Meta-Analysis: Reduced Risk of Anxiety with Psychostimulant Treatment in Children with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective: Anxiety is a commonly reported side-effect of psychostimulant treatment. Our goal was to quantify the risk of anxiety as a side effect of psychostimulant treatment for attention-deficit/hyperactivity disorder (ADHD).

Methods: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of psychostimulant medications in the treatment of children with ADHD. We used a fixed-effects meta-analysis to examine the risk ratio of anxiety reported as a side effect in children treated with psychostimulants compared with those treated with placebo. We used stratified subgroup analysis and meta-regression to examine the effects of stimulant type, dosage, duration of use, and trial design on the measured risk of anxiety.

Results: We identified 23 studies involving 2959 children with ADHD for inclusion in our meta-analysis. The risk of anxiety associated with psychostimulant treatment was significantly lower than that experienced with placebo (relative risk [RR] = 0.86 [95% CI: 0.77, 0.95], z = -2.90, p < 0.05). Higher doses of psychostimulants were associated with a reduced measured risk of anxiety of psychostimulants when compared with placebo (β = -0.0039 [95% CI: -0.00718, -0.00064], z = -2.34, p = 0.019).

Conclusions: Meta-analysis suggests that treatment with psychostimulants significantly reduced the risk of anxiety when compared with placebo. This finding does not rule out the possibility that some children experience increased anxiety when treated with psychostimulants, but suggests that those risks are outweighed by the number of children who experience improvement in anxiety symptoms (possibly as a secondary effect of improved control of ADHD symptoms). Clinicians should consider rechallenging children with ADHD who report new-onset or worsening anxiety with psychostimulants, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.

FIG. 1.

Selection of studies.

FIG. 2.

Risk of anxiety in children with attention-deficit/hyperactivity disorder (ADHD) treated with psychostimulants compared with placebo. Meta-analysis demonstrated a significantly decreased risk of anxiety when comparing psychostimulant to placebo (relative risk [RR] = 0.86 [95% CI: 0.77, 0.95], z = −2.90, p = 0.004). There was no significant evidence of heterogeneity or publication bias.

FIG. 3.

Meta-regression: Psychostimulant dose versus risk of anxiety. Meta-regression demonstrated a significant negative association between dosage of psychostimulants (x axis) and the risk of anxiety (y axis: β = −0.0039 [95% CI: −0.00718, −0.00064], z = −2.34, p = 0.019). Higher doses of psychostimulants were associated with a decreased risk of anxiety relative to placebo. Daily doses of psychostimulants are expressed in methylphenidate equivalents.