Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects

Abstract

Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis-orders in this age group and are used not infrequently off-label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta-review, we systematically searched network meta-analyses and meta-analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications - including antidepressants, antipsychotics, anti-attention-deficit/hyperactivity disorder (ADHD) medications and mood stabilizers - in children and adolescents with mental disorders. We included data from nine network meta-analyses, 39 meta-analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti-ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti-ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti-ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta-review of top-tier evidence regarding the safety of antidepressants, antipsychotics, anti-ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.

Keywords: Safety; adolescents; antidepressants; antipsychotics; children; meta-review; mood stabilizers; psychopharmacology; psycho­stim­ulants; tolerability.

Figure 1

PRISMA flow chart for inclusion of studies. Search 1: network meta‐analyses (NMA) and meta‐analyses (MA); Search 2: individual randomized controlled trials (RCTs); Search 3: cohort studies controlling for confounding by indication

Figure 2

Proportion of adverse events covered by the literature that were significantly worse or non‐significantly different from placebo, for antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity (ADHD) medications, and mood stabilizers in children and adolescents with mental illness. AMI – amisulpride, ATP – amitriptyline, ARI – aripiprazole, ASE – asenapine, ATO – atomoxetine, BUP – bupropion, CBZ – carbamazepine, CIT – citalopram, CLM – clomipramine, CLO – clonidine, CLZ – clozapine, DES – desipramine, DVX – desvenlafaxine, D‐AMP – d‐amphetamine, DUL – duloxetine, ESC – escitalopram, FLX – fluoxetine, FLU – fluphenazine, FVX – fluvoxamine, GUA – guanfacine, HAL – haloperidol, IMI – imipramine, LAM – lamotrigine, LIT – lithium, LDX – lisdexamphetamine, LOX – loxapine, LUR – lurasidone, MPH – methylphenidate, MIR – mirtazapine, MOD – modafinil, MOL – molindone, NFZ – nefazodone, NOR – nortriptyline, OLA – olanzapine, OXZ – oxcarbazepine, PAL – paliperidone, PAR – paroxetine, QUE – quetiapine, RIS – risperidone, SRT – sertraline, TOP – topiramate, TRIF – trifluoperazine, VPA – valproate, VFX – venlafaxine, VZD – vilazodone, ZIP – ziprasidone