Methylphenidate–risperidone combination in child psychiatry: A retrospective analysis of 44 cases

Annales Pharmaceutiques Françaises (2014) 72, 164—177

Disponible en ligne sur

ScienceDirect www.sciencedirect.com

ORIGINAL ARTICLE

Methylphenidate—risperidone combination in child psychiatry: A retrospective analysis of 44 cases Associations méthylphénidate-rispéridone en psychiatrie : analyse rétrospective sur 44 cas H. Javelot a,b,c,d,e,∗, C. Glay-Ribau a, F. Ligier b, L. Weiner d, N. Didelot f, M. Messaoudi c, M. Socha g, F. Body-Lawson b, B. Kabuth a,b a

Centre psychothérapeutique de Nancy-Laxou, 54520 Laxou, France Service de psychiatrie de l’enfant et de l’adolescent, hôpital d’enfants, 54500 Vandœuvre-lès-Nancy, France c ETAP — neuropsychopharmacology department, 54500 Vandœuvre-lès-Nancy, France d Psychiatry II and Inserm unit 1114, university hospital of Strasbourg, 67000 Strasbourg, France e Clinical pharmacy service, établissement public de santé Alsace Nord, 67170 Brumath, France f Centre sanitaire les Rives du Château, Croix Rouge franc¸aise, 54450 Blâmont, France g Service pharmacie, hôpital Brabois-Adultes, CHU de Nancy, 54500 Vandœuvre-lès-Nancy, France b

Received 2 October 2013; accepted 19 December 2013 Available online 30 January 2014

KEYWORDS Methylphenidate; Risperidone; Psychotimulantantipyschotic combinations; Attention deficit hyperactivity disorder;

Summary Introduction. — Psychotimulant-antipyschotic combinations are frequently used in child psychiatry, but have been rarely described in the literature. Method and patients. — We propose here a retrospective study of 44 children who received the combination methylphenidate (MPH)—risperidone (RIS). The sample is composed of children who received either MPH (n = 28) or RIS (n = 16) as primary treatment. A vast majority of the children had a comorbid attention deficit hyperactivity disorder (ADHD) diagnosis. Results. — For over 60% of patients, regardless of their initial monotherapy, bitherapy decreased the symptoms of ADHD and conduct disorder, sleep disorders and anxiety. Concerning the safety

∗ Corresponding author. Clinical Pharmacy Service — Mental Health Establishment (EPSAN), 141, avenue de Strasbourg, 67170 Brumath, France. E-mail address: [email protected] (H. Javelot).

0003-4509/$ — see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.pharma.2013.12.009

Methylphenidate—risperidone combination in child psychiatry

Child psychiatry

MOTS CLÉS Méthylphénidate ; Rispéridone ; Associations psychostimulantantipsychotique ; Trouble déficitaire de l’attention avec hyperactivité ; Psychiatrie de l’enfant

165

of the bitherapy, a compensation effect on weight gain and appetite was respectively observed in 70% and 50% of patients. Even though iatrogenic tachycardia can be encountered with both drugs, it has never been reported when they are associated and we have reported a total of 3 cases in our study. We have also observed a case of dyskinesia resolved with the discontinuation of the treatment. Discussion/conclusion. — MPH-RIS bitherapy appears to be particularly effective in ADHD with conduct disorder symptoms. Although tolerance may limit its use, the benefit/risk ratio seems favourable for a number of children. © 2013 Elsevier Masson SAS. All rights reserved.

Résumé Introduction. — Les associations psychostimulant-antipsychotique sont fréquemment utilisées en psychiatrie de l’enfant, mais ont rarement été décrites dans la littérature. Méthode et patients. — Nous proposons ici une étude rétrospective de 44 enfants qui ont rec ¸u l’association méthylphénidate (MPH)—rispéridone (RIS). La population est composée d’enfants qui ont rec ¸u soit le MPH (n = 28) ou soit la RIS (n = 16) comme premier traitement. Une grande majorité des enfants a un diagnostic de trouble déficitaire de l’attention (TDAH) comorbide. Résultats. — Pour plus de 60 % des patients, indépendamment de leur monothérapie initiale, la bithérapie a diminué les symptômes du TDAH, des troubles de la conduite, des troubles du sommeil et l’anxiété. En ce qui concerne la sécurité d’emploi de la bithérapie, un effet de compensation sur la prise de poids et l’appétit a été observé respectivement chez 70 % et 50 % des patients. Même si une tachycardie iatrogène peut être rencontrée avec les deux médicaments, aucun cas n’avait été rapporté lors de leur association et nous décrivons 3 cas dans notre étude. Nous avons également observé un cas de dyskinésie résolu avec l’arrêt du traitement. Discussion/conclusion. — La bithérapie MPH-RIS semble donc être particulièrement efficace dans le TDAH avec des symptômes de trouble des conduites. Bien que la tolérance peut limiter son utilisation, le rapport bénéfice/risque semble favorable pour un certain nombre d’enfants. © 2013 Elsevier Masson SAS. Tous droits réservés.

Introduction In recent years, great progress has been made in the understanding of the neurobiology of ADHD and its comorbidities [1—5]. Firstly, impairment in the frontal-striatal-pallidalthalamic circuits are well-established in ADHD [1], and, secondly, decreased density in the D2 /D3 receptors in subcortical areas are thought to contribute to the catecholaminergic neurotransmission dysregulation in the prefrontal cortex [5]. Besides this major hypothesis, noradrenergic projections seem also involved in the neurobiology of ADHD. Evidence for this hypothesis is based on: • the cognitive impairments reported in ADHD which seem to be closely related to noradrenergic inputs in prefrontal cortex; • and the relative efficacy of atomoxetine in ADHD, a noradrenergic reuptake inhibitor [5]. Conduct disorder, a frequent co-morbidity of ADHD, involve different brain areas (anterior cingulate cortex, left amygdala and right temporal cortex) and is characterized by reduced serotonin and cortisol levels and attenuated autonomic nervous system responses1 [3].

1 We summarize in Table 1 the main diagnosis and sub-diagnosis reported in this publication with key symptoms of DSM-IV-TR (Diagnostic and Statistical Manual of mental disorders.

Risperidone (RIS) is an atypical antipsychotic agent with D2 and 5-HT2A antagonistic activity. Its effectiveness in various childhood psychiatric disorders is widely supported, notably in pervasive developmental disorders (PDD) [6—9] and disruptive behaviour disorders (DBD) [10—14]. More specifically, RIS is recommended for aggression episodes that can occur in these disorders [15,16]. Methylphenidate (MPH) increases release and blocks the reuptake of dopamine and norepinephrine [5]. Psychostimulants like MPH are used in the treatment of hyperactivity, inattention and impulsivity in attention-deficit hyperactivity disorder (ADHD) [17—20]. However, ADHD rarely occurs as an isolated disorder in children [21], and is often observed in combination with DBD [22—24] and aggressive behaviour [25]. Although RIS may be useful in the treatment of comorbid ADHD, it is not the primary therapy of hyperactivity and inattention symptoms [22—28]. Thus, although both molecules induce opposite effects on the dopaminergic system, convergent data suggest that MPH-RIS combination might be an effective treatment for ADHD comorbid with DBD [29—32]. In a pioneering study, Cosgrove reported that 50 patients with ADHD treated with RIS and MPH showed a significant reduction in aggressive behaviours, thought disorders, appetite and sleep disturbances [29]. In 1999, Kewley reports his personal experience as a therapist and mentions his long use of MPH-RIS combination in cases of ADHD comorbid with DBD when past associations with clonidine or tricyclic antidepressants were

166 Table 1

H. Javelot et al. Main diagnosis and sub-diagnosis reported in the study with key symptoms of DSM-IV-TR.

Principaux diagnostics et sous-diagnostics rapportés dans l’étude avec les symptômes clés associés d’après le DSM-IV-TR.

Diagnosis and sub-diagnosis Attention-deficit and disruptive behavior disorders (DBD)

Key symptoms Attention deficit hyperactivity disorder (ADHD) Conduct disorder (CD)

Oppositional defiant disorder (ODD)

Pervasive developmental disorders (PDD)

Autistic disorder, Rett’s disorder, childhood disintegrative disorder, Asperger’s disorder and pervasive developmental disorder not otherwise specified

Inattention, hyperactivity, disruptive behavior, impulsivity Aggression to people and/or animals, destruction of property, deceitfulness or theft, serious violations of rules Actively refuses to comply with majority’s requests or consensus-supported rules, performs actions deliberately to annoy others, angry and resentful of others, argues often, blames others for his or her own mistakes, often loses temper, spiteful or seeks revenge, touchy or easily annoyed Autistic disorder is characterized by impairments in social interaction and communication, restricted interests and repetitive behaviors

American Psychiatric Association, 2000.

not as effective [30]. According to this author, this combination is associated with a favourable benefit-risk ratio in this population. In another study published in 2002, Bramble and Cosgrove observed 85% of their 170 patients with co-morbid ADHD treated for the most part with a psychostimulant [31]. They report that the addition of RIS was associated with a behavioural improvement in 92% or 100% of children according to the judgment made by the parents or prescribers, respectively. Aman et al. in 2004 also explored the potential value of the association MPH-RIS in ADHD comorbid with DBD [32]. This study compiled the results of two placebo-controlled, double-blind, 6-week studies on a total of 155 children [10,33]. Interestingly, the combination of RIS with a psychostimulant agent induced a significant decrease of hyperactivity symptoms compared to the administration of a stimulant drug alone. Other authors also reported the benefit of atypical antipsychotics such as RIS in the treatment of aggressive behaviours associated with ADHD [34,35]. Following the two short-term studies published by Aman et al. [32] and Snyder et al. [33], an open-label, 48-week study was performed on 77 children with DBD. In this study, RIS also proved to be effective in the treatment of DBD independently of the use of psychostimulants [11]. In an open-label, 3-week study, Kronenberger et al. [36] reported that the addition of quetiapine to MPH reduced ADHD symptoms and aggression in children whose symptoms did not respond enough to MPH alone. In a 12-week naturalistic study, Penzner et al. [37] assessed the safety and the efficacy of the combination of an antipsychotic and a stimulant through the follow-up of a group of 86 patients with oppositional or aggressive behaviours, treated with an antipsychotic, and another group of 77 patients treated with both a stimulant and an antipsychotic. Compared to the patients whose treatment consisted of an antipsychotic alone, the antipsychotic-psychostimulant combination did not affect antipsychotic efficacy measured by the Clinical

Global Impression (CGI) Severity Scores and the Children’s Global Assessment Scale (CGAS). Overall, the association of a psychotimulant with an antipsychotic drug, or more specifically MPH-RIS, seems to be well tolerated [29—38], although the risk of tardive dyskinesia is reported on case reports in the literature [39—42]. According to Penzner et al. [37], psychostimulants did not reduce antipsychotic effects on sedation, metabolic or hormonal parameters, weight or body mass index (BMI) in their sample of children with DBD. Calarge et al. [38] results also suggest that a psychostimulant-RIS concomitant treatment does not diminish the effects of antipsychotic drugs on weight compared to patients with RIS alone. Armenteros et al. [35] reported that patients previously treated with psychostimulant and secondarily with RIS or placebo are not significantly different on measures of weight and sedation. Finally, Kronenberger et al. [36] observed different results with a combination of quetiapine and MPH: a weight gain offsetting weight loss with MPH alone and sedation was noted in about half of the patients. In France, although antipsychotic-psychostimulant combinations are regularly prescribed, to our knowledge, there are no reports on clinical variables associated with its use. Thus, we performed a retrospective analysis on the clinical profile of 44 children who received a bitherapy of MPH-RIS, as well as the effectiveness and the safety of this combination.

Material and method We performed a descriptive analysis of the clinical profile, the effects and the tolerance of the MPH-RIS bitherapy in children and adolescents followed-up at the psychiatry department of our hospital. There were two groups in our population of 44 patients: those receiving MPH first

Methylphenidate—risperidone combination in child psychiatry (designated MPH group) and those receiving RIS first (designated RIS group). Our characterization of clinical profiles was made based on age, gender, psychosocial status and psychiatric diagnosis. A follow-up of the posologies and the interruption of mono- and bitherapies was conducted. The effects of the drug combinations were estimated with the Clinical Global Impression rating scale (CGI), which is a Likert scale ranging from 1 (dissatisfied) to 10 (very satisfied), and via the monitoring of psychiatric symptoms during the course of the treatment. All physicians were asked to rate children’s symptoms via the CGI even if the treatment had been discontinued. Finally, the adverse effects were first identified when patients were on monotherapy and their evolution was followed-up when they were receiving a bitherapy. We defined the following inclusion criteria: • children and adolescents who had benefited more from the association of two psychotropic drugs, MPH and RIS, whatever the duration of prescription of the drug combination, with or without other drugs: • male or female: • no lower limit of age and maximum of 18 years at the time of the onset of the combination therapy. The exclusion criteria were: • patients who received successively MPH and RIS (or vice versa), with no association of the two molecules; • patient older than 18 at the time of bitherapy. Seven child psychiatrists participated in the development of a questionnaire aiming to collect the demographic information described above. Bitherapies were recorded between April 2005 and December 2009.

167 others problems related to primary support group, including family circumstances (Z63).

Psychiatric diagnoses Tables 2 and 3 show the distribution of ADHD and non-ADHD patients, respectively in MPH and RIS groups.

MPH group During monotherapy, 85.7% (n = 24) of patients had ADHD including 66.7% (n = 16) of patients with comorbid ADHD. The most common comorbidities were conduct disorders, mixed disorder and reactive attachment disorder, representing 39.3% (n = 11) of comorbidities. During bitherapy, 89.3% (n = 25) of patients had ADHD but none of them suffered from ADHD only. The most common comorbidities were the same as those reported during monotherapy but their rates were higher (57.1%; n = 16). Table 2 shows the changes in principal diagnoses between mono- and bitherapy.

RIS group During monotherapy, diagnoses varied more than in the MPH group. The majority of patients had a mixed disorder (31.2%, n = 5), ADHD (25%, n = 4) or a PDD (18.7%, n = 3). During bitherapy, the proportion of mixed disorder and pervasive developmental disorder are relatively stable (37.5% and 25%, respectively, n = 6 and 4), while the proportion of ADHD increases (43.75% n = 7). Table 3 shows the changes in principal diagnoses between mono-and bitherapy.

Treatment follow-up

Results Age and gender Before the combination therapy MPH-RIS, 64% of patients (28 of 44) received MPH monotherapy and 36% (16 of 44) received RIS monotherapy. MPH group had 26 boys and 2 girls, while the RIS group consisted of 13 boys and 3 girls. The mean age at the onset of mono- and bitherapies were 7.9 ± 1.9 years and 10.4 ± 2.5 years respectively for the MPH group and 9.4 ± 2.9 years and 10.2 ± 3.3 years respectively for the RIS group.

Psychosocial status Patients with no Z-codes (factors influencing health status and contact with health services in the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10); see examples bellow [43]) represent less than 30% of patients in the MPH group and less than 40% of patients in the RIS group. In the MPH group, 39.3% (n = 11) of patients had a family history of other mental and behavioral disorders (Z81) and other problems related to primary support group, including family circumstances (Z63). In the RIS group, 18.7% (n = 3) of patients had a family history of other mental and behavioral disorders (Z81) or problems related to upbringing (Z62) and 43.7% (n = 7) presented

Table 4 shows the means and standard deviations of the initial and maximum doses in each group for mono- and bitherapy. Table 5 reveals the means, standard deviations and medians of the duration of mono- and bitherapy.

Drug combination effects CGI In the MPH group, CGI averaged 6 with a standard deviation of 2.3 and a median value of 7, while in the RIS group CGI averaged 7.1 with a standard deviation of 1.2 and a median of 7.

Evolution of psychiatric symptoms in the MPH group Table 6 shows the evolution of psychiatric symptoms during mono- and bitherapy in the MPH group. Before monotherapy, the predominant symptoms are those seen in ADHD. More than half of the patients also present the key symptoms of conduct disorder and anxiety. A quarter of patients have sleep disorders. More than 20% display social withdrawal behaviours or tics. Other symptoms are found in up to 18% of patients.

168

Table 2

Distribution of the evolution of main diagnoses between mono- and bitherapies (MPH group, n = 28).

Répartition de l’évolution des diagnostiques principaux entre la mono- et la bithérapie (groupe MPH, n = 28).

BiTh MonoTh

Pure ADHD

Pure ADHD ADHD + CD ADHD + SD ADHD + hyperanxiety ADHD + tics Others ADHD ADHD + MD ADHD + RAD ADHD + LP Others PDD Others

a

Total

0

ADHD + CD ADHD + SD ADHD + hyperanxietyADHD + ticsOthers ADHD 1

2

ADHD + MD ADHD + RADADHD + LP Others PDD

Others

2

1

8 5 2 1 1 1 3 3 0 0 4

1

28

1

3a

1 1a

1 1

1 1a 1a a

1 a

1

1

1 2a

1 a a

1 5

2

3

1

0

2

1

6

5

2

3

Total

BiTh = bitherapy/monoTh = monotherapy; CD = conduct disorder; SD = school disorder; MD = mixed disorder; RAD = reactive attachment disorder; LP = labile personality; PDD = pervasive developmental disorder. a Stability of diagnoses between the mono- and bitherapy.

H. Javelot et al.

Methylphenidate—risperidone combination in child psychiatry Table 3

169

Distribution of the evolution of main diagnoses between mono- and bitherapies (RIS group, n = 16).

Répartition de l’évolution des diagnostiques principaux entre la mono- et la bithérapie (groupe RIS, n = 16).

BiTh MonoTh

Pure ADHD

Pure ADHD ADHD + CD ADHD + SD ADHD + hyperanxiety MD RAD PDD Others

a

Total

0

ADHD + CD

ADHD + SD

ADHD + hyperanxiety

MD ± ADHD

RAD ± ADHD

Others

PDD ± ADHD

1 (−) 1a

2

1 2 1 0 5 1 3 3

2

16

1 a

1 (−) a

5 (3−/2+)a 1 (+)a 3 (2−/1+)a 1 1

0

2

6

1

4

Total

BiTh = Bitherapy/MonoTh = monotherapy; CD = conduct disorder; SD = school disorder; MD = mixed disorder; RAD = reactive attachment disorder; LP = labile personality; PDD = pervasive developmental disorder. For MD, RAD and PDD ± ADHD during biotherapy: the symbols + and − correspond to the number of patients without ADHD (−) or with ADHD (+). a Stability of diagnoses between the mono-and bitherapy.

Table 4 Means and standard deviations of the initial and maximum doses (max. doses) in methylphenidate (MPH) and risperidone (RIS) groups, for mono- and bitherapy. Moyennes et écarts-types des doses initials et maximales (max. doses) dans les groupes méthylphénidate (MPH) et rispéridone (RIS), pour la mono- et la bithérapie.

Monotherapy

Bitherapy MPH

MPH group (mg) RIS group (mg)

Table 5

RIS

Initial doses

Max. doses

Initial doses

Max. doses

Initial doses

Max. doses

14.8 ± 7.1 0.5 ± 0.2

27.1 ± 10.1 1 ± 0.4

27 ± 9 17.5 ± 10

30.9 ± 8.8 25.6 ± 10.5

0.6 ± 0.2 0.9 ± 0.3

1 ± 0.6 1.2 ± 0.8

Means, standard deviations and medians of the duration of mono- and bitherapy.

Moyennes, écarts-types et médianes de la durée de la mono- et de la bithérapie.

Duration of monotherapy

Mean Standard-deviation Median

MPH group(n = 28)

RIS group(n = 16)

915.6 days 830.4 days 645.5 days

298.2 days 458 days 162 days

Duration of bitherapy Suspendeda

Mean Standard-deviation Median

Continuedb

MPH group(n = 18)

RIS group(n = 8)

MPH-RIS group(n = 19)

467.4 days 508.7 days 238 days

440.9 days 350 days 337 days

543.9 days 511.9 days 181 days

RIS: risperidone; MPH: methylphenidate. a Before the end of the study. b To the end of the study.

170 Table 6

H. Javelot et al. Evolution of psychiatric symptoms during monotherapy and bitherapy in methylphenidate (MPH) group.

Évolution des symptômes psychiatriques durant la monothérapie et la bithérapie dans le groupe méthylphénidate (MPH).

MPH monotherapy Impulsiveness Hyperactivity Inattention Antisocial behavior Aggressiveness Opposition/provocation Mood disorders Sleep disorders Anxiety Autistic symptoms Social withdrawal Stereotypy Others Phobias Dyspraxia Dyslexia MPH-RIS bitherapy Impulsiveness Hyperactivity Inattention Antisocial behavior Aggressiveness Opposition/provocation Mood disorders Sleep disorders Anxiety Autistic symptoms Social withdrawal Stereotypy Others Phobias Dyspraxia Dyslexia

Regress

No effect

Aggravation

Emergence

Not applicable

Total

26 25 25 9 16 10 1 2 10

1 1 1 6 5 7 2 4 11

1 — — 1 2 1 — 1 1

— — — — — — — 5 —

— 2 2 12 5 10 25 16 6

28 28 28 28 28 28 28 28 28

4 — — — 1 1

2 1 7 3 1 4

— 4 — — — —

— 3 1 — — —

22 20 20 25 26 23

28 28 28 28 28 28

19 10 10 14 17 13 — 9 17

4 6 6 2 3 3 3 2 4

— — — — — — — 2 —

— — — — — — — — —

4 11 11 11 7 11 24 15 6

27 27 27 27 27 27 27 28 27

5 5 6 1 — 1

1 2 1 2 1 3

— — — — — —

— — — — — —

21 20 20 24 26 23

27 27 27 27 27 27

When they were taking MPH, key symptoms of ADHD decreased 89.3% (n = 25) (inattention and hyperactivity) and 92.3% (n = 26) (impulsivity). The key symptoms of conduct disorder, such as aggressive behaviours, regress in 69.6% of patients, and anxiety, social withdrawal and dyspraxia symptoms ameliorate in about half of patients. Other symptoms, such as mood disorders, sleep disorders, phobias, tics and dyslexia decrease in some patients. However, it was associated with the onset or worsening of stereotypies, sleep disorders or affective dissonance, respectively in 25%, 21.4% and 3.6% of patients (n = 7, 6 and 1). During bitherapy, all symptoms (except sleep disorder) were evaluated in 27 patients; for a patient, bitherapy was not assessable (treatment suspended after two days by the patient’s mother due to sleepwalking). Most symptoms regressed in more than 60% of patients on bitherapy: ADHD and conduct disorder related symptoms, sleep disorders, anxiety, and autistic symptoms. For a minority of patients, bitherapy had no effect on these symptoms. Bitherapy seemed the least effective on hyperactivity and

inattention (22.2% of patients, n = 6). In more than half of the patients, the combination therapy had no effect on the following symptoms: mood disorders, phobias, dyspraxia and dyslexia. Negative effects associated with the bitherapy were observed in only two patients whose sleep problems became worse.

Evolution of psychiatric symptoms in the RIS group Table 7 shows the evolution of psychiatric symptoms during mono- and bitherapy in the RIS group. Before monotherapy, in the RIS group, there were the following symptoms for more than 80% of patients: symptoms of ADHD, antisocial behaviour and aggression. Anxiety was also present in more than two thirds of patients. Approximately one third of patients presented opponent/provocative behaviours or sleep disorders. Autistic-like symptoms can be found in some patients (between 6.2 and 18.7%). Other symptoms (mood disorders, dyspraxia, dyslexia) are

Methylphenidate—risperidone combination in child psychiatry Table 7

171

Evolution of psychiatric symptoms during monotherapy and bitherapy in risperidone (RIS) group.

Évolution des symptômes psychiatriques durant la monothérapie et la bithérapie dans le groupe rispéridone (RIS).

RIS monotherapy Impulsiveness Hyperactivity Inattention Antisocial behavior Aggressiveness Opposition/provocation Mood disorders Sleep disorders Anxiety Autistic symptoms Social withdrawal Stereotypy Others Phobias Dyspraxia Dyslexia RIS-MPH bitherapy Impulsiveness Hyperactivity Inattention Antisocial behavior Aggressiveness Opposition/provocation Mood disorders Sleep disorders Anxiety Autistic symptoms Social withdrawal Stereotypy Others Phobias Dyspraxia Dyslexia

Regress

No effect

Aggravation

Emergence

Not applicable

Total

10 3 2 11 11 6 1 3 9

5 11 12 1 1 — 2 2 2

— — — 1 1 — — — —

— — 1 — — — — — —

1 2 1 3 3 10 13 11 5

16 16 16 16 16 16 16 16 16

— 2 1 — — —

1 — 2 — 2 4

— — — — — —

— — — — — —

15 14 13 16 14 12

16 16 16 16 16 16

15 14 15 8 6 1 2 3 7

— — — 2 4 2 1 1 3

— — — — — — — — —

— — — — — — — — —

1 2 1 6 6 13 13 12 6

16 16 16 16 16 16 16 16 16

1 — — — 1 2

— — 3 — 1 2

— 1 — — — —

— 2 — — — —

15 13 13 16 14 12

16 16 16 16 16 16

also present in some patients (up to 25% of them had dyslexia). With RIS alone, the symptoms of conduct disorder, anxiety, and stereotypies regressed in over 80% of our patients. At least 60% of patients showed a decrease of impulsivity and sleep disorders. In the vast majority of cases, RIS proved ineffective on: hyperactivity, inattention, social withdrawal and others autistic symptoms, mood disorders, dyspraxia and dyslexia. As in the MPH group, most symptoms declined for over 60% of patients on combination therapy: ADHD symptoms (impulsivity, hyperactivity, inattention), antisocial behavior, aggression, mood and sleep disorders, anxiety, and social withdrawal. Of these nine symptoms, five regressed in all patients in the RIS group, such as the key symptoms of ADHD and a key symptom of autistic spectrum (social withdrawal). Bitherapy had no effect on other symptoms (aggression, sleep, anxiety and mood) in approximately one third of patients. In at least half of the patients, bitherapy had no effect on opponent/provocative behaviours, dyspraxia,

dyslexia and others autistic symptoms. Only stereotypies seemed to worsen or appear during bitherapy (18.7% of patients, n = 3).

Drug combination tolerance Table 8 shows the evolution of adverse effects during bitherapy in the MPH and RIS groups.

MPH group The main side effect associated with MPH was a decreased appetite found in more than half of the patients; weight loss was observed in 25% of cases. Headaches were found in 14.3% of patients. Increased appetite associated with weight gain, drowsiness and abdominal pain were observed in only two patients. The evolution of tolerance under bitherapy was evaluated in 27 patients (excluding the patient with bitherapy suspended after two days due to sleepwalking). In most

172 Table 8

H. Javelot et al. Evolution of adverse effects during bitherapy in methylphenidate (MPH) and risperidone (RIS) groups.

Évolution des effets indésirables durant la bithérapie dans les groupes méthylphénidate (MPH) et rispéridone (RIS).

Regress

No effect

Aggravation

Emergence

Not applicable

Total

MPH group Increased appetite Decreased appetite Weight gain Weight loss Tardive dyskinesia Headache Drowsiness Constipation Abdominal pains Dry mouth Tachycardia Enuresis Aches

— 10 — 5 — — — — — — — — —

3 4 2 2 — 4 2 — 1 — — — —

— — — — — — — — — — — — —

8 — 7 — 1 1 1 — 1 — 1 1 1

16 13 18 20 26 22 24 27 25 27 26 26 26

27 27 27 27 27 27 27 27 27 27 27 27 27

RIS group Increased appetite Decreased appetite Weight gain Weight loss Tardive dyskinesia Headache Drowsiness Constipation Abdominal pains Dry mouth Tachycardia Asthenia Sweating

4 — 3 — — — — 1 — 1 — — —

2 — 2 — — — — — — — — — —

1 — 1 — — — 1 — — — — — —

— 4 — 3 — 2 1 — — — 2 1 1

9 12 10 13 16 14 14 15 16 15 14 15 15

16 16 16 16 16 16 16 16 16 16 16 16 16

cases, the bitherapy had no effect on the adverse effects associated with MPH, and, moreover, it does not worsen those side effects. With the bitherapy, almost two thirds of patients (10 of 16) had a regression of their decreased appetite. In addition, adverse effects absent during monotherapy appear (percentage of occurrence: 3.7%) such as tardive dyskinesia, tachycardia, enuresis and pain.

RIS group Compared to monotherapy with MPH, the main side effect associated with RIS was an increased appetite found in almost half of patients, with its corollary: weight gain (37.5% of cases). Drowsiness was observed in 18.7% of patients and transient decrease in appetite, constipation and dry mouth appeared in 6.2% of cases (one patient). Regarding increased appetite and weight gain, different trends were observed when adding MPH: regression in over half the cases, no effect in about 30% of cases, and increase in about 15% of cases. In contrast, decreased appetite and weight loss were observed in respectively 25% and 18.7% of patients. Worsening or onsets of drowsiness were observed in two patients. Finally, side effects absent with monotherapy appeared during bitherapy: tachycardia and headache (percentage of occurrence: 12.5%), and sweating (percentage of occurrence: 6.2%).

Discussion Study analysis General data General data reports allow us to describe a population relatively consistent with those conventionally receiving monotherapy with RIS or MPH. It is mostly a male population evolving in a disturbed psychosocial environment, as revealed by z-codes, and frequently comorbid with ADHD in both groups, or mixed disorders and PDD, specifically in the RIS group. The relationship between the severity of ADHD and the environment had been demonstrated, for example, in the study of Shaw et al. [44] reporting that children with comorbid ADHD are exposed to psychosocial factors more severe and pervasive compared to hyperactive children without conduct disorder. The contribution of environmental variables to externalizing disorders is also well established [45] and the factors involved are found in our study populations. The median of onset of symptoms associated with ADHD is approximately 7 years [46], whereas the onset of treatment with RIS is often late. We found this difference in our study, reflecting the difficulty of making diagnoses requiring the use of antipsychotics and caution due to the potential consequences of the introduction of these molecules.

Methylphenidate—risperidone combination in child psychiatry Our retrospective study allows a long-term evaluation of the effect of monotherapy and bitherapy in children and adolescents. The mean duration of this dual therapy was about one and a half year, while the bitherapy was discontinued after over a year in both groups. The main reason for stopping the bitherapy was associated with the occurrence of side effects, such as weight gain in the RIS group (see Table 8). Two other reasons were non-compliance and the discontinuation of the treatment, proposed by another physician, when the child joined another facility. The dosages used in this study are comparable to those used in other studies reporting cases of RIS-MPH association [32,35,37].

Drug combination’s effectiveness The use of MPH alone is usually associated with ADHD. In our sample, ADHD was initially pure or comorbid during monotherapy, but all children presented with a comorbid disorder in the combination therapy group. Comorbidities observed were those typically associated with ADHD, such as conduct disorder, mixed disorder and reactive attachment disorder [21]. ADHD is co-morbid with externalizing disorders such as conduct disorder or oppositional defiant disorder in 40% of some samples [47]. Mixed disorders according to the criteria of ICD-10 refer to conduct disorders co-morbid with an internalizing disorder (anxiety or depression) and is seen in approximately 25% of cases of ADHD [43,48,49]. Finally, early emotional deprivation is associated with the co-occurrence of ADHD and attachment disorder [50,51]. A small sample of our patients treated with MPH presented with ADHD and attachment disorder. The effects of MPH on ADHD symptoms are well known [17—20], while its action on comorbidities, although described on symptoms such as aggression is often inappropriate [52]. Thus, ADHD symptoms regress in the vast majority of patients with MPH alone, but the addition of RIS seem to potentiate the action of MPH on these symptoms, as Aman et al. [32] had previously observed. Moreover, if the interest of MPH alone is well established in the short term, its long-term effectiveness, especially in terms of academic achievement and social integration is less obvious [53]. Thus, in the MPH group in which children received MPH for about 2 and half years, a depletion effect of monotherapy could also explain the benefits observed with the addition of RIS. Moreover, for ADHD comorbid with conduct disorder, antisocial behavior, aggressiveness and opposition/provocation had already regressed with MPH monotherapy in a majority of patients, but the association with RIS also potentiates this effect, in accordance with the expected benefits of RIS [34,35] and previous work on the combination therapy MPH-RIS [29,32]. Anxiety regressed in less than half of the cases who were prescribed MPH, but in some cases anxiety symptoms became more severe. The addition of RIS had a beneficial effect in about 80% of cases. Comorbid anxiety disorders are estimated to be present in approximately 14% of ADHD patients [54] and since MPH alone does not seem to be the best treatment, the addition of RIS could reduce anxiety symptoms in some patients, even though a case report suggests caution [55]. Psychostimulants should be used cautiously in autistic spectrum disorders due to their potentially negative

173 effects on some symptoms (impairments in social abilities, exacerbation of restricted interests or repetitive behavior) [56—58], which is consistent with a case of impairment in communication that we have observed. In contrast, the observed effects on autistic symptoms were expected considering the effect attributed to RIS [6—9]. Onset or exacerbation of tics with MPH correspond to a common adverse effect during treatment with psychostimulants [59,60], and the beneficial effects shown later with RIS are also well known [61]. Interestingly, the beneficial effects of RIS on autistic-like symptoms were observed and appear not blocked by concomitant administration of MPH. Sleep disturbance observed in our study with MPH as monotherapy are common and are described as adverse effects that persist in the long run [62]. The improvement in this parameter with RIS was expected because of the sedative properties of this antipsychotic drug and is related to the previously described effects with psychotimulant-antipsychotic bitherapies [29,37]. However, Armenteros et al. [30] observed no impact of RIS versus placebo on sedation in patients treated with psychostimulants. The use of RIS in monotherapy has been widely reported in PDD [6—9] or mixed disorder [10—14], however, 25% of patients primarily receiving this treatment were diagnosed with ADHD. In fact, two patients suffered from ADHD comorbid with conduct disorder, while another patient initially diagnosed with ADHD was diagnosed with PDD. The latter first seemed to suffer from ADHD alone, but was diagnosed with a mixed disorder after the onset of the RIS treatment. RIS has a substantial effect on conduct disorder, anxiety, tics, impulsivity and sleep disorders in more than half of the patients. In contrast, RIS was ineffective on hyperactivity and inattention. Given the presence of ADHD symptoms in more than 80% of patients before the onset of the monotherapy and the relative ineffectiveness of RIS on these symptoms [26], antipsychotic alone seem insufficient in this population. In contrast, MPH adjunction bitherapy effectively counteracts impulsiveness, hyperactivity and inattention. As we previously mentioned, the positive impact of MPH on antisocial behaviors and aggression has been previously reported by Klein et al. [52]. Although psychostimulants are not an appropriate treatment for conduct disorder, Klein et al. [52] have found that in a group of 84 children, in which two-thirds met criteria for ADHD, the use of MPH improved antisocial and aggressive behavior. Moreover, it appears that the psychostimulant-responsive aggression depends on baseline level of aggression [63], which had already decreased with RIS in a vast majority of our patients. The beneficial effects of MPH on mood and anxiety are well-known i.e., [64,65], but in our population these symptoms, which had already regressed with RIS, undergo an additive effect associated with psychostimulants. Interestingly, the adjunction of MPH did not increase autistic symptoms, and it could be hypothesized that RIS protects the emergence of these symptoms in some children presenting with a major risk of symptoms exacerbation (including those with a diagnosis of PDD). It could also be noted that although children with autistic spectrum disorder seems to be particularly susceptible to adverse side effects with MPH [57], a beneficial effect with the psychostimulant is described in the treatment of autistic disorder comorbid with ADHD [56—58].

174 In both groups, the therapeutic effects of the two drugs on psychiatric symptoms seem to add up, especially with regard to ADHD symptoms, conduct disorder and anxiety, therefore there seems to be a real benefit for most patients [29]. These results are consistent with the findings of studies reporting the use of the association of MPH-RIS in pediatric populations suffering from ADHD comorbid with externalizing disorders [29,32,35]. Our results suggest that MPH-RIS bitherapy is associated with a decrease in autistic symptoms (MPH group) and it does not worsen or induce their occurrence (RIS group).

Drug combination’s safety Appetite increase and weight gain is another fundamental point since they are adverse effects of psychostimulants and antipsychotics. The results of our study showed that 70% of patients of the MPH group had decreased appetite and weight loss with MPH alone, but had a regression of these symptoms following the adjunction of RIS. Conversely, half of the patients in the RIS group had increased appetite and weight gain with RIS alone, but had a regression of these symptoms after the onset of MPH treatment. Several studies report similar results: for instance, Cosgrove [29] reported that the appetite of their subjects was normalized after the adjunction of RIS to MPH; Aman et al. [32] and Kronenberger et al. [36] also suggest an offsetting of the effects associated with antipsychotic and psychostimulant on weight gain. However, Armenteros et al. [35] reported that patients previously treated with psychostimulants showed secondary weight gain that was not significantly different compared to patients treated with RIS or a placebo. Calarge et al. [38] found that concomitant treatment psychostimulant-RIS does not reduce the impact of antipsychotics on weight, compared to patients with RIS alone. Sedation is another common side effect of antipsychotics, but only one case was observed in our study. It is possible that the bitherapy with a psychostimulant balances this side-effect, which was also suggested by Armenteros et al. [35] following the absence of sedative side-effects on the adjunctive therapy of RIS versus a placebo in children treated with psychostimulant. Tachycardia is also a common adverse effect of MPH and RIS, especially in children, i.e., [66—69]. Whereas it was not documented in our study with monotherapy, tachycardia was observed in 3 cases during bitherapy (one after adding RIS and two after adding MPH). This drug combination could therefore potentiate this adverse effect, but to our knowledge, there are no studies reporting this side effect. Indeed, only one study examined the cardiac safety of the combination therapy on twelve children in order to measure the effects of antipsychotics (half received RIS), more or less in combination with MPH (a quarter of children in the group), on the QT [70]. Their results show no changes in the QT interval and its dispersion with the antipsychotic alone or in combination with MPH. Finally, even though there were few cases of tardive dyskinesia in our sample, this side effect still needs to be addressed. In one patient in the MPH group, it was associated with the introduction of the RIS. It disappeared following the discontinuation of both drugs, which was also the case of a child who had been treated with MPH and RIS for a year before the onset of dyskinesia

H. Javelot et al. [42]. However, another case of an adolescent treated with MPH, RIS and fluoxetine is related to the onset of tardive dyskinesia 3 months after the introduction of RIS with the persistence of the extrapyramidal effect 6 weeks after discontinuation of the antipsychotic drug [42]. The interruption of the psychostimulant-antipsychotic combination should be also managed carefully, as suggested by the occurrence of dyskinesias with neuroleptic [41] or psychotimulant [39,71] discontinuations or during switches from RIS to MPH [72,73]. In about two-thirds of patients, clinicians were very satisfied or satisfied with the bitherapy (score greater than or equal to 7 on the CGI scale). This result confirms the positive effects of the bitherapy on psychiatric symptoms and its relatively good tolerance. Four patients had less than 5 on the CGI and these situations were directly related to cases of inefficiency of the bitherapy, particularly in very unstable family situations, showing the limits of pharmacological interventions and the need to combine them with psychosocial interventions.

Overview about the neuropsychopharmacology of psychostimulant-antipsychotic combinations Given the neurobiological data overviewed in the introduction, the neuropsychopharmacological hypotheses regarding pharmacotherapies used in ADHD should be further explored. Psychostimulants seem to exert their positive effects in ADHD with an inverted U-shaped relation between the level of catecholamine release and the prefrontal cortex abilities [2,5]. Reduced releases of noradrenaline and dopamine lead to ADHD symptoms, but excessive releases cause similar effects with an increase of stress through ␣1 and ␤1 noradrenergic receptors overstimulation [2]. Only a moderate stimulation of dopaminergic D1 -receptors and noradrenergic post-synaptic ␣2A -receptors improve prefrontal cortex functioning, and, in turn, ADHD symptoms [2]. Conversely, serotoninergic drugs seem to have a debatable effect on core symptoms of ADHD [1]. As explained previously, ADHD rarely occurs as an isolated disorder and co-morbidity with DBD is frequent. Indeed, decreased serotoninergic functioning causes a succession of behavioral disturbances from mood changes and impulsivity to aggression, which is observed in CD [3]. In these complex clinical situations, pharmacological regulation of aggression can require an add-on drug to psychostimulants. The neurobiology of aggression is now better understood. For instance, preclinical data show the importance of serotonin and dopamine through their action on 5HT1A/B , 5HT2A and D2 receptors [74]. These experiments have established that antagonists of the 5HT2A receptors, such as ritanserin or ketanserin, reduce aggression, while their agonists have opposite effects [75,76]. Similarly the D2 receptor antagonists such as tiapride or spirenone, reduce aggression, contrary to their agonists [77,78]. Therefore, the positive effects of RIS on aggression can be understood by its double interaction with D2 and 5HT2A receptors [74,79]. Moreover, the benefit of RIS, mirtazapine or pipamperone, a selective 5HT2A antagonist, in autism-related aggression and symptoms such as anger, aggression, and impulsivity in disorders

Methylphenidate—risperidone combination in child psychiatry such as mental retardation, suggests the role played by 5HT2A receptors in aggression and in other related symptoms [80]. Finally, RIS does not seem to affect amphetamineinduced dopamine release in the striatum [81], and, instead, it increases the release of noradrenaline in the cortex through its action on adrenergic ␣-2A receptors [81,82]. Although RIS acts as a D2 -antagonist, its blockage action at the striatum level may seem moderate compared to its action in the thalamus and in the temporal cortex [83]. It is well accepted that RIS can effectively thwart limbic catecholamine neurotransmission, which regulates prefrontal functioning, but this effect must be evaluated keeping in mind: • the expected beneficial effects on aggression; • the affinity of RIS for D1 -receptors, whose stimulation in the prefrontal cortex contributes to improve attentional processes, is lower (Ki = 21 nM and 3.3 nM for the D1 and D2 -receptors; [84]); • the fact that it does not preclude the beneficial effects obtained with psychostimulants [81]. Regarding the noradrenergic neurotransmission, the inverted-U model, described above, expects a benefit by stimulating ␣2A receptors. Although RIS is described as an ␣2A -receptors antagonist: • on the one hand, this effect corresponds to a dose of 0.4 mg/kg at an occupancy of only 11% of ␣2A receptors and this effect also contributes to the facilitation of catecholaminergic neurotransmission in the cortex [81,82]; • on the other hand, this effect is smaller to ␣1 -antagonist potential of RIS (Ki = 7.54 and 0.8 nM, for ␣2A and ␣1 affinities, respectively) that can help to limit stress effects related to excessive catecholamine release [2,81]. Finally, apart from the lack of interaction or contribution in the therapeutic effect of the combination psychostimulant-RIS, the antipsychotic provides, via its action on the serotonergic system and its high potential 5TH2A antagonism (Ki = 0.16 nM; [81,84]), a potentially beneficial effect on key DBD symptoms, such as aggression in the CD or anger in ODD, and similar or related symptoms frequently observed in PDD or mental retardation [80]. Taking together, these pharmacological data can partially explain the potential benefit of combining RIS and MPH in ADHD with CD-related disorders.

Conclusion In our study, MPH-RIS bitherapy appears potentially helpful in the management of ADHD with conduct disorder symptoms because of its efficacy and its relative good tolerance. Moreover, an in-depth reflexion about these data as well as other similar results in the literature might be particularly helpful for the management of co-morbid ADHD by incorporating more recent neurobiological and neuropsychopharmacological elements.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

175

References [1] Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 2005;57(11):1215—20. [2] Arnsten AF. Toward a new understanding of attentiondeficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 2009;23(Suppl. 1):33—41. [3] Cappadocia MC, Desrocher M, Pepler D, Schroeder JH. Contextualizing the neurobiology of conduct disorder in an emotion dysregulation framework. Clin Psychol Rev 2009;29(6):506—18. [4] Gonon F. The dopaminergic hypothesis of attentiondeficit/hyperactivity disorder needs re-examining. Trends Neurosci 2009;32(1):2—8. [5] Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry 2011;69(12):e145—57. [6] Hollway J, McCracken JT, McGough J, Shah B, Cronin P, Hong D, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347:314. [7] McDougle CJ, Stigler KA, Erickson CA, Posey DJ. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry 2008;69(Suppl. 4):15—20. [8] Miral S, Gencer O, Neslihan Inal-Emiroglu FN, Baykara B, Baykara A, Dirik E. Risperidone versus haloperidol in children and adolescents with AD. Eur Child Adolesc Psychiatry 2008;17:1—8. [9] Lemmon ME, Gregas M, Jeste SS. Risperidone use in autism spectrum disorders: a retrospective review of a clinic-referred patient population. J Child Neurol 2011;26:428—32. [10] Aman MG, De Smedt G, Derivan A, Lyons B, Findling RL. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry 2002;159:1337. [11] Turgay A, Binder C, Snyder R, Fisman S. Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs. Pediatrics 2002;110:e34. [12] Findling RL, Aman MG, Eerdekens M, Derivan A, Lyons B. Longterm, open-label study of risperidone in children with severe disruptive behaviors and below-average IQ. Am J Psychiatry 2004;161:677. [13] Croonenberghs J, Fegert JM, Findling RL, De Smedt G, Van Dongen S. Risperidone in children with disruptive behavior disorders and subaverage intelligence: a 1-year, open-label study of 504 patients. J Am Acad Child Adolesc Psychiatry 2005;44:64—72. [14] Findling RL. Atypical antipsychotic treatment of disruptive behavior disorders in children and adolescents. J Clin Psychiatry 2008;69:9—14. [15] Parikh MS, Kolevzon A, Hollander E. Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol 2008;18:157—78. [16] Buitelaar JK, van der Gaag RJ, Cohen-Kettenis P, Melman CT. A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities. J Clin Psychiatry 2001;62:239—48. [17] Spencer T, Biederman J, Wilens T, Harding M, O’Donnell D, Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry 1996;35:409—32. [18] The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Multimodal treatment study of children with ADHD. Arch Gen Psychiatry 1999;56:1073—86.

176 [19] Ghuman JK, Arnold LE, Anthony BJ. Psychopharmacological and other treatments in preschool children with attentiondeficit/hyperactivity disorder: current evidence and practice. J Child Adolesc Psychopharmacol 2008;18:413—47. [20] Fredriksen M, Halmøy A, Faraone SV, Haavik J. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies. Eur Neuropsychopharmacol 2012;23:508—27. [21] Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991;148:564—77. [22] Biederman J, Petty CR, Dolan C, Hughes S, Mick E, Monuteaux MC, et al. The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study. Psychol Med 2008;38:1027—36. [23] Biederman J, Petty CR, Monuteaux MC, Mick E, Parcell T, Westerberg D, et al. The longitudinal course of comorbid oppositional defiant disorder in girls with attentiondeficit/hyperactivity disorder: findings from a controlled 5-year prospective longitudinal follow-up study. J Dev Behav Pediatr 2008;29:501—7. [24] Connor DF, Steeber J, McBurnett K. A review of attentiondeficit/hyperactivity disorder complicated by symptoms of oppositional defiant disorder or conduct disorder. J Dev Behav Pediatr 2010;31:427—40. [25] King S, Waschbusch DA. Aggression in children with attention-deficit/hyperactivity disorder. Expert Rev Neurother 2010;10:1581—94. [26] Steer CR. Managing attention deficit/hyperactivity disorder: unmet needs and future directions. Arch Dis Child 2005;90:i19—25. [27] Günther T, Herpertz-Dahlmann B, Jolles J, Konrad K. The influence of risperidone on attentional functions in children and adolescents with attention-deficit/hyperactivity disorder and co-morbid disruptive behavior disorder. J Child Adolesc Psychopharmacol 2006;16:725—35. [28] Correia Filho AG, Bodanese R, Silva TL, Alvares JP, Aman M, Rohde LA. Comparison of risperidone and methylphenidate for reducing ADHD symptoms in children and adolescents with moderate mental retardation. J Am Acad Child Adolesc Psychiatry 2005;44:748—55. [29] Cosgrove PVF. Risperidone added to methylphenidate in attention deficit hyperactivity disorder. European Neuropsychopharmacology 1996;6:11—2. [30] Kewley GD. Risperidone in comorbid ADHD and ODD/CD. J Am Acad Child Adolesc Psychiatry 1999;38:1327—8. [31] Bramble DJ, Cosgrove PV. Parental assessments of the efficacy of risperidone in attention deficit hyperactivity disorder. Clin Child Psychol Psychiatry 2002;7:225—33. [32] Aman MG, Binder C, Turgay A. Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ. J Child Adolesc Psychopharmacol 2004;14:243—54. [33] Snyder R, Turgay A, Aman M, Binder C, Fisman S, Carroll A, et al. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41:1026—36. [34] Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41:26S—49S. [35] Armenteros JL, Lewis JE, Davalos M. Risperidone augmentation for treatment-resistant aggression in attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007;46:558—65. [36] Kronenberger WG, Giauque AL, Lafata DE, Bohnstedt BN, Maxey LE, Dunn DW. Quetiapine addition in methylphenidate

H. Javelot et al.

[37]

[38]

[39]

[40]

[41] [42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

treatment-resistant adolescents with comorbid ADHD, conduct/oppositional-defiant disorder, and aggression: a prospective, open-label study. J Child Adolesc Psychopharmacol 2007;17:334—47. Penzner JB, Dudas M, Saito E, Olshanskiy V, Parikh UH, Kapoor S, et al. Lack of effect of stimulant combination with secondgeneration antipsychotics on weight gain, metabolic changes, prolactin levels, and sedation in youth with clinically relevant aggression or oppositionality. J Child Adolesc Psychopharmacol 2009;19:563—73. Calarge CA, Acion L, Kuperman S, Tansey M, Schlechte JA. Weight gain and metabolic abnormalities during extended risperidone treatment in children and adolescents. J Child Adolesc Psychopharmacol 2009;19:101—9. Benjamin E, Salek S. Stimulant-atypical antipsychotic interaction and acute dystonia. J Am Acad Child Adolesc Psychiatry 2005;44:509—10. Connor DF, Benjamin S, Ozbayrak KR. Case study: neuroleptic withdrawal dyskinesia exacerbated by ongoing stimulant treatment. J Am Acad Child Adolesc Psychiatry 1995;34:1490—4. Feeney DJ, Klykylo W. Risperidone and tardive dyskinesia. J Am Acad Child Adolesc Psychiatry 1996;35:1421—2. Willemsen MAP, van der Wal KGH. Medication-induced mandibular luxation in a seven-year-old patient. Tijdschr Psychiatr 2008;50:61—4. World Health Organisation. ICD-10 classifications of mental and behavioural disorder: clinical descriptions and diagnostic guidelines. Geneva: World Health Organisation; 1992. Shaw DS, Owens EB, Giovannelli J, Winslow EB. Infant and toddler pathways leading to early externalizing disorders. J Am Acad Child Adolesc Psychiatry 2001;40:36—43. Cohen D. Probabilistic epigenesis: an alternative causal model for conduct disorders in children and adolescents. Neurosci Biobehav Rev 2010;34:119—29. Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006;163:716—23. Connor DF, Edwards G, Fletcher KE, Baird J, Barkley RA, Steingard RJ. Correlates of comorbid psychopathology in children with ADHD. Am Acad Child Adolesc Psychiatry 2003;42:193—200. Biederman J, Faraone SV, Keenan K, Benjamin J, Krificher B, Moore C, et al. Further evidence for family-genetics risk factors in attention deficit hyperactivity disorder: patterns of comorbidity in probands and relatives in psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 1992;49:728—38. Pfiffner L, McBurnett, Rathouz PJ, Judice S. Family correlates of oppositional and conduct disorders in children with attention deficit hyperactivity disorder. J Abnorm Child Psychol 2005;33:551—63. Kreppner JM, O’Connor TG, Rutter M. Can inattention/overactivity be an institutional deprivation syndrome? J Abnorm Child Psychol 2001;29:513—28. Stevens SE, Sonuga-Barke EJ, Kreppner JM, Beckett C, Castle J, Colvert E, et al. Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence. J Abnorm Child Psychol 2008;36:385—98. Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM, Pollack S. Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry 1997;54:1073—80. Swanson JM, Lerner M, Williams L. More frequent diagnosis of attention deficit hyperactivity disorder. N Engl J Med 1995;333:944. Steiner H, Remsing L, Work Group on Quality Issues. Practice parameters for the assessment and treatment of children and

Methylphenidate—risperidone combination in child psychiatry

[55]

[56]

[57]

[58]

[59]

[60] [61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

adolescents with oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry 2007;46:126—41. Hanna GL, Fluent TE, Fischer DJ. Separation anxiety in children and adolescents treated with risperidone. J Child Adolesc Psychopharmacol 1999;9:277—83. Quintana H, Birmaher B, Stedge D, Lennon S, Freed J, Bridge J, et al. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995;25(3):283—94. Handen BL, Johnson CR, Lubetsky M. Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder. J Autism Dev Disord 2000;30(3):245—55. Di Martino A, Melis G, Cianchetti C, Zuddas A. Methylphenidate for pervasive developmental disorders: safety and efficacy of acute single dose test and ongoing therapy: an open-pilot study. J Child Adolesc Psychopharmacol 2004;14(2):207—18. Wigal T, Greenhill L, Chuang S, McGough J, Vitiello B, Skrobala A, et al. Safety and tolerability of methylphenidate in preschool children with ADHD. J Am Acad Child Adolesc Psychiatry 2006;45:1294—303. Lerner M, Wigal T. Long-term safety of stimulant medications used to treat children with ADHD. Pediatr Ann 2008;37:37—45. Rampello L, Alvano A, Battaglia G, Bruno V, Raffaele R, Nicoletti F. Tic disorders: from pathophysiology to treatment. J Neurol 2006;253:1—15. Schachter HM, Pham B, King J, Langford S, Moher D. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. CMAJ 2001;165:1475—88. Blader JC, Pliszka SR, Jensen PS, Schooler NR, Kafantaris V. Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. Pediatrics 2010;126:e796—806. Gürkan K, Bilgic ¸ A, Türkoglu S, Kilic ¸ BG, Aysev A, Uslu R. Depression, anxiety and obsessive-compulsive symptoms and quality of life in children with attention-deficit hyperactivity disorder (ADHD) during three-month methylphenidate treatment. J Psychopharmacol 2010;24:1810—8. Rösler M, Retz W, Fischer R, Ose C, Alm B, Deckert J, et al. Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD. World J Biol Psychiatry 2010;11:709—18. Ballard JE, Boileau RA, Sleator EK, Massey BH, Sprague RL. Cardiovascular responses of hyperactive children to methylphenidate. JAMA 1976;236:2870—4. Safer DJ. Relative cardiovascular safety of psychostimulants used to treat attention-deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 1992;2:279—90. Posey DJ, Walsh KH, Wilson GA, McDougle CJ. Risperidone in the treatment of two very young children with autism. J Child Adolesc Psychopharmacol 1999;9:273—6. Masi G, Cosenza A, Mucci M, De Vito G. Risperidone monotherapy in preschool children with pervasive developmental disorders. J Child Neurol 2001;16:395—400.

177 [70] Nahshoni E, Spitzer S, Berant M, Shoval G, Zalsman G, Weizman A. QT interval and dispersion in very young children treated with antipsychotic drugs: a retrospective chart review. J Child Adolesc Psychopharmacol 2007;17:187—94. [71] McLaren JL, Cauble S, Barnett RJ. Aripiprazole induced acute dystonia after discontinuation of a stimulant medication. J Clin Psychopharmacol 2010;30:77—8. [72] Sabuncuoglu O. Risperidone-to-methylphenidate switch reaction in children: three cases. J Psychopharmacol 2007;21:216—9. [73] Hollis CP, Thompson A. Acute dyskinesia on starting methylphenidate after risperidone withdrawal. Pediatr Neurol 2007;37:287—8. [74] Ricci LA, Connor DF, Morrison R, Melloni Jr RH. Risperidone exerts potent anti-aggressive effects in a developmentally immature animal model of escalated aggression. Biol Psychiatry 2007;62(3):218—25. [75] Sakaue M, Ago Y, Sowa C, Sakamoto Y, Nishihara B, Koyama Y, et al. Modulation by 5-hT2A receptors of aggressive behavior in isolated mice. Jpn J Pharmacol 2002;89(1):89—92. [76] Shih JC, Ridd MJ, Chen K, Meehan WP, Kung MP, Seif I, et al. Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A. Brain Res 1999;835(2):104—12. [77] Nikulina EM, Kapralova NS. Role of dopamine receptors in the regulation of aggression in mice; relationship to genotype. Neurosci Behav Physiol 1992;22(5):364—9. [78] Sweidan S, Edinger H, Siegel A. D2 dopamine receptormediated mechanisms in the medial preoptic-anterior hypothalamus regulate effective defense behavior in the cat. Brain Res 1991;549(1):127—37. [79] Schwartzer JJ, Connor DF, Morrison RL, Ricci LA, Melloni Jr RH. Repeated risperidone administration during puberty prevents the generation of the aggressive phenotype in a developmentally immature animal model of escalated aggression. Physiol Behav 2008;95(1—2):176—81. [80] Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 2003;28(2):402—12. [81] Leysen JE, Gommeren W, Eens A, de Chaffoy de Courcelles D, Stoof JC, Janssen PA. Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 1988;247(2):661—70. [82] Marcus MM, Wiker C, Frånberg O, Konradsson-Geuken A, Langlois X, Jardemark K, et al. Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission. Int J Neuropsychopharmacol 2010;13(7):891—903. [83] Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS. Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 2003;23(1):5—14. [84] Franck N, Thibaut F. Pharmacology and mechanisms of action of neuroleptic agents. In: EMC Psychiatrie; 2005. p. 282—99.