Pharmacological response in juvenile bipolar disorder subtypes: A naturalistic retrospective examination.

This study reports on the naturalistic pharmacotherapy of 266 youths with bipolar disorder (BP), manic or hypomanic episode (158 males and 108 females, 13.8+/-2.8 years), first treated with monotherapy on valproic acid (VPA) (n=158, 59.4%), lithium (n=90, 33.8%) or atypical antipsychotics (n=18, 6.8%). Among the patients receiving mood stabilizers, 59.5% of those treated with VPA and 47.8% of those receiving lithium did not need other antimanic agents (mood stabilizers and/or atypical antipsychotics). Lower severity was associated with a greater persistence of both VPA and lithium monotherapy. Factors associated with greater persistence of VPA monotherapy were BP II and co-occurring generalized anxiety disorder, separation anxiety disorder and simple phobias. On the contrary, BP I and co-occurring psychotic symptoms and/or conduct disorder were associated with a lower persistence of VPA monotherapy. Factors associated with lower persistence of lithium monotherapy were younger age and the association with attention deficit hyper-activity disorder (ADHD). Type of BP and presence of psychotic symptoms and conduct disorder did not affect the lithium monotherapy. Overall, predictors of non-response (multiple stepwise logistic regression) in both VPA and lithium groups were baseline Clinical Global Impression (CGI) Severity score and comorbid conduct disorder; while psychotic symptoms and absence of comorbid generalized anxiety disorder were predictors of poorer treatment response only in the VPA group, and chronic course, comorbid ADHD and absence of comorbid panic disorder were predictors only in the lithium group. Such naturalistic data from an ordinary clinical setting have relevance to clinical practice.

A naturalistic exploratory study of the impact of demographic, phenotypic and comorbid features in pediatric obsessive-compulsive disorder.

BACKGROUND: Few studies have examined the impact of gender, age at onset, phenotype and comorbidity in pediatric obsessive-compulsive disorder (OCD) in children. In this naturalistic study we consider these characteristics of OCD in the framework of the 4 OCD phenotypes (contamination/cleaning, order/symmetry, obsessions/checking and hoarding) proposed by Leckman et al. SAMPLING AND METHODS: A consecutive series of 257 patients aged 13.6 +/- 2.8 years, diagnosed using a DSM-IV-based clinical interview (Schedule for Affective Disorders and Schizophrenia for School Age Children - Present and Lifetime Version), were included. RESULTS: Patients with OCD onset before 12 years of age presented a higher frequency of comorbid tic disorder and disruptive behavior disorders. The type of obsession varied with gender: order/symmetry was more frequent in males, contamination/cleaning in females. Order/symmetry had the highest comorbidity with tics, contamination/cleaning was the least severe according to the Clinical Global Impression Severity, and was associated with a high rate of comorbid anxiety and depression, similarly to sexual-religious obsessions. Hoarding was the severest according to the Clinical Global Impression Severity, and was associated with a high comorbidity with social phobia and bipolar disorder. Tic comorbidity was more prevalent in males, had an earlier onset, and a heavier comorbidity with attention deficit hyperactivity disorder and other disruptive behavior disorders. A comorbid attention deficit hyperactivity disorder was associated with an earlier onset of OCD and a poorer response to treatments. CONCLUSIONS: OCD phenotypes and comorbidities may have marked clinical and prognostic implications. Tertiary care population results may not generalize to less impaired juvenile populations.

Aripiprazole monotherapy in children and young adolescents with pervasive developmental disorders: a retrospective study.

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.

Pharmacotherapy in paediatric obsessive-compulsive disorder: a naturalistic, retrospective study.

BACKGROUND: Pediatric obsessive-compulsive disorder (OCD) can cause substantial impairment in academic, social and family functioning. Even though cognitive-behavioural therapy (CBT) is an effective treatment, the pharmacological option has to be taken into consideration. Effectiveness of serotonin reuptake inhibitors (SRIs) has been supported by several double-blind, placebo-controlled studies. OBJECTIVE: To report the response to pharmacotherapy in children and adolescents with OCD naturalistically followed up and treated with SRIs. METHODS: From a consecutive series of 257 patients (174 males and 83 females; mean age 13.6+/-2.7 years) diagnosed with OCD following a clinical interview according to DSM-IV criteria, 37 children improved significantly after psychotherapy and were excluded. The remaining 220 patients were included in the study. RESULTS: Eighty-nine patients (40.5%) were managed with SRI monotherapy and 131 with an SRI in combination with another medication. Compared with those who needed polypharmacy, patients managed with SRI monotherapy were younger at the time of the first consultation, had less severe symptoms at baseline, and more frequently presented with co-occurring anxiety and depressive disorders, while patients receiving polypharmacy presented with higher rates of bipolar disorder, tic disorder and disruptive behaviour disorders. 135 patients (61.4%) achieved a positive clinical response and were considered responders. When differences between responders and nonresponders at the end of follow-up were considered, irrespective of the pharmacological treatment (monotherapy or polypharmacy), responders had less severe disease at baseline, were younger at the time of the first consultation, more frequently presented with the contamination/cleaning phenotype and less frequently presented with the hoarding phenotype. Treatment refractoriness was associated with higher rates of conduct disorder and bipolar disorder, and lower rates of generalized anxiety disorder and panic disorder. Forty-three children received therapy with an atypical antipsychotic as an augmenting strategy, and 25 of these children (58.1%) became responders. Responders to augmentation were less severely impaired at baseline, while different subtypes of OCD were similar between responders and nonresponders, as were patterns of co-morbidity. CONCLUSION: Our study suggests that putative variables associated with response to pharmacological treatment of paediatric OCD can be defined, and can help improve treatment strategies.

Effectiveness of lithium in children and adolescents with conduct disorder: a retrospective naturalistic study.

BACKGROUND: The most severe forms of conduct disorder (CD) are disabling conditions, often resistant to treatment and likely to evolve into antisocial behaviours. Mood stabilizers and atypical antipsychotics are often used to treat severe cases of CD, as are antidepressants and psychostimulants less frequently, despite a relative lack of efficacy data. Use of lithium in hospitalized children and adolescents with CD has been evaluated in a small number of studies. AIM: To explore the efficacy and tolerability of lithium (administered either as monotherapy or in association with atypical antipsychotics) in children and adolescents with CD and to identify variables associated with positive or negative responses to such treatment. METHODS: This retrospective study included 60 consecutive patients (46 males and 14 females; range 8-17 years; mean age 14.2 +/- 2.4 years) who were treated with lithium for CD diagnosed on the basis of the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (K-SADS-PL) clinical interview and the DSM-IV criteria for CD. The sample consisted of 44 inpatients (who remained in hospital during the first 2 or 3 weeks of treatment and were then assessed as outpatients) and 16 outpatients; the follow-up period was 6-12 months (mean 8.4 +/- 2.2 months). While all patients were initially treated with lithium, an atypical antipsychotic could be added if necessary to achieve satisfactory control of symptoms. Outcome measures included the Modified Overt Aggression Scale (MOAS), the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales, and the Aggression Questionnaire (which assessed the type of aggression, i.e. predatory vs affective). Patients were considered responders to pharmacological treatment at the end of the follow-up period if they satisfied all of the following criteria: >or=50% decrease in MOAS score, CGI-I score of 1 or 2 ('very much improved' or 'much improved') and CGI-S score of 0.8 indicates good treatment efficacy). RESULTS: At the end of follow-up, 29 of 60 patients (48.3%) were classified as responders (10 receiving lithium monotherapy and 19 receiving lithium plus atypical antipsychotic therapy). For the sample as a whole, mean total MOAS score improved significantly (p < 0.001) and the effect size (pre- vs post-treatment) was 1.03. Mean MOAS verbal, and physical towards objects and other persons aggression scores, both in patients taking lithium as monotherapy and those also taking an add-on atypical antipsychotic, also improved significantly (p < 0.001) and the effect size was >or=0.80 for all items. Improvement in mean MOAS self-aggression score (p < 0.001) and an effect size of 0.59 was found when an atypical antipsychotic was added to lithium therapy. Predictors of a positive response to treatment were less severe disease at baseline, lower MOAS aggression scores and an impulsive (affective, nonpredatory) type of aggression. Gastrointestinal adverse effects, polydipsia and increased urinary frequency, tremor and increased thyroid stimulating hormone levels were the most frequently reported adverse effects. Two patients discontinued treatment because of adverse effects (vomiting and thyroid dysfunction). CONCLUSION: Lithium alone or in combination with an atypical antipsychotic may reduce aggressive behaviours in children and adolescents with CD. The adverse effects of such therapy are relatively common but rarely severe.

Clinical implications of DSM-IV subtyping of bipolar disorders in referred children and adolescents.

OBJECTIVE: According to DSM-IV, bipolar disorders (BDs) include four subtypes, BD I, BD II, cyclothymic disorder, and BD not otherwise specified (NOS). We explore the clinical implications of this subtyping in a naturalistic sample of referred youths with BD I, BD II, and BD-NOS. METHOD: The sample consisted of 217 patients, 135 males and 82 females, ages between 8 and 18 years (mean age, 13.6 +/- 2.9 years), diagnosed according to historical information, prolonged observations, and a structured clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version). The location of the study was the Stella Maris Scientific Institute of Child Neurology and Psychiatry of Pisa (Italy). RESULTS: Seventy-eight patients (35.9%) had BD I, 97 (44.7%) had BD II, and 42 (19.4%) had BD-NOS. Patients with BD I presented more frequently psychotic symptoms and elated rather than irritable mood. Patients with BD II were less severely impaired, presented more frequently depression as the intake affective episode, and had the highest comorbidity with anxiety disorders. Patients with BD-NOS presented an earlier onset of the disorder, a chronic rather than episodic course, an irritable rather than an elated mood, and a more frequent comorbidity with attention-deficit/hyperactivity disorder and oppositional defiant disorder. CONCLUSIONS: DSM-IV categorization of BD may have meaningful implications in youths, but needs to be detailed further.

Clinical and research implications of panic-bipolar comorbidity in children and adolescents.

A substantial portion of patients with juvenile bipolar disorder (BD) have a comorbid panic disorder (PD). The aim of our study was to analyze the cross-sectional and longitudinal implications of such comorbidity in children and adolescents with BD. The sample comprised 224 referred children and adolescents with BD, 140 males (62.5%) and 84 females (37.5%), mean age 13.8+/-2.8 years, diagnosed with a clinical interview (K-SADS-PL), and followed up naturalistically for 6 months. Fifty-one BD patients (22.8%) had a lifetime diagnosis of comorbid PD. Subjects with BD+PD and those without BD (BD-noPD) did not differ according to index age, age at onset of BD and bipolar phenotype (episodic vs. continuous course, irritable vs. elated mood). BD+PD was more frequent in females, was less severe at baseline according to the Clinical Global Impression severity score, and was more frequently associated with BD type 2. Moreover, BD+PD presented higher rates of comorbid anxiety disorders (namely separation anxiety disorder) and lower rates of externalizing disorders, namely attention deficit disorder (ADHD) than BD-noPD. However, this different pattern of externalizing comorbidity did not affect severity and improvement. Our findings suggest that PD is frequently comorbid in juvenile BD and can influence severity, pattern of comorbidity and course of BD. The data are compatible with the hypothesis that Panic-BD and ADHD-BD might represent distinct developmental pathways of bipolar disorder. Further research on this question may prove rewarding.

Bipolar co-morbidity in pediatric obsessive-compulsive disorder: clinical and treatment implications.

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.

Children with schizophrenia: clinical picture and pharmacological treatment.

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.

Developmental differences according to age at onset in juvenile bipolar disorder.

BACKGROUND: This study on a large sample of unselected, consecutive children and adolescents referred to a third-level hospital who received a diagnosis of bipolar disorder (BD) was aimed at exploring whether childhood-onset BD, as compared with adolescent-onset BD, presents specific clinical features in terms of severity, functional impairment, course, prevalent mood, pattern of co-morbidity, and treatment outcome. METHODS: A total of 136 patients, 81 males (59.6%) and 55 females (40.4%), mean age 13.5 +/- 2.9 years, meeting the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of BD according to a structured clinical interview Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (KSADS-PL), were included in the study. RESULTS: Eighty patients (58.8%) had a childhood-onset BD (before 12 years of age) and 56 (41.2%) had an adolescents-onset BD. Compared with the adolescent-onset BD, patients with childhood-onset were more frequently males and had a more frequent co-morbidity with attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). An episodic course was found in only 42.5% of bipolar children, but 76.8% of youngsters with adolescent-onset BD. Severity, 6-month treatment outcome, prevalent mood (elated versus irritable), and co-morbid anxiety did not differentiate the two groups. CONCLUSIONS: Our findings suggest that a very early age at onset may identify a form of BD with a more frequent subcontinuous course and a heavy co-morbidity with ADHD.

Conduct disorder in referred children and adolescents: clinical and therapeutic issues.

OBJECTIVE: Studies on referred children and adolescents with conduct disorder (CD) have relevant implications for prevention and treatment. We addressed this issue in a large sample of youths with CD, considering age at onset, sex, and response to treatments as variables. METHODS: The sample consisted of 198 patients (153 males and 45 females; age range, 8-18 years; mean age, 13.2 +/- 2.6 years), consecutively diagnosed as having CD during a 5-year period. The diagnoses were based on fulfillment of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, according to historical information, prolonged observations, and a clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version). Three subtypes of aggressive behaviors-"predatory" (controlled, planned, and goal-oriented), "affective" (impulsive, explosive, and unprofitable), and "mixed" (with both the features)-were considered in this study. RESULTS: Patients with prepubertal onset were younger at referral and had a poorer socioeconomic status. Their condition was more severe at the baseline, but their response to treatments did not differ from those with adolescent onset. Predatory and affective aggression and attention deficit hyperactivity disorder comorbidity were higher in children with prepubertal-onset CD. Regarding to sex, females were older and had a lower socioeconomic status. Their condition was more severe at the baseline and presented higher scores in self-aggression, but they responded better to treatments. Rates of attention deficit hyperactivity disorder were significantly lower in females, whereas other comorbidities (including substance abuse) were similar between sexes. Nonresponders to treatments received less frequently a psychosocial intervention, have more severe condition at the baseline, presented a more severe verbal and physical aggression, a lower affective/predatory index, and a higher rate of substance abuse. CONCLUSIONS: Age at onset and sex may be critical variables for prognosis of CD. Psychosocial intervention can significantly improve the treatment response.

Comorbidity of conduct disorder and bipolar disorder in clinically referred children and adolescents.

OBJECTIVE: The co-occurrence of conduct disorder (CD) and bipolar disorder (BD) has been frequently reported in referred children and adolescents. We address the implications of this comorbidity in a naturalistic sample of youths with BD, CD, and CD+BD. METHODS: The sample consisted of 307 patients (216 males and 91 females, age range 8-18 years, mean age 13.5 +/- 2.6 years) referred during a 5-year period and followed-up for at least 6 months, 106 with CD without BD, 109 with BD without CD, and 92 with CD+BD, diagnosed with a structured clinical interview (K-SADS-PL). RESULTS: Patients with CD alone were more predominantly males and with the lowest socio-economic status. Patients with CD without BD were the least severe at the baseline, while patients with BD alone presented the greatest improvement during the follow-up, and those with CD+BD had the poorest response. Patients with CD+BD presented higher rates of global aggression at the baseline, namely impulsive aggression, compared with CD alone, and the highest risk of substance abuse. Patients with BD alone presented higher rates of comorbid panic disorder and obsessive compulsive disorder, while patients with CD, with or without BD, had higher rates of ADHD. CONCLUSIONS: Bipolar-conduct disorder comorbidity may have meaningful implications in children and adolescents, in terms of presentation, course, and treatments.

Pharmacological treatment options for panic disorder in children and adolescents.

Although panic disorder usually emerges in early to middle adulthood, adults with panic disorder often retrospectively report that their panic symptoms began in childhood or early adolescence. The majority of these juvenile cases are being misdiagnosed, and/or do not come to clinical attention. Awareness of early-onset panic disorder, as well as a more precise definition of early signs and possible clinical subtypes, can favour timely diagnosis and treatment, reduce clinical impairment and improve the prognosis of these patients. In the context of a multimodal approach, pharmacological treatment can be helpful. This review focuses on the empirical evidence of pharmacotherapy in early-onset panic disorder, including selective serotonin re-uptake inhibitors, benzodiazepines and tricyclics. The data supporting efficacy are still limited, and no controlled studies are available. Practical guidelines for the management of these patients are provided, including treatment of the most frequent psychiatric comorbidities.