 studies, 1176 participants)
Fatigue	4.80% (95% CI 2.30% to 9.90%; 6 studies, 471 participants)	6.50% (95% CI 4.30% to 9.60%; 6 studies, 387 participants)	1% to 10%	5.70% (95% CI 3.00% to 10.4%; 17 studies, 2182 participants)	5.60% (95% CI 2.80% to 10.9%; 5 studies, 673 participants)	7.80% (95% CI 5.80% to 10.5%; 12 studies, 1509 participants)
Abdominal pain	11.5% (95% CI 7.70% to 16.8%; 13 studies, 1406 participants)	7.60% (95% CI 5.00% to 11.5%; 13 studies, 935 participants)	0% to 10%	10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants)^a	7.60% (95% CI 5.70% to 10.0%; 46 studies, 9229 participants)	16.3% (95% CI 11.6% to 22.4%; 33 studies, 2521 participants)
Decreased appetite	17.3 (95% CI 12.3% to 24.2%; 16 studies, 1751 participants)	4.30% (95% CI 2.40% to 7.40%; 16 studies, 1211 participants)	1% to 10%	31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants)^a	28.8% (95% CI 23.0% to 33.5%; 57 studies, 9662 participants)	39.7% (95% CI 27.0% to 54.0%; 27 studies, 1967 participants)
Vomiting	5.70% (95% CI 4.00% to 8.00%; 11 studies, 1140 participants)	5.10% (95% CI 3.5% to 7.4%; 11 studies, 776 participants)	1% to 10%	7.30% (95% CI 3.70% to 13.4%; 20 studies, 2731 participants)^a	7.10% (95% CI 2.80% to 17.0%; 11 studies, 1528 participants)	7.20% (95% CI 3.30% to 15.1%; 9 studies, 1203 participants)
Nausea	7.50% (95% CI 6.10% to 9.30%; 11 studies, 1174 participants)	5.20% (95% CI 3.80% to 7.10%; 11 studies, 821 participants)	> 10%	7.60% (95% CI 5.30% to 10.6%; 41 studies, 5612 participants)^a	8.00% (95% CI 7.00% to 9.10%; 22 studies, 3921 participants)	10.4% (95% CI 5.80% to 17.9%; 19 studies, 1691 participants)
Decreased weight	6.30% (95% CI 3.80% to 10.3%; 6 studies, 472 participants)	2.40% (95% CI 1.00% to 5.70%; 6 studies, 387 participants)	1% to 10%	8.70% (95% CI 4.80% to 15.3%; 26 studies, 5182 participants)^a	6.60% (95% CI 3.10% to 13.3%; 17 studies, 4855 participants)	16.6% (95% CI 8.70% to 30.6%; 9 studies, 327 participants)
CI: confidence interval; DK: Denmark; RCT: randomised clinical trials. ^aWe found substantially larger proportions of several adverse events in the present review compared to both the proportions of adverse events in the placebo group in the RCTs included in our 2015 review (Storebø 2015), and the National Summary of Product Characteristics from the UK, USA, and Denmark.

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Comparison 1. Comparative studies: number of serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any serious adverse events Show forest plot	2	72005	Risk Ratio (IV, Random, 95% CI)	1.36 [1.17, 1.57]

2 Central nervous system Show forest plot	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only

2.1 Seizures	1	234	Risk Ratio (IV, Random, 95% CI)	1.31 [0.07, 23.74]
2.2 Psychotic disorder	1	71771	Risk Ratio (IV, Random, 95% CI)	1.36 [1.17, 1.57]
3 Cardiovascular and respiratory system Show forest plot			Other data	No numeric data

3.1 Arrhythmias			Other data	No numeric data
3.2 Hypertension			Other data	No numeric data
3.3 Myocardial infarction			Other data	No numeric data
3.4 Ischaemic stroke			Other data	No numeric data
3.5 Heart failure			Other data	No numeric data

Comparison 1. Comparative studies: number of serious adverse events

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Comparison 2. Comparative studies: number of participants with non‐serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Central nervous system: sleep‐related adverse events Show forest plot	3		Risk Ratio (IV, Random, 95% CI)	Subtotals only

1.1 Insomnia and sleep problems	3	425	Risk Ratio (IV, Random, 95% CI)	2.58 [1.24, 5.34]
1.2 Nightmares	1	23	Risk Ratio (IV, Random, 95% CI)	1.15 [0.41, 3.21]
1.3 Snoring	1	23	Risk Ratio (IV, Random, 95% CI)	4.62 [0.25, 86.72]
1.4 Non‐breathing or gasping while sleeping	1	23	Risk Ratio (IV, Random, 95% CI)	2.77 [0.12, 61.65]
1.5 Sleepwalking	1	23	Risk Ratio (IV, Random, 95% CI)	2.75 [0.33, 22.69]
1.6 Various sleep positions	1	23	Risk Ratio (IV, Random, 95% CI)	2.77 [0.12, 61.65]
1.7 Enuresis	1	23	Risk Ratio (IV, Random, 95% CI)	4.62 [0.25, 86.72]
1.8 Talking in sleep	1	23	Risk Ratio (IV, Random, 95% CI)	0.46 [0.05, 4.38]
2 Central nervous system: other specific sleep‐related adverse events Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Number of hours sleep	1	10	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.32, 0.02]
2.2 Number of nocturnal movements	1	10	Mean Difference (IV, Random, 95% CI)	‐27.84 [‐57.90, 2.22]
2.3 Sleep quality	1	10	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.74, 0.34]
3 Central nervous system: other specific adverse events Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

3.1 Headache	1	235	Risk Ratio (IV, Random, 95% CI)	8.13 [0.48, 137.74]
3.2 Dizziness	1	335	Risk Ratio (IV, Random, 95% CI)	4.00 [0.23, 69.27]
4 Cardiovascular and respiratory system Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Systolic blood pressure	1	43	Mean Difference (IV, Random, 95% CI)	0.10 [‐6.27, 6.47]
4.2 Diastolic blood pressure	1	43	Mean Difference (IV, Random, 95% CI)	3.50 [‐1.42, 8.42]
4.3 Pulse rate	1	43	Mean Difference (IV, Random, 95% CI)	0.60 [‐7.95, 9.15]
5 Gastrointestinal system Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

5.1 Nausea	1	335	Risk Ratio (IV, Random, 95% CI)	2.64 [0.34, 20.29]
5.2 Abdominal pain	1	335	Risk Ratio (IV, Random, 95% CI)	0.79 [0.16, 3.84]
5.3 Decreased appetite	1	335	Risk Ratio (IV, Random, 95% CI)	15.06 [2.12, 106.83]
6 Musculoskeletal system Show forest plot	2		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Height	2	93	Std. Mean Difference (IV, Random, 95% CI)	‐0.93 [‐2.61, 0.75]
6.2 Weight	2	93	Std. Mean Difference (IV, Random, 95% CI)	‐0.27 [‐1.16, 0.62]
7 Musculoskeletal system: body mass index (BMI) Show forest plot	1	43	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐2.96, ‐0.24]

8 Musculoskeletal system: z scores Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 Height z score	1	275	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.43, 0.05]
8.2 Weight z score	1	275	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.30, 0.16]
8.3 BMI z score	1	275	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.22, 0.24]

Comparison 2. Comparative studies: number of participants with non‐serious adverse events

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Comparison 3. Comparative studies: number of participants withdrawn from methylphenidate treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants withdrawn from methylphenidate for unknown reasons Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

Comparison 3. Comparative studies: number of participants withdrawn from methylphenidate treatment

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Comparison 4. Non‐comparative studies: proportion of participants with serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any serious adverse event Show forest plot			Other data	No numeric data

2 Central nervous system Show forest plot			Other data	No numeric data

2.1 Sudden death			Other data	No numeric data
2.2 Suicide			Other data	No numeric data
2.3 Suicide attempt			Other data	No numeric data
2.4 Suicide thoughts			Other data	No numeric data
2.5 Psychotic symptoms			Other data	No numeric data
2.6 Seizure			Other data	No numeric data
2.7 Syncope			Other data	No numeric data
2.8 Tremor			Other data	No numeric data
2.9 Psychiatric problems			Other data	No numeric data
2.10 Severe depression			Other data	No numeric data
2.11 Overdose			Other data	No numeric data
2.12 Eating disorder			Other data	No numeric data
2.13 Aphasia			Other data	No numeric data
2.14 Headache			Other data	No numeric data
2.15 Neurological disorder			Other data	No numeric data
2.16 Sleep disorder			Other data	No numeric data
2.17 Mood disorder			Other data	No numeric data
2.18 Loss of consciousness			Other data	No numeric data
2.19 Family stress			Other data	No numeric data
2.20 Impotence			Other data	No numeric data
2.21 Severe aggression			Other data	No numeric data
2.22 Severe anorexia			Other data	No numeric data
2.23 Amphetamine intoxication			Other data	No numeric data
3 Cardiovascular and respiratory system Show forest plot			Other data	No numeric data

3.1 Respiratory, thoracic and mediastinal disorders			Other data	No numeric data
3.2 Cardiac problems			Other data	No numeric data
3.3 Tachycardia			Other data	No numeric data
3.4 Severe hypertension			Other data	No numeric data
3.5 Epistaxsis			Other data	No numeric data
3.6 Viral illness			Other data	No numeric data
4 Gastrointestinal system Show forest plot			Other data	No numeric data

4.1 Gastrointestinal disease			Other data	No numeric data
4.2 Liver disease			Other data	No numeric data
5 Musculoskeletal system: fractures Show forest plot			Other data	No numeric data

6 Immune system: autoimmune disease Show forest plot			Other data	No numeric data

Comparison 4. Non‐comparative studies: proportion of participants with serious adverse events

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Comparison 5. Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants withdrawn from methylphenidate treatment due to serious adverse events Show forest plot			Other data	No numeric data

1.1 Serious adverse events			Other data	No numeric data
1.2 Hallucinations			Other data	No numeric data
1.3 Severe anorexia			Other data	No numeric data
1.4 Suicide attempt			Other data	No numeric data
2 Proportion of participants withdrawn from methylphenidate treatment due to adverse events of unknown severity Show forest plot			Other data	No numeric data

Comparison 5. Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to serious adverse events

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Comparison 6. Non‐comparative studies: proportion of participants with adverse events of unknown severity

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants with adverse events of unknown severity Show forest plot			Other data	No numeric data

Comparison 6. Non‐comparative studies: proportion of participants with adverse events of unknown severity

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Comparison 7. Non‐comparative studies: proportion of participants with non‐serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐serious adverse events Show forest plot			Other data	No numeric data

2 Central nervous system Show forest plot			Other data	No numeric data

2.1 Affect lability			Other data	No numeric data
2.2 Aggression			Other data	No numeric data
2.3 Anorexia			Other data	No numeric data
2.4 Anxiety			Other data	No numeric data
2.5 Fingernail biting			Other data	No numeric data
2.6 Daydreams			Other data	No numeric data
2.7 Difficulty falling asleep			Other data	No numeric data
2.8 Depression			Other data	No numeric data
2.9 Disturbed sleep			Other data	No numeric data
2.10 Dizziness			Other data	No numeric data
2.11 Drowsiness			Other data	No numeric data
2.12 Dysthymia			Other data	No numeric data
2.13 Emotional lability			Other data	No numeric data
2.14 Euphoria/hypomania			Other data	No numeric data
2.15 Asthenia and fatigue			Other data	No numeric data
2.16 Headache			Other data	No numeric data
2.17 Increased need to sleep			Other data	No numeric data
2.18 Involuntary movements			Other data	No numeric data
2.19 Irritability			Other data	No numeric data
2.20 Nervousness			Other data	No numeric data
2.21 Nightmares			Other data	No numeric data
2.22 Restlessness and agitation			Other data	No numeric data
2.23 Sadness			Other data	No numeric data
2.24 Stares			Other data	No numeric data
2.25 Excessive talking			Other data	No numeric data
2.26 Taciturnity ('talking too little')			Other data	No numeric data
2.27 Tics			Other data	No numeric data
2.28 Isolation and lack of interest in others			Other data	No numeric data
2.29 'Zombie like' demeanour			Other data	No numeric data
2.30 Somnolence			Other data	No numeric data
2.31 Obsession			Other data	No numeric data
2.32 Mood disorder			Other data	No numeric data
2.33 Confusional state			Other data	No numeric data
2.34 Sleep disorder			Other data	No numeric data
2.35 Propensity to cry			Other data	No numeric data
2.36 Sedation			Other data	No numeric data
2.37 Daytime sleepiness			Other data	No numeric data
2.38 Dysphoria			Other data	No numeric data
2.39 Logorrhoea			Other data	No numeric data
2.40 Impaired concentration			Other data	No numeric data
2.41 Difficulty waking up			Other data	No numeric data
2.42 Urinary incontinence			Other data	No numeric data
2.43 Paralysis			Other data	No numeric data
2.44 Affective disorder			Other data	No numeric data
2.45 Jumbled thoughts			Other data	No numeric data
2.46 Bulimia			Other data	No numeric data
2.47 Sleep late			Other data	No numeric data
2.48 Tooth grinding			Other data	No numeric data
2.49 Tremor			Other data	No numeric data
2.50 Stuttering			Other data	No numeric data
2.51 Flushing			Other data	No numeric data
2.52 Apathy			Other data	No numeric data
2.53 Abnormal behaviour			Other data	No numeric data
2.54 Stereotypies			Other data	No numeric data
2.55 Quietness			Other data	No numeric data
2.56 EEG changes			Other data	No numeric data
2.57 Did not like themselves			Other data	No numeric data
2.58 Sleep walking			Other data	No numeric data
2.59 Personality and behaviour disorders			Other data	No numeric data
2.60 Vertigo			Other data	No numeric data
3 Cardiovascular and respiratory system Show forest plot			Other data	No numeric data

3.1 Cough			Other data	No numeric data
3.2 Pharyngolaryngeal pain			Other data	No numeric data
3.3 Upper respiratory tract infection			Other data	No numeric data
3.4 Tachycardia			Other data	No numeric data
3.5 Abnormal ECG			Other data	No numeric data
3.6 Nasal congestion			Other data	No numeric data
3.7 Palpitation			Other data	No numeric data
3.8 Systolic blood pressure			Other data	No numeric data
3.9 Diastolic blood pressure			Other data	No numeric data
3.10 Pulse rate			Other data	No numeric data
3.11 ECG‐QT			Other data	No numeric data
3.12 Cold fingers			Other data	No numeric data
3.13 Sweating			Other data	No numeric data
3.14 Hypertension			Other data	No numeric data
3.15 Hypotension			Other data	No numeric data
3.16 Respiratory, thoracic and mediastinal disorders			Other data	No numeric data
3.17 Proportion of patients with micro‐nucleated (Mn) peripheral lymphocytes			Other data	No numeric data
4 Gastrointestinal system Show forest plot			Other data	No numeric data

4.1 Abdominal pain			Other data	No numeric data
4.2 Constipation			Other data	No numeric data
4.3 Decreased appetite			Other data	No numeric data
4.4 Decreased weight			Other data	No numeric data
4.5 Diarrhoea			Other data	No numeric data
4.6 Dry mouth			Other data	No numeric data
4.7 Gastrointestinal adverse events			Other data	No numeric data
4.8 Nausea			Other data	No numeric data
4.9 Upset stomach			Other data	No numeric data
4.10 Vomiting			Other data	No numeric data
4.11 Dyspepsia			Other data	No numeric data
4.12 Gastroenteritis			Other data	No numeric data
4.13 Increased appetite			Other data	No numeric data
4.14 Xerostomia			Other data	No numeric data
5 Musculoskeletal system Show forest plot			Other data	No numeric data

5.1 Chest pain			Other data	No numeric data
5.2 Height			Other data	No numeric data
5.3 Weight			Other data	No numeric data
5.4 BMI			Other data	No numeric data
5.5 Height z score			Other data	No numeric data
5.6 Weight z score			Other data	No numeric data
5.7 BMI z score			Other data	No numeric data
5.8 Increased mobility			Other data	No numeric data
5.9 Bone mineral density			Other data	No numeric data
6 Immune system Show forest plot			Other data	No numeric data

6.1 Nasopharyngitis			Other data	No numeric data
6.2 Pyrexia			Other data	No numeric data
6.3 Allergies			Other data	No numeric data
6.4 Cold symptoms			Other data	No numeric data
6.5 Pharyngitis			Other data	No numeric data
6.6 Viral infection			Other data	No numeric data
6.7 Rash			Other data	No numeric data
6.8 Rhinitis			Other data	No numeric data
6.9 Ear disorders			Other data	No numeric data
6.10 Fever			Other data	No numeric data
6.11 Infections			Other data	No numeric data
7 Urogenital system: enuresis Show forest plot			Other data	No numeric data

8 Other body systems Show forest plot			Other data	No numeric data

8.1 Hair loss			Other data	No numeric data
8.2 Skin problems			Other data	No numeric data
8.3 Accidental injury			Other data	No numeric data
8.4 Voice frequency			Other data	No numeric data
8.5 Hypersalivation			Other data	No numeric data
8.6 Nasal bleeding			Other data	No numeric data
8.7 Chromosomal aberration			Other data	No numeric data

Comparison 7. Non‐comparative studies: proportion of participants with non‐serious adverse events

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Comparison 8. Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to non‐serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants withdrawn from methylphenidate treatment due to non‐serious adverse events Show forest plot			Other data	No numeric data

2 Proportion of participants withdrawn from methylphenidate for unknown reasons Show forest plot			Other data	No numeric data

Comparison 8. Non‐comparative studies: proportion of participants withdrawn from methylphenidate treatment due to non‐serious adverse events

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Comparison 9. Patient reports/series: number of participants with serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Central nervous system Show forest plot			Other data	No numeric data

1.1 Psychotic conditions			Other data	No numeric data
1.2 Seizures			Other data	No numeric data
1.3 Cerebral arteritis			Other data	No numeric data
1.4 Self‐harm and suicidal behaviour			Other data	No numeric data
1.5 Death			Other data	No numeric data
1.6 Dyskinesia			Other data	No numeric data
2 Cardiovascular and respiratory system Show forest plot			Other data	No numeric data

2.1 Cardiovascular events			Other data	No numeric data
2.2 Hypertension			Other data	No numeric data
3 Gastrointestinal system: hepatoxicity Show forest plot			Other data	No numeric data

4 Urogenital system: priapism Show forest plot			Other data	No numeric data

Comparison 9. Patient reports/series: number of participants with serious adverse events

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Comparison 10. Patient reports/series: number of participants with non‐serious adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Central nervous system: movement‐related outcomes Show forest plot			Other data	No numeric data

1.1 Tics			Other data	No numeric data
1.2 Involuntary movements or dyskinesia			Other data	No numeric data
2 Central nervous system: mood disorders Show forest plot			Other data	No numeric data

2.1 Depression and disturbed mood			Other data	No numeric data
2.2 Irritability			Other data	No numeric data
2.3 Aggression			Other data	No numeric data
2.4 Mania/euphoria			Other data	No numeric data
3 Central nervous system: sleep problems Show forest plot			Other data	No numeric data

3.1 Disturbed sleep			Other data	No numeric data
3.2 Other sleep problems			Other data	No numeric data
4 Central nervous system: voice and speech disorders Show forest plot			Other data	No numeric data

4.1 Voice problems			Other data	No numeric data
4.2 Stuttering			Other data	No numeric data
5 Central nervous system: other specific adverse events Show forest plot			Other data	No numeric data

5.1 Anorexia			Other data	No numeric data
5.2 Obsessive compulsive disorder (OCD) symptoms			Other data	No numeric data
5.3 Headache			Other data	No numeric data
5.4 EEG changes			Other data	No numeric data
6 Cardiovascular and respiratory system Show forest plot			Other data	No numeric data

6.1 Vasculopathy			Other data	No numeric data
6.2 Cardiovascular problems			Other data	No numeric data
6.3 Bleeding			Other data	No numeric data
6.4 Tachycardia			Other data	No numeric data
7 Gastrointestinal system Show forest plot			Other data	No numeric data

7.1 Loss of appetite			Other data	No numeric data
7.2 Nausea and vomiting			Other data	No numeric data
8 Musculoskeletal system: growth Show forest plot			Other data	No numeric data

9 Immune system: allergic reactions Show forest plot			Other data	No numeric data

10 Urogenitial system Show forest plot			Other data	No numeric data

10.1 Testicular failure			Other data	No numeric data
10.2 Sexual adverse events			Other data	No numeric data
10.3 Incontinence			Other data	No numeric data
10.4 Enuresis			Other data	No numeric data
11 Other body systems Show forest plot			Other data	No numeric data

11.1 Skin reactions			Other data	No numeric data
11.2 Problems with sedation			Other data	No numeric data
11.3 Eye problems			Other data	No numeric data

Comparison 10. Patient reports/series: number of participants with non‐serious adverse events

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