To the best of our knowledge, our study was the first meta-analysis to investigate the therapeutic effects of probiotics against the symptoms of depression in children and adolescents. Nevertheless, we found only a limited number of RCTs focusing on this issue. Overall, our results based on five trials with 692 participants showed no significant difference in the degree of improvement in depressive symptoms between those treated with probiotics and the controls. Discretion is needed when interpreting our findings taking into account the significant heterogeneity from the diversity of participants ranging from normal individuals[20, 22] to those with different neurodevelopmental disorders[18, 19, 21]. Such heterogeneity, together with the limited number of eligible RCTs as well as an absence of study targeting those diagnosed with depressive disorders, precluded a robust conclusion based on the evidence of the current study to rule out the therapeutic effect of probiotics against depressive symptoms in children and adolescents. Further studies focusing on participants with neurodevelopmental disorders, especially those diagnosed with depression, are warranted to elucidate this issue.
Unlike a previous meta-analysis recruiting adults only with stress and those diagnosed with depression or anxiety that reported an overall improvement in depressive symptoms[5], our findings demonstrated no significant therapeutic effect of probiotics against depressive symptoms in children and adolescents. Despite the discrepancy in overall outcome, our result that demonstrated no notable alleviation in depressive symptoms in the normal population compared with the controls was consistent with that of subgroup analysis of that meta-analytic study that showed no significant improvement in depressive symptoms in stressful individuals without a diagnosis of depression or anxiety[5]. Therefore, the results of both our study and that meta-analysis [5] did not support the use of probiotics for treating mood symptoms in the general population either in adults or in children/adolescents. Nevertheless, because our subgroup analysis on the normal population only included two studies with 240 participants[20, 22], our finding needs to be interpreted with caution.
When focusing on those with neurodevelopmental disorders, our results were in favor of probiotics despite the lack of statistical significance. However, significant heterogeneity remained in our analysis even after exclusion of studies focusing on the general population. In addition to the known anti-inflammatory effect of probiotics[10, 11], other probiotics-associated therapeutic benefits specific to different neurodevelopmental disorders have been reported. For instance, using a mouse model of ASD, a prior study revealed an abnormal increase in intestinal mucosal permeability that resulted in a systemic elevation in inflammatory substances that in turn aggravated the ASD-like behavior[13]. In addition, another study based on the same murine ASD model showed a correction of the leaky gut epithelium after administration of Bacteroides fragilis (a probiotic)[14]. Compatible with these findings, a prior meta-analysis demonstrated that oral administration of probiotics blends was associated with an alleviation of the overall behavioral symptoms of ASD[6], while another meta-analytic study showed no significant therapeutic effect of probiotics against the symptoms of ADHD[3]. Therefore, these findings may suggest specific roles of probiotics in different neurodevelopmental disorders. Indeed, in current meta-analysis, only one study showed a significantly superior treatment effect of probiotics to that of the controls on the symptoms of depression in those diagnosed with ASD[18], while two other studies that focused on ADHD[19] and Tourette’s syndrome [21], respectively, failed to show a significant difference in therapeutic effects against depressive symptoms between the probiotics and control groups. Therefore, despite our overall finding of a non-significant therapeutic effect of probiotics against depressive symptoms based on the subgroup of studies that recruited participants with neurodevelopmental diagnoses, benefits of certain probiotics in the treatment of specific neurodevelopmental disorders cannot be ruled out. Further large-scale clinical investigations are required to explore the therapeutic potentials of probiotics against different neurodevelopmental disorders.
Apart from the possibility of a differential therapeutic impact of probiotics on various neurodevelopmental disorders, a previous meta-analysis on adults highlighted significant benefits of probiotics in the treatment of depressive symptoms only in those with a diagnosis of anxiety or depressive disorders[5]. Although three out of our five included studies focused on those with a diagnosis of neurodevelopmental disorders[18, 19, 21], none of their participants had a diagnosis of depression or anxiety. While the participants of one study showed minimal depressive symptoms (e.g., mean baseline CDI between 4.1 to 5)[19], the baseline mean CDI score was even higher in the control group (i.e., 12) than that in the probiotics group (i.e., 7) in another trial[21]. On the other hand, the only study that supported the therapeutic effects of probiotics over the controls on the symptoms of depression recruited children and adolescents with a borderline anxiety/depression in both groups based on their CBCL score (i.e., around 64)[18] which was close to the criteria for diagnosing borderline anxiety/depression (i.e., T-score of 65–70)[24]. Therefore, our finding of no significant therapeutic benefit associated with probiotics compared with the controls may be partly attributable to a relatively low depressive symptom severity of the participants. The lack of available study focusing on children and adolescents with a diagnosis of depression warrants further large-scale clinical investigations to elucidate the therapeutic effects of probiotics in these populations.
The results of our secondary outcome showed fair acceptability regarding the use of probiotics among children and adolescents. However, information about the tolerability of probiotics was insufficient for analysis. In addition, we were unable to conduct subgroup analysis targeting the influence of age, duration of treatment, and number of probiotic strains on the therapeutic benefit due to the limited number of available studies.
Several limitations associated with this study need to be considered for correct interpretation of the derived evidence. First, the current investigation was considered a pilot study due to the limited number of available studies with the inclusion of only five trials with 692 participants. Second, the level of evidence of our findings was downgraded to very low because of the high level of heterogeneity across the included studies. Third, limited information about potential confounders including age, treatment duration, number of probiotic strains, as well as factors that may affect treatment outcomes such as dietary habits and consumption of other nutritional supplements precluded our elucidation of their influences. Finally, although previous reports suggested potential treatment benefits of probiotics in those with a neurodevelopmental diagnosis (e.g., ASD)[6] as well as those with more severe depressive symptoms[5], we were unable to reach significant conclusions due to the dearth of studies focusing on children or adolescents with specific neurodevelopmental disorders or targeting those with diagnoses of anxiety or depression. Further large-scale investigations are required to address these issues.