Clozapine Treatment for Aggressive Behaviors in Youths with Neurodevelopmental Disorders.

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.

Deficits in emotion recognition and processing in children with high callous-unemotional traits: the role of the MAOA gene.

Children with high Callous-Unemotional (CU) traits show deficits in recognizing and processing facial expressions. Alterations in emotion recognition have been linked to a higher synaptic concentration of monoaminergic neurotransmitters. The current study investigated the relationship between the MAOA-Low-activity alleles and the ability to recognize and process facial expressions in 97 male children (8-12 years old) diagnosed with disruptive behavior disorder. Participants completed a computerized emotion-recognition task while an eye-tracking system recorded the number (Fixation Count, FC) and length (Fixation Duration, FD) of fixations to the eye region of the emotional stimuli. Children with high CU traits exhibited lower scores in recognition of sadness and anger, and lower FC and FD for sadness and fear than children with low CU traits. Children carrying the MAOA-Low-activity alleles displayed lower FD for sadness, and FD and FC for fear than those carrying the MAOA-High-activity alleles. These genetic effects appeared even stronger in children with CU traits. Moderation analysis revealed that CU traits were associated with lower FC and FD for fear, and lower FD for sadness, probably due to the MAOA-Low-activity alleles. Our findings, although to be replicated, suggest MAOA-Low-activity alleles as potential genetic biomarkers to identify CU children in need of training focused on emotion processing.

Efficacy of Methylphenidate for Internet Gaming Disorder and Internet Addiction in Patients with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Internet Gaming Disorder (IGD) and Internet Addiction (IA) are related clinical conditions often comorbid with Attention-Deficit/Hyperactivity Disorder (ADHD). OBJECTIVE: We evaluated the efficacy of MPH for IGD/IA symptoms in ADHD patients. METHODS: We enrolled 38 drug-naive patients diagnosed with ADHD (Attention-Deficit/Hyperactivity Disorder) and IGD/IA. At baseline, all patients underwent a clinical assessment for IGD/IA symptoms and then received the most appropriate therapy according to their clinical profile. Twenty-one patients received MPH (methylphenidate) treatment, and 17 patients did not. Patients were re-evaluated after three months of treatment. RESULTS: Findings revealed significant reductions in IGD/IA symptoms over time, while no significant effect of MPH on symptom reduction was found. Clinical predictors of symptom reduction were identified, including IQ (Intelligence Quotient) and comorbid anxiety. CONCLUSION: This longitudinal prospective study contributes to the understanding of IGD/IA treatment in ADHD patients and highlights the importance of considering individual clinical characteristics when predicting treatment response. However, MPH may not directly impact IGD/IA symptom reduction.

Internet Gaming Disorder in Children and Adolescents with Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have been related to an increased risk for behavioral addictions including online gaming. However, the relationship between these two conditions and Internet gaming disorder (IGD) is still debated. The aim of this study is to address this topic by exploring the prevalence of IGD in a consecutive sample of ASD youth and ADHD youth, compared with a normal control group, and by assessing selected psychopathological and neuropsychological features in ASD and ADHD patients with and without IGD. This study included 77 ASD patients (67 males, mean age 13.58 ± 2.75 years), 94 ADHD patients (79 males, mean age 11.46 ± 2.47 years), and 147 normal controls (NC) (mean age 13.9 ± 3.0 years, 114 males) that received structured measures for IGD (IAT, IGDS9-SF, and UADI). In the ADHD group, 72.34% of the sample were above the IGD cut-off, compared with 45.45% in the ASD group and 9.5% in the NC group. ASD patients with IGD presented with greater severity and more severe attention problems, with no difference in the ASD core symptoms between patients with and without IGD. In the comparison between the ASD and ADHD groups according to the presence of IGD, ASD patients with IGD were the most severe group according to the CGI (Clinical Global Impression) scale. The follow-up, conducted on 45 patients affected by ASD, showed an improvement in CGI and CGAS (Children's Global Assessment Scale) scores, but not in the IGD symptoms. These findings could place the diagnosis of ASD as a negative prognostic factor in the follow-up of aspects of video game addiction compared with ADHD.

The "Measure of Empathy in Early Childhood": Psychometric Properties and Associations with Externalizing Problems and Callous Unemotional Traits.

Empathy is crucial to the development of socio-emotional skills in youth and empathy development is central to understanding and subtyping youth with externalizing problems. This study explored for the first time the psychometric properties of the Measure of Empathy in Early Childhood (MEEC) in a sample of 652 Italian children aged 6 to 8 years. The gender invariance of MEEC scores and their associations with other measures of empathy and prosocial behavior, and children's externalizing problems and callous-unemotional (CU) traits were also evaluated. Results indicated that with some modifications, a 5-factor structure of the Italian version of MEEC scores fitted the data and was invariant across gender. Results further supported the reliability and validity of MEEC total and subscale scores. Practical implications of these results are discussed.

Systematic Review and Meta-Analysis: Altered Autonomic Functioning in Youths With Emotional Dysregulation.

OBJECTIVE: To systematically investigate if there is a significant association between markers of autonomic functioning and emotional dysregulation (ED) in children and adolescents. METHOD: Based on a preregistered protocol (PROSPERO: CRD42021239635), PubMed, Web of Knowledge/Science, Ovid MEDLINE, Embase, and APA PsycInfo databases were searched until April 21, 2021, to identify empirical studies reporting indices of autonomic nervous system (ANS) functioning in youths meeting DSM (version III, IV, IV-TR, 5 or 5-TR) or International Classification of Diseases (ICD) (version 9 or 10) criteria for any psychopathological/neurodevelopmental condition and assessed for ED with a validated scale. Eligible outcomes included correlation coefficients between ED and ANS measures or differences in ANS measures between youths with and without ED. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS) and the Newcastle-Ottawa Scale (NOS) for cohort studies. Random-effects meta-analyses were used for data synthesis. RESULTS: There were 12 studies (1,016 participants) included in the descriptive review and 9 studies (567 participants) included in the meta-analyses. No evidence of a significant association between ED and altered cardiac or electrodermal functioning was found. However, exploratory meta-regressions suggested a possible association between reduced resting-state cardiac vagal control and increased ED. CONCLUSION: This study did not find evidence of an association between ED and autonomic dysfunction. However, preliminary evidence that reduced vagal control at rest might be a transdiagnostic marker of ED in young people was found. Additional studies comparing autonomic measures in youths with and without ED are needed and should also assess the effects of interventions for ED on ANS functioning. STUDY PREREGISTRATION INFORMATION: Systematic Review and Meta-Analysis: Is Autonomic Nervous System Functioning Atypical in Children and Adolescents With Emotional Dysregulation? https://www.crd.york.ac.uk/prospero/; CRD42021239635.

The Role of Environmental Sensitivity in the Relationship Between Childhood Maltreatment and Self-Conscious Emotions of Shame and Guilt: A Brief Report.

The association between childhood maltreatment and self-conscious emotions has been proven by the literature, but with limited attention to the specific moderating mechanisms involved. Highly sensitive individuals show emotional reactivity, ease of overstimulation, which make them more influenced by childhood maltreatment experiences. The study aims to test whether environmental sensitivity moderated the link between childhood maltreatment and self-conscious emotions of shame and guilt. The sample included 128 children referred for Oppositional Defiant Disorder (M age = 9.05; SD = 1.34). Results showed a significant interaction between maltreatment and environmental sensitivity on guilt and shame (B = 1.81, SE = .84, p < .05; B = 1.69, SE = .83, p < .05): highly sensitive children presented higher levels of shame and guilt following experiences of maltreatment as compared to low sensitive children. These findings may contribute to the literature on the role of environmental sensitivity as an individual trait moderating the effect of a contextual experience.

Hikikomori (Severe Social Withdrawal) in Italian Adolescents: Clinical Features and Follow-Up.

Severe social withdrawal, including staying alone in one's bedroom, non-attendance at school or work, and minimal or absent social contacts, sometimes only through electronic devices, can be found in several psychiatric disorders, or in a 'primary' form, firstly defined in Japan as 'Hikikomori'. The distinction between primary and secondary forms is questionable, as it prevalently depends on the quality of psychiatric assessment. To date, few studies specifically explored Hikikomori in an adolescent population outside Japan. The aim of the present study is to describe clinical features of a consecutive group of 80 referred youth (13 to 18 years, 57 males) with social isolation, of which 40 were followed up on for 4-6 months, to characterize clinical features and outcome. All the participants presented psychiatric comorbid disorders, prevalently anxiety disorders, mood disorders, and autism spectrum disorder. Suicidality (ideation and behavior) was reported in 32.5% of the participants, and 20% of the participants attempted suicide. More than half of the participants exceeded the cut-off of the Internet Addiction Test, and 42.4% met the criteria for the Internet Gaming Disorder. At the follow-up appointment, an improvement of social withdrawal was reported in 75% of the sample; 67.5% of the participants significantly improved according to the CGI-improvement scale; and 55% of the participants had an improvement of functioning according to the C-GAS. Our findings suggest that Hikikomori is a transnosographic entity, with high rates of suicidality and Internet addiction, and that can it improve when it is timely diagnosed and treated.

Contemporary diagnosis and treatment of conduct disorder in youth.

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.

[Conduct disorder in female adolescents: evidence from the FemNAT-CD Project.] / Il disturbo della condotta in adolescenti di sesso femminile: evidenze dal Progetto FemNAT-CD.

Conduct Disorder is a diagnosis associated with behaviors at risk for the health and development of the subject, with high social costs and with serious consequences for the adolescent's life context. This disorder is predominantly found in the male population. However, girls with Conduct Disorder often have particularly severe and pervasive symptoms, with a high psychiatric comorbidity. The purpose of this article is to summarize the objectives of the project "FemNAT-CD", in order to promote greater knowledge of the clinical characteristics of females who show a Conduct Disorder in adolescence. This paper will describe studies related to FemNAT-CD project concerning neuro-biological, neuro-cognitive and clinical characteristics of Conduct Disorder in female adolescents as well as new psychotherapeutic and pharmacological approaches.

Adolescent schizophrenia: state of the art and proposals to improve transition management in Italy.

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.

Persistent Non-Suicidal Self-Injury and Suicidality in Referred Adolescents: A Longitudinal Study Exploring the Role of Cyclothymic Temperament.

Non-suicidal self-injury (NSSI) is deliberate harm to the body surface without suicidal intent, though it may be a predictor of suicide attempts. Our aim was to test the hypothesis that persisting and recovering NSSI may have a different longitudinal risk for suicidal ideation and behavior and that the intensity of Cyclothymic Hypersensitive Temperament (CHT) may increase this risk. Fifty-five patients (mean age 14.64 ± 1.77 years) referred for mood disorders according to the DSM-5 were consecutively recruited and followed-up for a mean of 19.79 ± 11.67 months and grouped according to the presence/absence of NSSI at baseline and follow-up into three groups: without NSSI (non-NSSI; n = 22), with NSSI recovered at follow-up (past-NSSI; n = 19), and with persistent NSSI at follow-up (pers-NSSI; n = 14). At follow-up, both NSSI groups were more severely impaired and failed to improve internalizing problems and dysregulation symptoms. Both NSSI groups reported higher scores in suicidal ideation compared to non-NSSI, but only pers-NSSI presented higher scores in suicidal behavior. CHT was higher in pers-NSSI, followed by past-NSSI and then by non-NSSI. Our data support a continuity between NSSI and suicidality, and they suggest the prognostic validity of persistent NSSI, associated with highest CHT scores.

Psychopathic Traits, Externalizing Problems, and Prosocial Behavior: The Role of Social Dominance Orientation.

Psychopathic traits in community and referred youths are strongly associated with severe externalizing problems and low prosocial behavior. However, less is known about the mechanisms that may link youth psychopathy and these outcomes. Social dominance orientation (SDO), defined as the general individual orientation toward unequal and dominant/subordinate relationships, might represent a valuable construct to explore to better understand the association between psychopathic traits, externalizing problems, and prosocial behavior. Based on this, the current study aimed to investigate the relationship between psychopathic traits, SDO, externalizing problems, and prosocial behavior in a community sample (N = 92, 45.57% females, mean age = 12.53, and SD = 0.60) and in a clinical (N = 29, 9% female, mean age = 12.57, and SD = 0.57) samples of adolescents with Oppositional Defiant Disorder or Conduct Disorder. Results showed that SDO mediated the relationship between psychopathic traits and externalizing problems and between psychopathic traits and prosocial behavior only in the clinical sample. These findings can provide valuable information on psychopathic trait correlates in youths with aggressive behavior disorders; treatment implications are discussed.

Corrigendum: Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series.

[This corrects the article DOI: 10.3389/fneur.2023.1085948.].

Steroid treatment response to post SARS-CoV-2 PANS symptoms: Case series.

Background: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by a wide spectrum of symptoms, including the onset of obsessive-compulsive disorder and/or severely restricted food intake, associated with emotional symptoms, behavioral symptoms, developmental regression, and somatic symptoms. Among the possible triggering agents, infectious agents have been extensively explored. More recently, sporadic case reports describe a possible association between PANS and SARS-CoV-2 infection but data on clinical presentation and treatment are still scarce. Methods: We describe a case series (10 children) with acute onset or relapse of PANS symptoms after SARS-CoV-2 infection. Standardized measures (CBCL, CPRS, C-GAS, CGI-S, Y-BOCS, PANSS, and YGTSS) were used to describe the clinical picture. The efficacy of a pulse treatment with steroids for three consecutive months was assessed. Results: Our data suggest that the clinical presentation of the COVID-19-triggered PANS is largely similar to that reported in typical PANS, including acute onset, with OCD and/or eating disorders, and associated symptoms. Our data suggest that treatment with corticosteroids may be beneficial for both global clinical severity and global functioning. No serious adverse effects were observed. Both OCD symptoms and tics consistently improved. Among psychiatric symptoms, affective and oppositional symptoms appeared more sensitive to the steroid treatment than the other symptoms. Conclusion: Our study confirms that COVID-19 infection in children and adolescents could trigger acute-onset neuropsychiatric symptoms. Thus, in children and adolescents with COVID-19, a specific neuropsychiatric follow-up should be routinely included. Even if a small sample size and a follow-up with only two points (baseline and endpoint, after 8 weeks) limit the conclusions, it seems that steroid treatment in the acute phase may be beneficial and well tolerated.

Pharmacological strategies for the management of the antisocial personality disorder.

INTRODUCTION: Antisocial personality disorder (AsPD) is a pervasive pattern of violation of others' rights, related to the concept of psychopathy. AsPD is stable over time from adolescence, with evidence of conduct disorder (CD) before 15 years. DSM-5 included a specifier 'with limited prosocial emotions' (LPE), which characterizes adolescents with higher developmental vulnerability to develop AsPD. Despite being relatively frequent with considerable societal impact, AsPD is a difficult-to-treat condition with high comorbidity rates and poor evidence for effective pharmacological interventions. AREAS COVERED: We conducted a narrative review and searched PubMed up to September 2022. We included RCTs and naturalistic studies evaluating pharmacological interventions on AsPD in adults, including those with comorbid substance use disorder or psychopathic traits. Evidence in youths with CD, callous-unemotional (CU) traits and aggression were also reviewed, exploring the role of CU traits as moderators of response. EXPERT OPINION: Psychosocial interventions are the first option, with possible improvement of CU traits, beyond behavioral and affective symptoms, particularly if implemented early during development. Limited information, based on low-quality studies, supports the pharmacological options. Second-generation antipsychotics, lithium, anti-epileptic drugs, and stimulants are first-line medications, according to different target symptoms. Developmental pathways including ADHD suggest a specific role of psychostimulants.

CRISIS AFAR: an international collaborative study of the impact of the COVID-19 pandemic on mental health and service access in youth with autism and neurodevelopmental conditions.

BACKGROUND: Heterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services. METHODS: Using a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups. RESULTS: Clustering revealed four subgroups. One subgroup-broad symptom worsening only (20%)-included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup. LIMITATIONS: Notable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic. CONCLUSIONS: Concomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis.

Social withdrawal and gender differences: Clinical phenotypes and biological bases.

Evidence from everyday life suggests that differences in social behaviors between males and females exist, both in animal and in humans. These differences can be related to socio-cultural determinants, but also to specialized portions of the brain (the social brain), from the neurotransmitter to the neural network level. The high vulnerability of this system is expressed by the wide range of neuropsychiatric disorders associated with social dysfunctions, particularly social withdrawal. The principal psychiatric disorders with prominent social withdrawal are described, including hikikomori-like syndromes, and anxiety, depressive, autistic, schizophrenic, and personality disorders. It is hypothesized that social withdrawal can be partially independent from other symptoms and likely reflect alterations in the social brain itself, leading to a similar, transdiagnostic social dysfunction, reflecting defects in the social brain across a variety of psychopathological conditions. An overview is provided of gender effects in the biological determinants of social behavior, including: the anatomical structures of the social brain; the dimorphic brain structures, and the modulation of their development by sex steroids; gender differences in "social" neurotransmitters (vasopressin and oxytocin), and in their response to social stress. A better comprehension of gender differences in the phenotypes of social disorders and in the neural bases of social behaviors may provide new insights for timely, focused, innovative, and gender-specific treatments.

Comorbidities in Youth with Bipolar Disorder: Clinical Features and Pharmacological Management.

BACKGROUND: Bipolar Disorder (BD) is a highly comorbid condition, and rates of cooccurring disorders are even higher in youth. Comorbid disorders strongly affect clinical presentation, natural course, prognosis, and treatment. METHODS: This review focuses on the clinical and treatment implications of the comorbidity between BD and Attention-Deficit/Hyperactivity Disorder, disruptive behavior disorders (Oppositional Defiant Disorder and/or Conduct Disorder), alcohol and substance use disorders, Autism Spectrum Disorder, anxiety disorders, Obsessive-Compulsive Disorder, and eating disorders. RESULTS: These associations define specific conditions which are not simply a sum of different clinical pictures, but occur as distinct and complex combinations with specific developmental pathways over time and selective therapeutic requirements. Pharmacological treatments can improve these clinical pictures by addressing the comorbid conditions, though the same treatments may also worsen BD by inducing manic or depressive switches. CONCLUSION: The timely identification of BD comorbidities may have relevant clinical implications in terms of symptomatology, course, treatment and outcome. Specific studies addressing the pharmacological management of BD and comorbidities are still scarce, and information is particularly lacking in children and adolescents; for this reason, the present review also included studies conducted on adult samples. Developmentally-sensitive controlled clinical trials are thus warranted to improve the prognosis of these highly complex patients, requiring timely and finely personalized therapies.