Weight and body mass index increase in children and adolescents exposed to antipsychotic drugs in non-interventional settings: a meta-analysis and meta-regression.

Antipsychotics increase weight, BMI and waist size, particularly in pediatric patients. Switching antipsychotics is common practice, thus defining the risk for each antipsychotic in real-life settings can be important for clinical guidance. We conducted a meta-analysis on antipsychotic-related changes in body measures in pediatric observational studies. Of 934 publications found on PubMed, we analyzed 38, including nine treatment arms: no treatment, mixed antipsychotic treatment, first-generation antipsychotics, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. Changes in weight, BMI, BMI-Z and waist size were meta-analyzed according to the duration of clinical observations: 6, 12, > 12 months. Meta-regressions probed influencing factors. Weight in Kg was increased at 6, 12, > 12 months by olanzapine [+ 10.91, + 10.7, data not available (n/a)], mixed antipsychotic treatment (n/a, + 9.42, + 12.59), quetiapine (+ 5.84, n/a, n/a) and risperidone (+ 4.47, + 6.01, + 9.51) and without treatment (n/a, + 2.3, n/a). BMI was increased at 6, 12, > 12 months by olanzapine (+ 3.47, + 3.42, n/a), clozapine (n/a, + 3, n/a) mixed antipsychotic treatment (+ 3.37, + 2.95, + 3.32), risperidone (+ 2, + 2.13, + 2.16), quetiapine (+ 1.5, + 1.82, n/a), aripiprazole (n/a, + 1.7, + 2.1) and without treatment (n/a, + 0.75, n/a). BMI-Z was increased at 6, 12, > 12 months by olanzapine (+ 0.94, + 0.98, + 0.89), clozapine (n/a, + 0.8, n/a), risperidone (+ 0.62, + 0.61, + 0.48), quetiapine (+ 0.57, + 0.54, n/a), mixed antipsychotic treatment (+ 0.51, + 0.94, + 0.44), without treatment (n/a, + 0.37, n/a) and aripiprazole (no gain, + 0.31, n/a). Waist size in cm was increased at 6, 12 months by risperidone (+ 8.8, + 11.5), mixed antipsychotics treatment (+ 9.1, + 10.2) and quetiapine (+ 6.9, + 9.1). Overall, olanzapine and clozapine displayed maximum risk, followed by risperidone, quetiapine and aripiprazole (more risky at longer terms); ziprasidone was associated with no gains. No time-based trends emerged, suggesting a drug-specific risk magnitude. Meta-regressions evidenced variable roles for persistence in therapy and follow-up length, increased risk for drug-naïve patients, and a ceiling effect determined by higher baseline BMI/BMI-Z values.

Putative Mechanisms of Action and Clinical Use of Lithium in Children and Adolescents: A Critical Review.

BACKGROUND: Lithium is a first-line treatment for bipolar disorder in adults, but its mechanism of action is still far from clear. Furthermore, evidences of its use in pediatric populations are sparse, not only for bipolar disorders, but also for other possible indications. OBJECTIVES: To provide a synthesis of published data on the possible mechanisms of action of lithium, as well as on its use in pediatric samples, including pharmacokinetics, efficacy, and safety data. METHODS: Clinical trials in pediatric samples with at least one standardized measure of efficacy/ effectiveness were included in this review. We considered: i) randomized and open label trials, ii) combination studies iii) augmentation studies iv) case series including at least 5 patients. RESULTS: Different and non-alternative mechanisms of action can explain the clinical efficacy of lithium. Clinical studies in pediatric samples suggest that lithium is effective in managing manic symptoms/episodes of bipolar disorder, both in the acute phase and as maintenance strategy. Efficacy on depressive symptoms/phases of bipolar disorder is much less clear, while studies do not support its use in unipolar depression and severe mood dysregulation. Conversely, it may be effective on aggression in the context of conduct disorder. Other possible indications, with limited published evidence, are the acute attacks in Kleine-Levin syndrome, behavioral symptoms of X-fragile syndrome, and the management of clozapine- or chemotherapy- induced neutropenia. Generally, lithium resulted relatively safe. CONCLUSIONS: Lithium seems an effective and well-tolerated medication in pediatric bipolar disorder and aggression, while further evidences are needed for other clinical indications.

Lithium treatment in bipolar adolescents: a follow-up naturalistic study.

BACKGROUND: Although lithium is currently approved for the treatment of bipolar disorders in youth, long term data, are still scant. The aim of this study was to describe the safety and efficacy of lithium in referred bipolar adolescents, who were followed up at the 4th (T1) and 8th (T2) month of treatment. METHODS: The design was naturalistic and retrospective, based on a clinical database, including 30 patients (18 males, mean age 14.2±2.1 years). RESULTS: Mean blood level of lithium was 0.69±0.20 mEq/L at T1 and 0.70±0.18 mEq/L at T2. Both Clinical Global Impression-Severity (CGI-S) and Children Global Assessment Scale (C-GAS) scores improved from baseline (CGI-S 5.7±0.5, C-GAS 35.1±3.7) to T1 (CGI-S 4.2±0.70, C-GAS 46.4±6.5; P<0.001), without significant differences from T1 to T2. Thyroid-stimulating hormone significantly increased from 2.16±1.8 mU/mL at baseline to 3.9±2.7 mU/mL at T2, remaining within the normal range, without changes in T3/T4 levels; two patients needed a thyroid hormone supplementation. Creatinine blood level did not change. No cardiac symptoms and electrocardiogram QTc changes occurred. White blood cell count significantly increased from 6.93±1.68 103/mmc at baseline to 7.94±1.94 103/mmc at T2, and serum calcium significantly increased from 9.68±0.3 mg/dL at baseline to 9.97±0.29 mg/dL at T2, both remaining within the normal range; all the other electrolyte levels were stable and normal during the follow-up. The treatment with lithium was well tolerated, probably due to the relatively low lithium blood levels. Gastrointestinal symptoms (16.7%), sedation (9.7%) and tremor (6.4%) were the most frequently reported side effects. CONCLUSION: Lithium was effective and safe in adolescent bipolar patients followed-up for eight months.