Long term methylphenidate exposure and growth in children and adolescents with ADHD. A systematic review and meta-analysis.

BACKGROUND: Methylphenidate (MPH) is an efficacious treatment for ADHD but concerns have been raised about potential adverse effects of extended treatment on growth. OBJECTIVES: To systematically review the literature, up to December 2018, conducting a meta-analysis of association of long-term (> six months) MPH exposure with height, weight and timing of puberty. RESULTS: Eighteen studies (ADHD n = 4868) were included in the meta-analysis. MPH was associated with consistent statistically significant pre-post difference for both height (SMD = 0.27, 95% CI 0.16-0.38, p < 0.0001) and weight (SMD = 0.33, 95% CI 0.22-0.44, p < 0.0001) Z scores, with prominent impact on weight during the first 12 months and on height within the first 24-30 months. No significant effects of dose, formulation, age and drug-naïve condition as clinical moderators were found. Data on timing of puberty are currently limited. CONCLUSIONS: Long-term treatment with MPH can result in reduction in height and weight. However, effect sizes are small with possible minimal clinical impact. Long-term prospective studies may help to clarify the underlying biological drivers and specific mediators and moderators.

Effects of methylphenidate on cognitive functions in children and adolescents with attention-deficit/hyperactivity disorder: evidence from a systematic review and a meta-analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of neuropsychological impairments. The relationship between these neuropsychological deficits and the defining symptoms of ADHD seems more complex than originally thought. Methylphenidate (MPH) is an effective treatment for ADHD symptoms, but its impact on cognition is less clearly understood. METHODS: With a common systematic search strategy and a rigorous coding and data extraction strategy across domains, we searched electronic databases to identify published placebo controlled trials that compared MPH and placebo on executive and nonexecutive memory, reaction time, reaction time variability and response inhibition in children and adolescents (5-18 years) with a formal diagnosis of ADHD. RESULTS: Sixty studies were included in the review, of which 36 contained sufficient data for meta-analysis. Methylphenidate was superior to placebo in all five meta-analyses: executive memory, standardized mean difference (SMD) .26, 95% confidence interval (CI): -.39 to -.13; non-executive memory, SMD .60, 95% CI: -.79 to -.41; reaction time, SMD .24, 95% CI: -.33 to -.15; reaction time variability, SMD .62, 95% CI: -.90 to -.34; response inhibition, SMD .41, 95% CI: -.55 to -.27. CONCLUSIONS: These data support the potentially important effects of MPH on various aspects of cognition known to be associated with ADHD. Consideration should be given to adding cognitive outcomes to the assessment of treatment outcome in ADHD, considering the complexity of the relationship between ADHD symptoms and cognition.

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

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.

Predictive factors for persistent use and compliance of immediate-release methylphenidate: a 36-month naturalistic study.

AIM: The objective of this study was to evaluate predictors of long-term adherence to treatment with methylphenidate (MPH). METHODS: A total of 134 children (ages 4-16) with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) determined by specific protocols, including a semistructured parent interview, Conners' Teacher/Parent Rating Scales, cognitive and learning evaluation, and child self-reports for anxiety and depression, were assessed monthly for up to 36 months. At the end of the study (36 months), three outcomes were evaluated (continuing medication, medication withdrawn due to functional remission, and medication withdrawn for other reasons including poor compliance). Outcomes were first analyzed by mean of the chi-squared test, Mann-Whitney-U test, or t-test, and predictive models were subsequently generated using Cox proportional hazards model analysis. Age, ADHD subtype, co-morbidity, cognitive functioning, side effects, and family and social characteristics were considered as independent variables. RESULTS: Thirty-six months after starting MPH, 62 children (46%) were still on treatment, 32 (24%) had stopped MPH due to functional remission, and 40 (30%) had suspended MPH for other reasons. Within the last group, 20 suspended for poor compliance, 10 for decrease of efficacy, 5 for side effects, and 5 because they entered in an atomoxetine clinical trial. The presence of associated disorders, younger age, female gender, and not living with both parents were predictors for continuing medication until end of the study (36 months); absence of associated disorders and older age were predictors of discontinuation medication due to functional remission before the end of study, older age, and hyperactive subtype were predictors of discontinuing medication for other reasons. CONCLUSION: Clinical outcome of ADHD treatment is heterogeneous: Specific clinical and social predictive parameters for long-term MPH use and compliance can be identified. An accurate tailoring of clinical intervention to the individual child appears crucial for good outcome.

Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: a systematic review and meta-analysis.

To evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with depressive disorder, the main electronic databases and the reference lists of retrieved articles and reviews were searched up to January 2007. Randomized controlled studies (RCT) were assessed for methodological quality, taking into consideration the specific diagnostic and severity evaluation tools used, and a meta-analysis on the efficacy of SSRIs compared placebo was undertaken. In all, 13 studies were included, covering a total of 2530 children and adolescents. Eleven studies met the criteria for inclusion in the meta-analysis. The pooled odds ratio was 1.57 (95% C.I. 1.29-1.91). Only fluoxetine appeared to offer a moderately significant benefit profile (OR=2.39). All studies differed in diagnostic tools and primary efficacy measures. SSRI treatment, especially with fluoxetine, may be effective on child and adolescent depression. Nevertheless, additional RCTs with sound methodological designs, validated diagnostic instruments, large sample sizes, and consistent outcomes are necessary to determine the role of SSRIs, alone or in combination with psychological interventions in the treatment of depression in children and adolescents.