Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: A review of the randomized controlled studies

Centre for Pharmacological Therapy in Child & Adolescent Neuropsychiatry, Department of Neuroscience "B.B. Brodie", University of Cagliari, Italy.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology (Impact Factor: 4.37). 05/2011; 21(8):600-20. DOI: 10.1016/j.euroneuro.2011.04.001
Source: PubMed


In children and adolescents the Second Generation Antipsychotics (SGAs) represent the class of psychotropic drugs whose use has grown more significantly in recent years: they are primarily used for treatment of patients with disruptive behavior disorders, mood disorders and pervasive developmental disorders or mental retardation. In order to compare the efficacy and tolerability of antipsychotics against placebo or each other, a systematic Medline/PubMed search for randomized, double blind studies on SGA in patients younger than 18 years of age at enrollment, was conducted. Papers on schizophrenia, discussed in another article of this specific issue, were excluded by the efficacy analysis. A set of standard efficacy and safety indices, such as treatment effect sizes (ES), the Numbers Needed to Treat (NNT) and Numbers Needed to Harm (NNH), was used to compare medications. 32 studies analyzing efficacy and/or tolerability of SGAs in children and adolescents with bipolar, autistic or disruptive behavior disorders, and Tourette syndrome were identified. SGAs efficacy on mania, extreme mood variability, irritability, aggression and disruptive behavior appears to be greater than for psychotic symptoms in schizophrenia: average NNT was 2-5, whereas for schizophrenia it varies between 3 for risperidone and 10 for olanzapine, quetiapine, and aripiprazole. As for schizophrenia, different SGAs show a similar efficacy for specific non-psychotic disorders, but they significantly differ in their safety profile. In randomized studies, adverse effects were usually relatively minor, easily predictable and manageable, whereas long-term open-label studies have indicated that some adverse event, such as the metabolic effects, may be severe and potentially life threatening on the long-term. Taken together, these findings suggest that the choice of a specific treatment should be guided primarily by the safety profile of specific antipsychotics, considering specific risk factors (i.e. obesity and BMI, family history of diabetes or cardiovascular disorder, etc) for the single patient.

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    • "Although current clinical research into the use of APDs in the adolescent population over both short term periods of between one and two months, and longer-term periods of up to six months has found some benefits in the treatment of some mental illness symptomology (Kumra et al., 2008; Stigler et al., 2004; Zuddas et al., 2011), there is limited data on the potential for long-term alterations to adult behaviours (Milstein et al., 2013; Shu et al., 2014; Varela et al., 2014). Although the effects of childhood/adolescent APD use on adult behaviours is unknown in a clinical setting, current animal studies have shown that early drug treatment for a period of up to four weeks can result in various significant alterations in the dopaminergic and serotonergic pathways in the brain long-term (Maciag et al., 2006; Memarzia et al., 2014; Milstein et al., 2013; Moran-Gates et al., 2006; Varela et al., 2014; Vinish et al. 2012), including permanent changes in the distribution of NT receptors and dendritic architecture (Maciag et al., 2006; Milstein et al., 2013; Moran-Gates et al., 2006), with minimal evidence of the direct effects on behaviour. "
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    ABSTRACT: Childhood/adolescent antipsychotic drug (APD) use is exponentially increasing worldwide, despite limited knowledge of the long-term effects of early APD treatment. Whilst investigations have found that early treatment has resulted in some alterations to dopamine and serotonin neurotransmission systems (essential to APD efficacy), there have only been limited studies into potential long-term behavioural changes. This study, using an animal model for childhood/adolescent APD treatment, investigated the long-term effects of aripiprazole, olanzapine and risperidone on adult behaviours of male and female rats. Open-field/holeboard, elevated plus maze (EPM), social interaction and forced swim (FS) tests were then conducted in adult rats. Our results indicated that in the male cohort, early risperidone and olanzapine treatment elicited long-term hyper-locomotor effects (open-field/holeboard and FS tests), whilst a decrease in depressive-like behaviour (in FS test) was observed in response to olanzapine treatment. Furthermore, anxiolytic-like behaviours were found following testing in the open-field/holeboard and EPM in response to all three drug treatments. Effects in the female cohort, however, were to a far lesser extent, with behavioural attributes indicative of an increased depressive-like behaviour and hypo-locomotor activity exhibited in the FS test following early risperidone and olanzapine treatment. These results suggest that various APDs have different long-term effects on the behaviours of adult rats.
    Journal of Psychopharmacology 11/2015; DOI:10.1177/0269881115616383 · 3.59 Impact Factor
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    • "Most of SGA-treated patients will gain and maintain high weight and insulin resistance for long time, even after changes in life style and/or use of anti-diabetic drugs. The burgeoning literature on metabolic issues associated with the use of SGAs [47] [130] [110] [15] [3] have increased opportunities for the rational development singletarget prophylactic agents, which can protect physical health and improve compliance of patients treated with SGAs [141] [130]. A careful selection of the specific SGA is important for risk/benefit evaluation, since clozapine and olanzapine are known to cause the most severe profile of metabolic side effects [110], while quetiapine , aripiprazole and ziprasidone display significantly lower risk of metabolic alterations [72]. "
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    ABSTRACT: Second generation antipsychotics (SGAs), such as clozapine, olanzapine, risperidone and quetiapine, are among the most effective therapies to stabilize symptoms schizophrenia (SZ) spectrum disorders. In fact, clozapine, olanzapine and risperidone have improved the quality of life of billions SZ patients worldwide. Based on the broad spectrum of efficacy and low risk of extrapyramidal symptoms displayed by SGAs, some regulatory agencies approved the use of SGAs in non-schizophrenic adults, children and adolescents suffering from a range of neuropsychiatric disorders. However, increasing number of reports have shown that SGAs are strongly associated with accelerated weight gain, insulin resistance, diabetes, dyslipidemia, and increased the cardiovascular risk. These metabolic alterations can develop in as short as six months after the initiation of pharmacotherapy, which is now a controversial fact in public disclosure. Although the percentage of schizophrenic patients, the main target group of SGAs, is estimated in only 1% of the population, during the past ten years there was an exponential increase in the number of SGAs users, including millions of non-SZ patients. The scientific bases of SGAs metabolic side effects are not yet elucidated, but the evidence shows that the activation of transcriptional factor SRBP1c, the D1/D2 dopamine, GABA2 and 5HT neurotransmitions are implicated in the SGAs cardiovascular toxicity. Polypharmacological interventions are either non- or modestly effective in maintaining low cardiovascular risk in SGAs users. In this review we critically discuss the clinical and molecular evidence on metabolic alterations induced by SGAs, the evidence on the efficacy of classical antidiabetic drugs and the emerging concept of antidiabetic polyphenols as potential coadjutants in SGA-induced metabolic disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Pharmacological Research 07/2015; 101. DOI:10.1016/j.phrs.2015.07.022 · 4.41 Impact Factor
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    • "In particular: (a) psychostimulants have been proven effective in reducing the hyperactivity and impulsivity, present in up to a third of ASD cases (Simonoff et al., 2008; Harfterkamp et al., 2012). Their efficacy is somewhat lower compared to effects in children with " pure " ADHD, while side effects (i.e., irritability, lethargy, tics, sadness, and social withdrawal) tend to be more frequent and severe in autistic children with comorbid ADHD (Research Units on Paediatric Psychopharmacology Autism Network, 2005; Simonoff et al., 2013); (b) SGAs, particularly risperidone and aripiprazole, have been shown to control irritability, agitation, compulsions and aggressiveness, with evidence of maintained efficacy for up to 6 months of treatment in the majority of patients (Marcus et al., 2009; Politte and McDougle, 2014; Zuddas et al., 2011); (c) SSRIs display some efficacy on anxiety and repetitive behaviours in adults, but not in children and adolescents with autism (Williams et al., 2010). This lack of efficacy in the paediatric ASD population is likely related to age-specific differences in underlying neurobiological mechanisms, to target symptoms (autistic individuals report anxiety as distressing and stereotypic behaviours as relaxing), and to the use of assessment tools and outcome measures that have been validated only in individuals without ASD (Reiersen and Handen, 2011). "
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    ABSTRACT: Paediatric psychopharmacology holds great promise in two equally important areas of enormous biomedical and social impact, namely the treatment of behavioural abnormalities in children and adolescents, and the prevention of psychiatric disorders with adolescent- or adult-onset. Yet, in striking contrast, pharmacological treatment options presently available in child and adolescent psychiatry are dramatically limited. The most important currently unmet needs in paediatric psychopharmacology are: the frequent off-label prescription of medications to children and adolescents based exclusively on data from randomized controlled studies involving adult patients; the frequent lack of age-specific dose, long-term efficacy and tolerability/safety data; the lack of effective medications for many paediatric psychiatric disorders, most critically autism spectrum disorder; the scarcity and limitations of randomized placebo-controlled trials in paediatric psychopharmacology; the unexplored potential for the prevention of psychiatric disorders with adolescent- and adult-onset; the current lack of biomarkers to predict treatment response and severe adverse effects; the need for better preclinical data to foster the successful development of novel drug therapies; and the effective dissemination of evidence-based treatments to the general public, to better inform patients and families of the benefits and risks of pharmacological interventions during development. Priorities and strategies are proposed to overcome some of these limitations, including the European Child and Adolescent Clinical Psychopharmacology Network, as an overarching Pan-European infrastructure aimed at reliably carrying out much needed psychopharmacological trials in children and adolescents, in order to fill the identified gaps and improve overall outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2015; DOI:10.1016/j.euroneuro.2015.06.009 · 4.37 Impact Factor
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