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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 9, December 2012—Guest Commentator: Antonio Y. Hardan, MD, Stanford University School of Medicine



Treatment with Paliperidone in Children with Behavior Disorders Previously Treated with Risperidone: An Open-label Trial

Fernández-Mayoralas DM, Fernández-Jaén A, Muñoz-Jareño N, et al
Clin Neuropharmacol. 2012;35(5):227-230.

Objectives: Paliperidone is the main active metabolite of risperidone, with certain pharmacokinetic and tolerability characteristics that suggest it may be used in special groups, such as children. Our purpose is to document the clinical experience with the use of paliperidone in children with severe behavior problems that were partially refractory to treatment with risperidone and psychological treatment.

Methods: This is a prospective 16-week open-label study of paliperidone in 18 patients (mean age, 13.4 years) with severe and excessive irritability in the context of generalized developmental disorders or attention-deficit/hyperactivity disorder. Patients who had exhibited an inadequate response to treatment with risperidone (1.5–2 mg/day) over a treatment period of 6 months were treated with paliperidone at 3 mg/day. Symptom severity at the beginning of the study and in response to paliperidone were rated with the Clinical Global Impression (CGI) scale and Overt Aggression Scale.

Results: A significant difference was documented between the mean score before treatment and the score after the drug intervention with paliperidone. There was a noticeable clinical improvement in 50% of the cases, as reflected in the CGI. Severity of aggressive behavior, as assessed by the Overt Aggression Scale, decreased significantly after paliperidone treatment: mean (SD), 2.7 (0.92) before treatment versus 1.5 (0.60) after treatment. This compound was safe and well tolerated.

Conclusion: Half of the patients clearly responded to paliperidone extended release. Tolerance to this treatment was distinctly better than to risperidone. These preliminary results lay the foundation for further research into the use of paliperidone to treat pediatric disruptive behavior disorders within the context of randomized, double-blind, controlled clinical trials.

Clinical Commentary
Disruptive behaviors commonly occur in a variety of childhood-onset neuropsychiatric disorders and can be very disabling. Currently, medications including risperidone and aripiprazole are used to target these disruptive behaviors commonly found in children and adolescents with behavioral disorders. However, they do have side effects including lethargy and weight gain. Paliperidone is the primary active metabolite of risperidone, and paliperidone ER had been shown to be effective in improving clinical symptoms of schizophrenia. The current open-label trial assessed the effectiveness and tolerability of paliperidone ER for disruptive behaviors in individuals with generalized developmental disorders or ADHD who did not respond to risperidone and psychoeducation. The small pilot study provides some evidence that paliperidone ER might be effective in improving aggression and disruptive behaviors with fewer side effects compared to risperidone 1.5 to 2 mg. However, findings from this study should be examined with caution in light of several methodological limitations including the open-label design and the heterogeneity of the sample included. Large, randomized, controlled trials are needed in well-characterized and homogenous clinical populations to determine the effectiveness of paliperidone ER.


Randomized Controlled Double-Blind Trial of Optimal Dose Methylphenidate in Children and Adolescents with Severe Attention-Deficit/Hyperactivity Disorder and Intellectual Disability

Simonoff E, Taylor E, Baird G, et al
J Child Psychol Psychiatry. 2012 Jun 7. doi: 10.1111/j.1469-7610.2012.02569.x. [Epub ahead of print]

Background: Attention-deficit/hyperactivity disorder (ADHD) is increased in children with intellectual disability. Previous research has suggested that stimulants are less effective than in typically developing children, but no studies have titrated medication for individual optimal dosing or tested the effects for longer than 4 weeks.

Methods: One hundred and twenty-two drug-free children 7–15 years of age with hyperkinetic disorder and IQ scores of 30–69 were recruited to a double-blind, placebo-controlled trial that randomized participants using minimization by probability. Patients were stratified by referral source and IQ level in a one-to-one ratio. Methylphenidate was compared with placebo. Dose titration comprised at least 1 week each of low (0.5 mg/kg/day), medium (1.0 mg/kg/day), and high dosages (1.5 mg/kg/day). Parent and teacher ADHD index of the Conners Rating Scale-Short Version at 16 weeks provided the primary outcome measures. Clinical response was determined with the Clinical Global Impressions-Improvement scale (CGI-I). Adverse effects were evaluated by a parent-rated questionnaire, weight, pulse, and blood pressure. Analyses were by intention to treat.

Results: Methylphenidate was superior to placebo with effect sizes of 0.39 [95% confidence intervals (CIs) 0.09, 0.70] and 0.52 (95% CIs 0.23, 0.82) for the parent and teacher Conners ADHD index. Four (7%) children on placebo versus 24 (40%) of those on methylphenidate were judged improved or much improved on the CGI. IQ and autistic symptoms did not affect treatment efficacy. Active medication was associated with sleep difficulty, loss of appetite, and weight loss, but there were no significant differences in pulse or blood pressure.

Conclusions: Optimal dosing of methylphenidate is practical and effective in some children with hyperkinetic disorder and intellectual disability.

Clinical Commentary
Inattention, hyperactivity, and impulsivity are commonly observed in individuals with intellectual disability (ID), but can often go unrecognized in this population. Previous studies of methylphenidate in children and adolescents with severe ADHD primarily excluded individuals with ID. The present double-blind, placebo-controlled trial randomized immediate-release methylphenidate and titrated it over at least 3 weeks in children with ID between the ages of 7 to 15 years. The results suggest that this medication is helpful in improving clinical symptoms. Although overall safety was noted to be good, adverse effects were observed. Findings suggest that individuals with ID should be monitored closely while using slow titration schedules. Finally, clinicians should pay particular attention to identifying and treating individuals with ID and comorbid ADHD, as this combination often goes unrecognized.

The Effects of Aripiprazole on Electrocardiography in Children with Pervasive Developmental Disorders

Ho JG, Caldwell RL, McDougle CJ, et al
J Child Adolesc Psychopharmacol. 2012; 22(4):277-83. doi: 10.1089/cap.2011.0129.

Objectives: Psychotropic medications, including atypical antipsychotics, have historically been scrutinized for cardiac effects and risk of sudden death. Aripiprazole is an atypical antipsychotic approved for pediatric use in schizophrenia, bipolar I disorder, and autistic disorder. Adult studies have evaluated the effects of aripiprazole on electrocardiograms, but no pediatric studies have been published to date.

Methods: Electrocardiographic data were collected from children and adolescents participating in a 14-week, prospective, open-label study (n=25) of aripiprazole for irritability in pervasive developmental disorder not otherwise specified and Asperger's disorder. A 12-lead electrocardiogram was obtained at the baseline and endpoint visits. The electrocardiograms were evaluated for abnormal findings, and the PR, QRS, QT(c), and RR intervals were recorded. The QT interval was corrected using Bazett's, United States FDA Pharmacology Division, and Frederica's formula.

Results: Twenty-four subjects received both baseline and posttreatment electrocardiograms. The mean age was 8.6 years (range 5–17 years). The average final aripiprazole dose was 7.8 mg/day (range 2.5–15 mg/day). There were no significant differences noted with the PR, QRS, RR, and QT(c) intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QT(c). No posttreatment QT(c) exceeded 440 ms.

Conclusions: To our knowledge, this is the first systematic evaluation of the cardiac effects of aripiprazole in children and adolescents. The results are consistent with previously published literature in adults indicating that aripiprazole has no significant cardiac effects and can be deemed a low risk for causing sudden death. It will be important to confirm these findings in a randomized controlled trial.

Clinical Commentary
Antipsychotic medications, such as thioridazine and clozapine, have historically been linked to possible cardiac effects. Aripiprazole, a second-generation antipsychotic, has been approved for use in adults with schizophrenia, bipolar I, and major depressive disorder, as well as for use in pediatric populations for schizophrenia, bipolar I, and irritability associated with autistic disorder. Changes in electrocardiograms, including prolongation of the QTc interval have been associated with abnormal arrhythmias and sudden death. Previous studies have found no prolongation of the QTc interval in adults after taking aripiprazole. The present open-label study is consistent with the adult literature, suggesting that there is little cardiac risk for pediatric patients with pervasive developmental disorder taking aripiprazole. These results should be taken with caution in light of the methodological limitations of the study, mainly its uncontrolled design. Large randomized and long-term trials are warranted to have final conclusions regarding the cardiovascular safety of aripiprazole in pediatric populations, including individuals with autism spectrum disorders.

Axis I and II Comorbidity and Psychosocial Functioning in Female Adolescents with Borderline Personality Disorder

Kaess M, von Ceumern-Lindenstjerna IA, Parzer P, et al
Psychopathology. 2012 Aug 7. [Epub ahead of print]

Background: Borderline personality disorder (BPD) is known to be associated with high rates of comorbidity and severe impairment of psychosocial functioning in adults. The aim of this study was to investigate Axis I and Axis II disorders, as well as psychosocial functioning, in a clinical sample of adolescents with BPD and to compare these with participants with mixed psychiatric diagnoses.

Methods: Female adolescent patients were consecutively recruited from the child and adolescent psychiatry department of a university hospital. Axis I and Axis II diagnoses were assessed by experienced clinicians using well-established semi-structured interviews, along with psychosocial functioning.

Results: The final sample (87 participants) comprised 31 participants with a diagnosis of BPD and 56 participants with mixed psychiatric diagnoses. The most common comorbid disorders in the adolescent BPD sample were mood, eating, dissociative, and substance use disorders in Axis I, and cluster C personality disorders in Axis II. The BPD group showed a significantly higher average number of comorbid Axis I and Axis II diagnoses and significantly lower psychosocial functioning compared with the clinical control group. Regression analyses revealed that psychosocial functioning was predicted by socioeconomic status and comorbid disorders, as well as the unique influence of BPD itself.

Conclusion: Adolescent BPD in females is accompanied by high rates of psychiatric comorbidity and poor psychosocial functioning. This underscores the need for diagnosis of BPD at its early stages, in order to facilitate appropriate interventions.

Clinical Commentary
Borderline personality disorder (BPD) is characterized by pervasive instability in emotion regulation, impulse control, interpersonal relationships, and self-image. Adults with BPD often have high rates of comorbid mood, anxiety, and substance use disorders. However, limited information is available on the comorbidity of youths affected with BPD. The present study examined comorbid conditions and psychosocial functioning in adolescent females with diagnosed BPD compared to a mixed diagnosis clinical sample. Similar to adult populations, the BPD group showed high rates of mood, eating, dissociative, and substance use disorders as well as cluster C personality disorders including avoidant, dependent, and obsessive-compulsive disorder. Due to the high rates of comorbidities and poor psychosocial functioning in adolescents with BPD, clinicians need to pay particular attention to and assess systematically for Axis I disorders in this population. Intervening early in the course of the disorder in youths with BPD is crucial to help improve long-term outcome as supported by previous investigations. Psychotherapeutic interventions as well as medications including antidepressants, mood stabilizers, and antipsychotics have been shown to treat some of the symptoms of BPD.


Developmental Pathways for Different Subtypes of Early-Onset Bipolarity in Youths

Masi G, Mucci M, Pfanner C, et al
J Clin Psychiatry. 2012 Sep 4. [Epub ahead of print]

Objective: Two main patterns of comorbidity have been described in bipolar disorder in children and adolescents: the first including preexisting attention-deficit/hyperactivity disorder (ADHD) and related disruptive behavior disorders and the second including anxiety disorders, namely, the association of co-occurring multiple anxiety disorders, usually predating the onset of bipolarity. This study was aimed at exploring whether ADHD and multiple anxiety disorders may exhibit different pathways to specific bipolar phenotypes.

Method: We compared 49 youths (7 to 18 years) with bipolar disorder + ADHD without anxiety, 76 youths with bipolar disorder + multiple anxiety disorders without ADHD, and 52 youths with bipolar disorder without ADHD or multiple anxiety disorders who were referred to a third-level hospital and diagnosed according to DSM-IV-TR in the period 2005-2011. Subjects were evaluated for current and lifetime Axis I psychiatric disorders by using a structured clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version) and followed up for at least 6 months.

Results: Compared to both patients with bipolar disorder + multiple anxiety disorders and patients with bipolar disorder without ADHD and multiple anxiety disorders, patients with bipolar disorder + ADHD without anxiety were more frequently male, were younger, had an earlier onset of bipolar disorder, had a prevalent chronic course and irritable mood, were more likely to present with a bipolar disorder not otherwise specified diagnosis, had a greater clinical severity and functional impairment, had a manic/mixed index episode, had a higher risk of conduct disorder, and were more resistant to treatments, according to the CGI-Improvement scores (P< .0001). Patients with bipolar disorder + multiple anxiety disorders were similar to those with bipolar disorder without ADHD or multiple anxiety disorders, except for a higher rate of diagnosis of bipolar II disorder, more use of antidepressants, and less use of atypical antipsychotics.

Conclusions: The presence of comorbid ADHD versus anxiety disorders is indicative of fundamental differences in the phenomenology of bipolar disorder in youth. While ADHD prior to bipolar disorder is associated with a specific bipolar phenotype, bipolar patients with multiple anxiety disorders are similar to "typical" bipolar patients.

Clinical Commentary
There is still debate about the clinical phenotypes of bipolar disorder in children and adolescents. This is due to differences in presentation of the early-onset form compared to adult onset as well as frequent comorbidities which can often blur diagnostic categories. The present study examined youths with bipolar disorder and either comorbid ADHD or multiple comorbid anxiety disorders including at least two of the following: separation anxiety disorder, panic disorder, generalized anxiety disorder, and specific phobias. Consistent with previous studies, this research suggests that bipolar disorder plus ADHD might represent a distinct early-onset phenotype with different course and worse prognosis. Clinicians should be particularly aware of the differential diagnosis and treatment for children and adolescents with these conditions.


An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Risperidone in Adolescents with Schizophrenia

Pandina G, Kushner S, Karcher K, Haas M.
Child Adolesc Psychiatry Ment Health. 2012;6(1):23. [Epub ahead of print]

Background: Data on the long-term efficacy, safety, and tolerability of risperidone in adolescents with schizophrenia are limited. The objective of this study was to evaluate the efficacy and safety of maintenance risperidone treatment in adolescents with schizophrenia.

Methods: This open-label study of adolescents aged 13 to 17 years with schizophrenia was a single extension study of two short-term double-blind risperidone studies and also enrolled subjects directly in open-label risperidone treatment. The risperidone dose was flexible and ranged from 2 to 6 mg/day. Most subjects enrolled for 6 months; a subset enrolled for 12 months. Assessment tools included the Positive and Negative Syndrome Scale total and factor scores, Clinical Global Impressions, Children's Global Assessment Scale, adverse event (AE) monitoring, vital signs, laboratory testing, and extrapyramidal symptom rating scales.

Results: A total of 390 subjects were enrolled; 48 subjects had received placebo in a previous double-blind study; 292 subjects had received risperidone as part of their participation in one of two previous controlled studies; and 50 subjects were enrolled directly for this study. A total of 279 subjects enrolled for 6 months of treatment, and 111 subjects enrolled for 12 months of treatment. Overall, 264 (67.7%) subjects completed this study: 209 of the 279 subjects (75%) in the 6-month group and 55 of the 111 subjects (50%) in the 12-month group. The median mode dose was 3.8 mg/day. At 6 months, all three groups experienced improvement from open-label baseline in symptoms of schizophrenia as well as general assessments of global functioning. Improvements were generally maintained for the duration of treatment. The most common AEs (greater than or equal to 10% of subjects) were somnolence, headache, weight increase, hypertonia, insomnia, tremor, and psychosis. Potentially prolactin-related AEs (PPAEs) were reported by 36 (9%) subjects. The AE profile in this study was qualitatively similar to those of other studies in adult subjects with schizophrenia and in other psychiatric studies of risperidone in pediatric populations.

Conclusions: Risperidone maintenance treatment in adolescents over 6 to 12 months was well tolerated, consistent with related studies in this clinical population, and associated with continued efficacy.

Clinical Commentary
Limited information is available on the long-term efficacy and safety of risperidone in youths, and previous trials of risperidone use for various disorders have focused primarily on adults. This is the first study to examine the effectiveness and side-effect profile of risperidone in adolescents with schizophrenia over 6–12 months. The open-label study provides evidence of efficacy in this population, with side effects similar to those experienced in other pediatric populations such as children with disruptive behavior. However, findings should be interpreted with caution in light of its open-label design. Note that this study also only examined the treatment course up to 1 year. Thus, when using risperidone to treat children and adolescents with schizophrenia, clinicians should take extra caution to assess potential risks and side effects, especially over longer periods of time.

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