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Objectives: The aim of this study was to assess effectiveness and tolerability of Clozapine in the treatment of aggression in youth with Neurodevelopmental Disorders. Methods: Patients were consecutively admitted at our third-level university hospital with nationwide catchment from June 2018 to October 2022, and followed up to July 2023. Eligibility criteria were as follows: (1) Autism Spectrum Disorder (ASD) and/or Intellectual Disability/Borderline Cognitive Functioning, (2) behavioral dyscontrol with physical aggression; (3) age range between 8 and 18 years; (4) clinical indication for Clozapine treatment after at least two failed trials with other Second-Generation Antipsychotics (SGAs); (5) availability of an at least 6-month-long follow-up. To evaluate the response to Clozapine, we used the Clinical Global Impressions (CGI) rating scales (Clinical Global Impressions-Severity [CGI-S] and Clinical Global Impressions-Improvement [CGI-I]), the Children's Global Assessment Scale (CGAS), and the Aberrant Behavior Checklist (ABC). Results: Twenty-six children and adolescents (21 boys, age 13.47 ± 2.05 years, follow-up duration 9.77 ± 3.50 months) were included in the analysis. Clinical severity (CGI-S) and functional impairment (Clinical Global Assessment Scale) significantly improved, as well as the ABC Total Score and the scores in several subscales. Sixteen patients (61.54%) were responders (CGI-I ≤2), and 13 (50.00%) displayed remission of aberrant behaviors (ΔABC-Total >35), while response/remission condition was not affected by add-on medications and psychotherapy. Most frequent side effects were increased appetite (50.00%), sialorrhea (38.46%), and increased repetitive behaviors (26.92%). Two patients presented epileptic seizures, while no patients presented leucopoenia. Conclusions: Our results suggest that Clozapine may be helpful in ameliorating treatment-resistant aggression in youth with neurodevelopmental conditions. Possible pharmacological strategies for the management of most frequent side effects are also suggested.

Introduction: Conduct disorder (CD) is characterized by repetitive and persistent antisocial behaviors, being among the most frequently reported reasons of referral in youth. CD is a highly heterogeneous disorder, with possible specifiers defined according to age at onset, Limited Prosocial Emotions (LPE) otherwise known as Callous-Unemotional (CU) traits, Emotional Dysregulation (ED), and patterns of comorbidity, each with its own specific developmental trajectories., Areas Covered: The authors review the evidence from published literature on the clinical presentations, diagnostic procedures, psychotherapeutic and psychoeducational approaches, and pharmacological interventions from RCT and naturalistic studies in youth. Evidence from studies including youths with LPE/CU traits, ED and aggression are also reviewed, as response moderators., Expert Opinion: Due to its clinical heterogeneity, relevant subtypes of CD should be carefully characterized to gain reliable information on prognosis and treatments. Thus, disentangling this broad category in subtypes is crucial as a first step in diagnosis. Psychosocial interventions are the first option, possibly improving LPE/CU traits and ED, especially if implemented early during development. Instead, limited information, based on low-quality studies, supports pharmacological options. Second-generation antipsychotics, mood stabilizers, and stimulants are first-line medications, according to different target symptoms, such as aggression and emotional reactivity. Developmental pathways including ADHD suggest a specific role of psychostimulants.

In mental health care, transition refers to the pathway of a young person from a child and adolescent mental health service (CAMHS) to an adult mental health service (AMHS). In Italy, the age of transition from adolescents to adults' mental health services is at the age of 18. Difficulties in transitioning have shown to favor patients' and families' disengagement and discontinuity of care with pharmacological treatment dropouts. On the other hand, a smooth and effective transition may improve the management of the disease and increase the chances of improvement of young schizophrenic patients. This project of roundtables, including child neuropsychiatrists (CNPs) and adult psychiatrists (Psy) throughout Italy, was aimed at exploring the problems of transition in clinical practice and collecting the proposals to improve transition management. The need to fill some cultural and organizational aspects strongly emerged to improve the transition process of adolescents with schizophrenia to adults' mental health services. On the one hand, specific training programs for both Psy and CNPs on the transition process are hoped for. On the other hand, both Psy and CNPs have expressed a need for shared official protocols, direct handover between the services including a period of shared management, and building of territorial multidisciplinary teams. All these aspects imply having a national mental health policy dedicated to taking charge of young people with mental health disorders, and accompanying them across the border between children and adults' mental health services. Improving transitional care can facilitate not only recovery but also prevention of mental illness for young people. Allocation of resources should aim at matching the epidemiological burden and reducing the heterogeneity between Italian regions.

Introduction: Lurasidone is an atypical antipsychotic agent approved in the European Union for the treatment of schizophrenia in adults and adolescents (13-17 years). Clinical trials have shown a generally favorable balance between efficacy and tolerability., Areas Covered: This paper provides a review and commentary regarding the use of lurasidone in adults and adolescents with schizophrenia. The available information about efficacy, tolerability, dosing, and switching is analyzed, highlighting the strategies that may be most useful in real-world clinical practice. Virtual case studies, designed based on the authors' clinical experience with real-world patients, are provided., Expert Opinion: Lurasidone is efficacious in adolescents and adults in a wide range of symptoms of schizophrenia. Choosing the right dose for each patient and combining lurasidone with other medications is key to treatment success. Lurasidone has proven effective both in adolescents and adults in treating the acute phase of schizophrenia and reducing the risk of relapse. It has shown a relatively favorable tolerability profile, with minimal effects on metabolic parameters and prolactin levels.

Objective: To meta-analytically examine the trends and correlates of antipsychotic use in youth with mood disorders., Methods: Systematic literature search without language restriction in PubMed/MEDLINE/PsycINFO from database inception through March 2015 using the following search terms: (antipsychotic* OR neuroleptic* OR "dopamine blocker*" OR antidopaminergic) AND (child* OR adolescen* OR pediatric OR youth) AND (prescription* OR prescrib* OR use OR utilization OR database OR pharmacoepidemiolog* OR frequency OR rate OR rates). Random effects meta-analysis and meta-regression analyses were conducted., Study Selection: Included were studies reporting on the frequency of (1) mood disorders in antipsychotic-treated youth (≤ 19 years) and (2) antipsychotic use in youth with mood disorders., Data Abstraction: Two independent investigators abstracted data on study, patient, and treatment characteristics., Results: Forty-one studies were meta-analyzed (N = 518,919, mean ± SD age = 12.8 ± 1.8 years, males = 65.7%). Altogether, 24.2% of antipsychotic-treated youth had a mood disorder diagnosis (studies = 34, depression spectrum disorder = 10.9%, bipolar spectrum disorder = 13.6%). In longitudinal studies, the overall proportion increased significantly from 17.3% in 2000 (range, 1996-2009) to 24.5% in 2006 (range, 2004-2011) (odds ratio [OR] = 1.50; 95% confidence interval [CI], 1.26-1.79; P < .0001). This increase was driven entirely by bipolar spectrum diagnoses (2001 = 11.1%, 2006 = 16.3%, P < .0001), rather than depression spectrum diagnoses (2001 = 9.1%, 2007 = 9.2%, P = .77). Among youth with mood disorders (8 studies), 24.0% received antipsychotics (depression spectrum disorder = 4.6%; bipolar spectrum disorder = 44.0%)., Conclusions: The proportion of youth with mood disorder diagnoses increased significantly among antipsychotic-treated youth, driven entirely by an increase in youth with bipolar spectrum disorders. Progress in understanding the reasons for these trends and for an evaluation of the appropriateness of the observed antipsychotic prescribing requires more detailed information than is available in traditional pharmacoepidemiologic databases., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

During the past decade, a substantial increase in the use of second generation antipsychotics (SGAs) has occurred for a number of juvenile psychiatric disorders, often as off-label prescriptions. Although they were thought to be safer than older, first generation antipsychotics, mainly due to a lower risk of neurological adverse reactions, recent studies have raised significant concerns regarding their safety regarding metabolic, endocrinological and cardiovascular side effects. Aim of this paper is to update with a narrative review, the latest findings on safety of SGAs in youths. Results suggest that different SGAs may present different safety profiles. Metabolic adverse events are the most frequent and troublesome, with increasing evidences of heightened risk for type II diabetes mellitus. Results are discussed with specific emphasis on possible strategies of an active monitoring, which could enable both paediatricians and child psychiatrists to a possible prevention, early detection, and a timely management of such effects.

Although multi-component psychotherapeutic interventions are first-line treatments for Disruptive Behavior Disorders (DBD), pharmacotherapy is often associated for more severe patients. Our aim was to explore effectiveness of an associated pharmacotherapy in referred children with DBD receiving a one-year psychotherapeutic intervention. Aggression, callous unemotional (CU) traits and emotional dysregulation were outcome measures. The sample included 144 children, aged 8-12 years, 41 (29%) with an ADHD comorbidity. Fifty-five (38%) patients received an additional pharmacotherapy with one medication, methylphenidate, a second generation antipsychotic, or a mood stabilizer. Data were collected before and after the one-year treatment. According to the Child Behavior Checklist (CBCL), aggressive behaviors, rule-breaking behaviors and emotional dysregulation improved in the whole group, as well as parent- and child-reported CU traits. The hierarchical regression model showed that additional pharmacotherapy significantly predicted lower scores at the CBCL aggressive behaviors and emotional dysregulation, but not CU traits at the end of the treatment. The interaction between methylphenidate and ADHD comorbidity predicted lower aggressive behaviors after the treatment. In summary, this naturalistic investigation suggest that an additional pharmacotherapy significantly improved aggression and emotional dysregulation, but not CU traits. When ADHD was comorbid, methylphenidate was more effective than antipsychotics or mood stabilizers in reducing aggression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The atypical antipsychotic quetiapine has been used in different psychotic and non-psychotic disorders in children and adolescents in randomized clinical trials, open-label studies and chart reviews. Most of these studies suggest that quetiapine may be a promising agent with a potential for use in young patients. The aim of this paper is to critically review available literature on quetiapine in the treatment of children and adolescents with a variety of psychiatric disorders, including psychotic disorders, bipolar disorders (manic and depressive episodes), conduct disorder, autism spectrum disorder, Tourette's syndrome and personality disorders. Furthermore, we report on possible neurochemical pathways involved during treatment with quetiapine, and discuss some issues that are clinically relevant in daily practice, such as titration strategies, safety and tolerability, and monitoring possible side effects. Controlled studies support the short-term efficacy for treating psychosis, mania, and aggression within certain diagnostic categories. However, although quetiapine seems well tolerated in various pediatric populations during acute and intermediate treatments, and hyper-prolactinemia and extra-pyramidal side effects are consistently low among studies, weight gain and alterations in lipid profile need to be closely monitored. Furthermore, the distal benefit/risk ratio during long-term treatment remains to be determined.

A massive asymptomatic creatine kinase elevation (MACKE) has been described during antipsychotic exposure in adult psychotic patients without signs of neuroleptic malignant syndrome (NMS), or other most frequent reasons for high creatine kinase (CK) serum level (intramuscular injections, restraints, intense physical activity, dystonic reactions). In this article, we review this clinical condition, and report three cases of MACKE in nonpsychotic, drug-naïve youth during treatment with second generation antipsychotics. The diagnosis of MACKE should be considered after ruling out other possible common reasons of CK increase. The finding of MACKE should indicate a need for weekly monitoring of the CK level only when there are reasons to believe elevated CK is toxic or harmful. Further investigations are recommended when signs and symptoms raise a suspicion of NMS or rhabdomyolysis, including flu-like syndrome, fever, weakness, alteration of consciousness, muscle rigidity, tachycardia, hyper-/hypotension, and dark urine. A drug discontinuation should be considered when possible signs of NMS or rhabdomyolysis are suspected, or in cases of very high and persisting CK levels. Empirical evidence indicates that there is not a "safe" antipsychotic medication; therefore, a switch to another antipsychotic with a different profile is not necessarily a safe option. The spontaneously remitting or intermittent course suggests that the "true" MACKE should be kept distinct from both rhabdomyolysis and NMS. Raising awareness with MACKE may reduce the need for unnecessary diagnosis of NMS or rhabdomyolysis, which may otherwise lead to an unnecessary discontinuation of an effective therapeutic agent.

In children and adolescents with conduct disorder (CD), pharmacotherapy is considered when non-pharmacological interventions do not improve symptoms and functional impairment. Risperidone, a second-generation antipsychotic is increasingly prescribed off-label in this indication, but its efficacy and tolerability is poorly studied in CD, especially in young people with normal intelligence. The Paediatric European Risperidone Studies (PERS) include a series of trials to assess short-term efficacy, tolerability and maintenance effects of risperidone in children and adolescents with CD and normal intelligence as well as long-term tolerability in a 2-year pharmacovigilance. In addition to its core studies, secondary PERS analyses will examine moderators of drug effects. As PERS is a large-scale academic project involving a collaborative network of expert centres from different countries, it is expected that results will lead to strengthen the evidence base for the use of risperidone in CD and improve standards of care. Challenging issues faced by the PERS consortium are described to facilitate future developments in paediatric neuropsychopharmacology.

Bipolar Disorders (BD) are often comorbid with disruptive behaviour disorders (DBDs) (oppositional-defiant disorder or conduct disorder), with negative implications on treatment strategy and outcome. The aim of this study was to assess the efficacy of quetiapine monotherapy in adolescents with BD comorbid with conduct disorder (CD). A consecutive series of 40 adolescents (24 males and 16 females, age range 12-18 years, mean age 14.9 ± 2.0 years), diagnosed with a clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version [K-SADS-PL]) according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria were included. All the patients were treated with quetiapine monotherapy (mean final dose 258 ± 124 mg/day, range 100-600 mg/day). At the end-point (3 months), 22 patients (55.0%) were responders (Clinical Global Impressions-Improvement [CGI-I] score of 1 or 2 and CGI-Severity [CGI-S] ≤ 3 and improvement of at least 30% Children's Global Assessment Scale [C-GAS] during 3 consecutive months). Both CGI-S and C-GAS significantly improved (p<0.0001). Nine out of the 16 patients with suicidality (56.3%) had a reduction in this severe symptom during the follow-up. Nonresponders were more frequently males, and more frequently had an attention-deficit/hyperactivity disorder (ADHD) comorbidity. Eight patients (20.0%) experienced moderate to severe sedation and eight (20.0%) experienced increased appetite and weight gain. In these severely impaired adolescents, quetiapine monotherapy was well tolerated and effective in>50% of the patients.

The aim of this study is to assess efficacy of augmentation of SSRIs with risperidone or aripiprazole in youths with tic-related Obsessive-Compulsive Disorder (OCD) non responders to an SSRI monotherapy. 120 consecutive patients (age range 7-18 years) were treated with an SSRI monotherapy for at least 12 weeks, 51 (42.5%) were responders, and the 69 non-responders (mean age 13.7 ± 2.4 years) were included in this study. 35 patients received an augmentation with risperidone (1.7 ± .8 mg/day), and 34 with aripiprazole (8.9 ± 3.1 mg/day) for 12 weeks. Regarding the OCD symptomatology, at the endpoint the Clinical Global Impression-Severity score (CGI-S) improved from 5.6 ± .8 (severely ill), to 3.2 ± .9 (mild to moderately ill) (p < .0001), and the Children-Global Assessment Scale (C-GAS) from 40.3 ± 5.2 to 53.8 ± 9.2 (p < .0001). Thirty-nine patients (56.5%) were responders in OCD symptomatology (CGI-I score 1 or 2, CGI-S score 3 or less and C-GAS score 50 or more during three consecutive months after a 12-week treatment). Compared to non responders, they were less impaired at the baseline in CGI-S (p < .0001) and C-GAS (p < .0001). Subtypes of OCD and comorbidity did not affect the response. No differences were found between risperidone and aripiprazole augmentation. 47 patients (68.1%) significantly improved tics, without differences between risperidone and aripiprazole. None discontinued medications because of side effects, but risperidone was associated with weight gain and sedation, and aripiprazole to mild/moderate agitation. In tic-related pediatric OCD, augmentation of SSRIs with risperidone or aripiprazole was tolerated and effective in about half of the patients non responding to an SSRI., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Tourette's disorder (TD) in children and adolescents is frequently co-morbid with attention-deficit/hyperactivity disorder (ADHD). Dopamine-blockers are the first line treatment for TD, whereas dopamine-agonists, such as stimulants, are the gold-standard in the treatment of ADHD. These contrasting effects supported concerns about the risk that stimulants for treating ADHD may trigger or worsen co-morbid tics. Aripiprazole, a partial dopamine agonist, acts as an antagonist at dopamine D2 receptors in hyperdopaminergic conditions and displays agonist properties under hypodopaminergic conditions. The present study describes the use of aripiprazole (10.0 ± 4.8 mg/day) in a consecutive group of 28 patients with a primary diagnosis of TD and co-morbid ADHD, combined subtype. The Yale Global Tic Severity Scale (YGTSS) and the ADHD-Rating Scale (ADHD-RS-IV) were used as primary outcome measures and both significantly improved (p<0.001) after the treatment. Global measures of severity (Clinical Global Impressions-Severity) and of functional impairment (Children's Global Assessment Scale) also significantly improved during the treatment (p<0.001). At the YGTSS there was a reduction of 42.5%, in motor tics, of 47.9% in phonic tics (44.7% for the combined scores), and of 32.3% in tic impairment. Nineteen patients (67.9%) had a reduction of at least 50% of the YGTSS score (motor+phonic tics). The improvement at the ADHD-RS-IV score was 22.5%, 12 patients (42.8%) presented an improvement of 30%, but only 2 (7.1%) an improvement greater than 50%. Using a logistic regression model, a reduction of at least 30% in ADHD-RS-IV score was more likely to occur in the obsessive-compulsive disorder co-morbid group. Aripiprazole was well tolerated and none of the patients discontinued medication because of side effects. In summary, aripiprazole resulted in an effective treatment for TD, but it was only moderately effective on co-occurring ADHD symptomatology. Our preliminary data suggest that aripiprazole may represent a possible therapeutic option, among other possible monotherapies addressing both tics and ADHD.

Schizophrenia in subjects younger than 13 years is defined as very-early-onset schizophrenia, and its prevalence is estimated at 1 in 10 000, while early-onset schizophrenia occurs between 13 and 17 years, and its prevalence is about 0.5%. Only a minority of youths show a complete recovery, and the majority of patients present a moderate to severe impairment at the outset. Treatment of schizophrenia always needs both pharmacological and nonpharmacological interventions. Nonpharmacological interventions include counselling for the patients and the family, psychological support, behavioural treatments, social and cognitive rehabilitation, assistance in social and scholastic activities, enhancement of social skills and family support. Pharmacological treatment is necessary for remission and control of positive and negative symptoms. Furthermore, proper pharmacotherapy can greatly increase the efficacy of psychosocial interventions. Available literature on pharmacotherapy in children and adolescents with schizophrenia is critically reviewed, including both first- and second-generation antipsychotics. Data on efficacy and safety are reported for all the marketed atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole), based on randomized, placebo-controlled studies and the most relevant open-label or naturalistic studies. Adverse effects of concern are closely analysed, such as extrapyramidal side effects and tardive dyskinesia, metabolic syndrome (including hyperglycaemia and hyperlipidaemia), weight gain, hyperprolactinaemia, hepatotoxicity, seizures, and cardiovascular and haematological adverse effects. Finally, practical guidelines for the management of specific clinical situations are provided: the first phases and the long-term approach to pharmacotherapy, the treatment refractoriness and the use of clozapine in youths, the agitated adolescent and the treatment of negative symptoms and of affective co-morbidity. Current experience indicates that, based on low rates of remission, low effect size of medications and frequent adverse effects, mainly metabolic syndrome, further research is warranted, with both randomized, placebo-controlled studies and long-term, naturalistic follow-up of large samples of patients with different age ranges.

The aim of this study was to assess efficacy of aripiprazole augmentation of serotonin reuptake inhibitor (SRI) treatment in adolescents with obsessive-compulsive disorder (OCD) who did not respond to 2 initial trials with SRI monotherapy. A consecutive series of 39 adolescents (28 males and 11 females; age range, 12 to 18 years; mean age, 14.6 ± 1.2 years), with OCD diagnosed based on a clinical interview and according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, were included. The mean final aripiprazole dosage was 12.2 ± 3.4 mg/d. At the endpoint, 27 patients (59.0%) had a Clinical Global Impression (CGI)-Improvement score 1 or 2 (very much or much improved) and a Clinical Global Impression-Severity (CGI-S) score 3 or below and were thus considered responders. The CGI-S improved from 6.0 ± 0.9 at the baseline (severely to extremely severely ill) to 3.5 ± 1.0 (mild to moderately ill) at the end of the follow-up (P < 0.0001), whereas the Children's Global Assessment Scale improved from 39.2 ± 5.8 to 49.8 ± 9.0 (P < 0.0001). Compared with nonresponders, responders were less impaired at the baseline in functional impairment (Children's Global Assessment Scale; P = 0.004) but not in clinical severity (CGI-S). Subtypes of OCD comorbidity and absence of insight did not affect clinical response. Mild transitory agitation (10.3%), mild sedation (10.3%), and sleep disorders (7.7%) were reported, but any of the patients discontinued medication because of adverse effects.In these severely impaired adolescents, aripiprazole augmentation of SRIs was well tolerated and effective in more than half of the patients.

Objective: The aim of this study was to evaluate the efficacy of olanzapine in girls with anorexia nervosa, restricting subtype (ANr)., Methods: Thirteen patients (mean age 13.7 +/- 2.3 years, age range 9.6-16.3 years) enrolled in a multimodal treatment for ANr were evaluated with standardized measures at baseline and after 1 and 6 months after starting low-dose olanzapine monotherapy (mean dose 4.13 mg/day)., Results: A significant improvement was evident on weight (body mass index, BMI), global functioning (Children's Global Assessment Scale, CGAS), eating attitudes (Eating Attitudes Test-26, EAT-26), anxious-depressive symptoms (Child Behavior Checklist, CBCL) and hyperactivity (Structured Inventory for Anorexic and Bulimic Syndromes, SIAB). At the end of the 6-month follow up, 7 patients were responders according to an improvement of at least 50% in the EAT-26 results. The only measure that improved significantly in responders, but not in nonresponders, was hyperactivity (SIAB). Clinical improvement, in terms of both body mass index (BMI) recovery and global functioning, paralleled the improvement of hyperactivity, was evident at the end of the first month of treatment, and further increased in the following 5 months, with minimal side effects., Conclusions: Low-dose olanzapine monotherapy may be useful as adjunctive treatment of youths with ANr. It is suggested that efficacy may be mediated by a decrease of hyperactivity.

Background: Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterized by impairment in social interactions, in verbal and non-verbal communication, and by restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. The appropriate use of pharmacotherapy can improve some aberrant symptoms and behaviours and increase the person's response to non-pharmacological interventions., Objective: To describe clinical outcomes, or symptom changes, and adverse effects during naturalistic treatment with aripiprazole monotherapy in children with PDDs and severe behavioural disorders (such as aggression against self and/or others, hostility, hyperactivity, severe impulsiveness)., Method: This retrospective naturalistic study included 34 patients (23 males and 11 females, age range 4.5-15 years, mean age 10.2 +/- 3.3 years), admitted during 2006-2007, diagnosed according to DSM-IV criteria and followed up for 4-12 months (mean 7.0 +/- 3.6 months). Outcome measures were three global measures of clinical and functional impairment and improvement from baseline: the Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales; the Children's Global Assessment Scale (C-GAS); and the Childhood Autism Rating Scale (CARS), a specific measure of PDD symptoms., Results: The mean baseline CGI-S was 5.7 +/- 0.8 (markedly ill/severely ill). The mean final dosage of aripiprazole was 8.1 +/- 4.9 mg/day. At the endpoint, 11 patients (32.4%) were 'much improved' or 'very much improved' (CGI-I score of 1 or 2), 12 patients (35.3%) were 'minimally improved' (CGI-I score of 3) and 10 (29.4%) were 'unchanged' or 'worsened' (CGI-I score of 4 or 5). C-GAS and CARS scores significantly improved (p < 0.0001, effect sizes 0.59 and 0.62, respectively). Nine patients (26.5%) experienced moderate to severe agitation, which was associated with self-injurious behaviours in five of these patients, and five patients presented with sleep disorders. Twelve patients (35.3%) discontinued medication during the follow-up because of lack of efficacy or adverse effects., Conclusions: In these severely impaired children with PDDs, aripiprazole monotherapy was associated with a significant improvement in maladaptive behaviours in one-third of patients. Agitation and insomnia were the most frequent adverse effects. Further controlled studies in larger samples to explore possible predictors of efficacy are warranted.

This paper reports on implications of bipolar disorder (BD) co-morbidity in 120 children and adolescents with obsessive-compulsive disorder (OCD) (84 males, 36 females, age 13.7 +/- 2.8 years), diagnosed using a clinical interview according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria, and naturalistically followed-up for 12 +/- 6 months. The aim of this naturalistic, retrospective study was to explore the effect of BD co-morbidity, disentangling it from other co-occurring variables, namely the co-morbidity with disruptive behavior disorders. Forty three patients (35.8%) had a bipolar co-morbidity. Compared with OCD patients without BD, they had an earlier onset of OCD, a greater severity and functional impairment, more frequent hoarding obsessions and compulsions, and a poorer response to treatments. They had a higher co-morbidity with attention-deficit/hyperactivity disorder (ADHD) and oppositional-defiant disorder (ODD), and a lower co-morbidity with generalized anxiety disorder (GAD). Finally, they received more mood stabilizers, and 30.2% of them did not receive serotonin-selective reuptake inhibitors (SSRIs) because of pharmacological (hypo)mania. When all the OCD responders and nonresponders were compared, nonresponders (n = 42, 35%) were more severe at baseline and at end of the follow-up, had more frequently hoarding obsessions and compulsions, and had more frequent BD, ODD, and conduct disorder (CD) and less GAD and panic disorder. In the final regression model, hoarding obsessions and compulsions, co-morbidity with ODD, and CD were negative predictors of treatment outcome. This study suggests that even though bipolar co-morbidity is frequent and affects phenomenology and co-morbidity in pediatric OCD, its effect on treatment response seems prevalently accounted for by co-morbidity with disruptive behavior disorders. The significance of the hoarding subtype deserves further research on larger samples of pediatric patients.

Awareness of childhood-onset schizophrenia is rapidly increasing, with a more precise definition now available of the clinical picture and early signs, the outcome and the treatment strategies. Premorbid developmental impairments, including language, motor and social deficits, are more frequent and more pronounced in earlier- than in later-onset forms of schizophrenia. This 'pan-dysmaturation' is reported from the first months of life in more than half of the children who will develop childhood-onset schizophrenia, and it suggests a more severe and early disruption of brain development compared with the adolescent- and adult-onset disorder. The insidious onset in at least 75% of children, the high rates of premorbid problems and the hesitancy on the part of clinicians to make a diagnosis of schizophrenia in a child usually delay the recognition of the syndrome. Elementary auditory hallucinations are the most frequent positive symptom, while visual and tactile hallucinations are rarer. Delusions are less complex than in adolescents and are usually related to childhood themes. Negative symptoms are largely predominant, namely flat or inappropriate affect. A marked deterioration from the previous level of functioning is present in all these children, and an impaired outcome is reported in approximately 50-60% of them. The main diagnostic challenges are with differentiating childhood-onset schizophrenia from affective disorders (both depression and bipolar disorder) with psychotic symptoms, pervasive developmental disorders and severe personality disorders. Post-traumatic stress disorder and obsessive-compulsive disorder without insight may also be misdiagnosed as schizophrenia. Furthermore, approximately 10% of children from the community report nonpsychotic hallucinations or delusions. Finally, children with atypical psychotic features that do not strictly fit diagnostic criteria for schizophrenia have been described, and new labels have been proposed to categorise these clinical patterns, such as multidimensionally impaired disorder and multiple complex developmental disorder. In the context of a multimodal approach, including behavioral, social, scholastic and familial interventions, a pharmacological treatment is usually the core treatment. Available experience from the few controlled studies, open studies and case reports on pharmacotherapy in children with schizophrenia aged <12 years is critically analysed in this review, with particular reference to the use of atypical antipsychotics in clinical practice. To date, the major evidence supports the efficacy of risperidone and olanzapine, while clozapine seems an effective option in treatment-refractory cases. Published experience with newer atypical antipsychotics (quetiapine, ziprasidone, aripiprazole) is still lacking in this age range. Safety data (namely extrapyramidal symptoms, weight gain, hyperprolactinaemia, haematological adverse effects, seizures, hepatotoxicity, metabolic effects, neuroleptic malignant syndrome and cardiovascular effects) are reviewed and discussed, along with strategies for management.

The most severe forms of conduct disorder (CD) are highly stable and disabling disorders, more likely to persist in time and to evolve into disruptive or antisocial behaviors. One crucial issue in the prognosis of these forms of CD is the high resistance to both non-pharmacological and pharmacological treatments, with antipsychotic drugs being frequently used in refractory cases. Aim of this study was: (1) to explore efficacy and tolerability of olanzapine treatment in adolescents with severe CD; (2) to identify predictors of olanzapine treatment outcome. This was a retrospective study, based on clinical records of the first 23 adolescents diagnosed as having a CD, diagnosed with a clinical interview (K-SADS), either pure or with comorbid diagnoses, and treated with olanzapine. All these patients did not respond satisfactorily to non-pharmacological intervention and to adequate dosages of mood stabilizers (lithium and/or valproate). The sample consisted of 16 males and seven females, 16 inpatients and seven outpatients (mean age 13.6 +/- 1.9 years, range 11-17.2 years), followed-up for a period ranging from 6 to 12 months (mean 8.8 +/- 2.7 months). Outcome measures included the Modified Overt Aggression Scale (MOAS), Clinical Global Impression-Improvement (CGI-I) and Children Global Assessment Scale (CGAS). During the follow-up, all patients were involved in non-pharmacological treatments (psychotherapy, family therapy, or day-hospital group treatments). Based on both an improvement of at least 50% at MOAS and a score 1 or 2 at CGI-I, 14 out of 23 patients (60.9%) were classified as responders at the end of the follow-up. Significant improvement at the last observation was found in MOAS (P < 0.001) and CGAS (P < 0.001) scores. Olanzapine dosage was 8 +/- 3.2 mg/day (range 5-20 mg/day). Mean weight gain at the end of the follow-up was 4.6 +/- 3 kg. The predictors of a positive treatment response was an impulsive-affective versus controlled-predatory type of aggression. Age at onset of CD and comorbid disorders did not affect treatment response. These preliminary findings suggest that olanzapine may improve behavior in adolescents with severe and treatment-refractory CD and impulsive aggression.

Awareness of bipolar spectrum disorders in children is rapidly increasing, with a more precise definition of their clinical subtypes and early signs. Paediatric bipolar disorder can lead to an important impairment in scholastic, familial and social functioning, and to a higher risk for substance abuse and suicide. In the context of a multimodal approach, the core treatment of early-onset bipolar disorder is pharmacological. This review focuses on the empirical evidence for pharmacotherapy in paediatric bipolar disorder. Mood stabilizers, including lithium, and older and newer anticonvulsivants will be considered, in mono- or polypharmacy. Atypical antipsychotics will be considered in more severe and/or treatment-resistant manic or mixed episodes. Finally, the prophylaxis of intercritical phases and the management of specific challenging conditions, such as bipolar depression and attention deficit hyperactivity disorder, with bipolar comorbidity, will be reviewed.

Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterised by impaired social interaction, reduced verbal and nonverbal communication, and restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. As part of a multimodal approach that includes educational and behavioural interventions, appropriate use of pharmacotherapy in patients with PDDs can improve some symptoms and behaviours and increase the patient's response to nonpharmacological interventions. Pharmacotherapy is aimed at stabilising the dysregulated systems that are thought to underlie the abnormal behaviours, namely the serotonergic and dopaminergic systems.This paper critically reviews the available literature on the pharmacotherapy of PDDs in children and adolescents. Pharmacological, efficacy and safety data on drugs acting on serotonin (serotonergic agents such as clomipramine, fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine), on both serotonin and norepinephrine (venlafaxine and mirtazapine), dopamine (dopamine-blocking antipsychotics such as haloperidol and pimozide), and on both serotonin and dopamine (atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine and ziprasidone) are presented. The paper concludes with a brief discussion of other psychotropic medications, such as the opioid antagonists, alpha-adrenoceptor agonists (clonidine and guanfacine), psychostimulants, mood stabilisers, glutamatergic compounds (lamotrigine, amantadine), buspirone, and secretin. Available evidence suggests that atypical antipsychotics (mainly risperidone and olanzapine) are particularly indicated when more serious behavioural symptoms, such as aggression, self-injurious behaviours and hyperactivity, are prominent. Serotonergic agents may be effective in children with repetitive phenomena or affective symptoms. Social relatedness is more frequently refractory to both atypical antipsychotics and serotonergic agents. Further research into the drug treatment of PDDs, including placebo-controlled trials and long-term, naturalistic follow-up studies of large samples of patients of different age ranges, is warranted.

Background: Only sparse and short-term data are available on pharmacologic treatments in very young children with pervasive developmental disorders (PDD). The purpose of this 3-year naturalistic study (March 1999-April 2002) is to describe the clinical outcome of a consecutive sample of preschool children with PDD treated with risperidone monotherapy., Method: The sample consisted of 45 boys and 8 girls aged 3.6 to 6.6 years (mean +/- SD age = 4.6 +/- 0.7 years) with a DSM-IV diagnosis of autistic disorder or PDD, not otherwise specified. Outcome measures included the Children's Psychiatric Rating Scale (CPRS), Clinical Global Impressions-Improvement scale (CGI-I), Children's Global Assessment Scale (CGAS), and a checklist for risperidone side effects., Results: Patients received risperidone for a period ranging from 1 to 32 months (7.9 +/- 6.8 months). Twenty-five patients (47.2%) continued to receive risperidone after the study was completed, while 28 (52.8%) discontinued due to side effects (22.6% [N = 12]), parents' choice (18.9% [N = 10]), lack of efficacy (5.7% [N = 3]), and decision of the treating psychiatrist (5.7% [N = 3]). The optimal dose was 0.55 +/- 0.2 mg/ day. Significant improvement at the last observation was found in CPRS (p < .0001) and CGAS (p < .0001) scores. On the basis of both an improvement of 25% in CPRS score and a score of 1 or 2 on the CGI-I, 46.8% (N = 22) of subjects were considered responders. Behavioral disorders and affect dysregulation were more sensitive to treatment than was interpersonal functioning. Responders received higher doses of medication for a longer period and had a greater weight gain than did nonresponders. Increased prolactin levels without clinical signs (65% [24 of 37]) and increased appetite (15% [8 of 531) were the most frequent side effects., Conclusion: These findings suggest that low-dose risperidone may positively affect the clinical outcome in young children with PDD not only in the short-term, but also in the long-term period.

Although hyperprolactinemia is a common side effect during risperidone treatment in adult patients, no information is available on young children. The aim of this study is to report on serum prolactin levels in 25 young autistic children (22 males and 3 females, age range 3.9-7 years, mean age 4.10 years) during treatment with risperidone (dosage range 0.25-0.90 mg/day, mean dosage 0.52 mg/day). Prolactin levels were measured at baseline and after 10 weeks of treatment. The clinical outcome measure used was the Clinical Global Impression-Improvement. Serum prolactin was 9.77 +/- 3.94 ng/mL at baseline and 25.92 +/- 13.9 ng/mL during the 10th week of treatment (p < 0.001). Six children (24%) showed prolactin levels lower than 15 ng/mL, which is the upper normal level; eight children (28%) had prolactin levels higher than two times the upper limit (30 ng/mL). Hyperprolactinemia did not show significant correlations with age, weight, or risperidone dosage. There was no relation with clinical outcome. Dose reduction of risperidone resulted in a decrease of prolactin levels. None of the children showed clinical signs of hyperprolactinemia. Given the paucity of available data on potential effects of long-term hyperprolactinemia, a monitoring of prolactin during treatment with risperidone and other typical and atypical antipsychotics may be warranted.

Objective: To describe tolerability and efficacy of risperidone in very young children with pervasive developmental disorders., Method: Twenty-four children aged 3.6 to 6.6 years (mean 4.6 years +/- 8 months) enrolled during 1999 and 2000 participated in a 16-week open-label trial with risperidone monotherapy. Outcome measures included the Children's Psychiatric Rating Scale (CPRS), Childhood Autism Rating Scale (CARS), Clinical Global Impression-Improvement (CGI-I), and Children's Global Assessment Scale (C-GAS)., Results: Two subjects did not complete the trial because of side effects. The optimal dose was 0.5 mg/day. After the treatment a 21% improvement in CPRS and a 14% improvement in CARS total scores was found. Items related to behavioral control (hyperactivity, fidgetiness, rhythmic motions) and affect regulation (lability of affect, angry affect) improved more than 25%. Based on improvement of at least 25% on the CPRS and a score of 1 or 2 on the CGI-I, eight subjects were considered responders. Functional impairment (C-GAS) improved more than 25%. Thirteen subjects (54%) were free of any side effects; in the other participants risperidone was well tolerated. Only three subjects had a weight gain greater than 10%., Conclusions: Low-dose risperidone may positively affect symptoms in young autistic children, improving disruptive/hyperactive behavior and affective dysregulation. Further controlled studies in this age group are warranted.

The aim of this preliminary study was to examine the short-term efficacy and safety of the atypical antipsychotic risperidone in preschool autistic children. The sample consisted of 10 subjects (7 males and 3 females) aged 3 9/12 to 6 6/12 years (mean age 4.7 years). A 16-week open-label trial with risperidone monotherapy was initiated at a starting dose of 0.25 mg daily and was increased to a maximum dose of 0.50 mg (0.027 mg/kg daily). Outcome measures were the Childhood Autism Rating Scale, the Children's Psychiatric Rating Scale, Clinical Global Impression (improvement score), and the Children's Global Assessment of Functioning. Two subjects did not complete the trial because of side effects (tachycardia and flushes, fever and hyporexia). After the 16-week treatment, data from the eight children who completed the trial indicated a modest improvement in the Childhood Autism Rating Scale total score, Children's Psychiatric Rating Scale total score, and Children's Global Assessment of Functioning. According to the Clinical Global Impression, the global improvement score for four subjects was much improved or very much improved; the score for the other four children was minimally improved. None of the children exhibited behavioral deterioration. The side effects in the eight children were not severe.

A 15 year-old adolescent boy with a severe treatment refractory bipolar disorder type I, most recent episode manic, severe with psychotic features had previously required hospitalizations and treatment with lithium and/or carbamazepine and high doses of standard neuroleptics without any response. A treatment with a combined clozapine-lithium therapy was progressively started in a hospital setting (clozapine 300 mg/day; lithium 1350 mg/day). After 15 days a dramatic improvement in mood and psychotic symptoms was evident. After four weeks there was 50% improvement on the BPRS (from 74 to 37). The mean CGAS score changed from 25 to 72. At the CGI-Severity of Illness subscale, a 57% decrease was evident; at the CGI-Global Improvement subscale there was a 75% increase. The only significant side effects were sedation and fatigue, but they were not so severe as to induce a reduction of dosage. The boy was discharged from the hospital after three weeks and successfully returned to school with no modifications in treatment. After a nine-month treatment there was no reoccurrence of psychotic or manic symptoms. The implications of pharmacological therapy in treatment refractory manic episodes with psychotic features are discussed.

According to the DSM-IV, all types of psychiatric disorders can be observed in mentally retarded subjects, with prevalence estimated to be three or four times higher than in the general population. Clinical features, longitudinal course and triggering factors are influenced by the characteristics of the intellectual disability. The aim of this paper is to discuss the specificity of the psychopharmacological therapy in mental retardation (sensitivity to specific psychotropic drugs, incidence of side effects, predictive criteria for evaluating risk factors, etc.) and to propose an update in the pharmacotherapy in the most important psychiatric disorders (mood disorders, psychotic disorders, behavioral disorders, anxiety disorders, attention deficit disorders with or without hyperactivity.

The most complex problems in the use of neuroleptics for schizophrenia are the frequency of nonresponders, the severity of extrapyramidal side effects and tardive dyskinesia, especially in chronic treatment, the persistence of treatment-refractory symptoms, such as negative symptoms. All these problems are more frequent and severe in children and adolescents with early-onset schizophrenia. The classic neuroleptics act on the postsynaptic dopaminergic receptors, especially the D2 receptors, situated in various areas of the Central Nervous System. More recently, the so-called dopaminergic hypothesis of schizophrenia has been criticized and other neurotransmitter systems have been involved, particularly serotonin. The more recently synthesized neuroleptics, with combined action on dopamine and serotonin receptors, have been called atypical neuroleptics; the atypical neuroleptics currently used in clinical practice are clozapine and risperidone. These anti-psychotic drugs are known to be clinically more effective, especially on negative symptoms, have a lower incidence of extrapyramidal side effects, produce significant improvements in some refractory patients. A large number of the studies concern adults; the studies on young populations are much fewer and less rigorous. The aim of this critical review is to describe clinical use of atypical neuroleptics clozapine and risperidone in children and adolescents with early-onset schizophrenia.