REVIEW OF: Valle D et al, J Child Adolesc Psychopharmacol 2025;35(8):441–446

STUDY TYPE: Systematic review

Aggression and irritability in autism can be devastating for families and notoriously hard to treat. When relationship-based or other evidence-based ­approaches aren’t enough, what’s a clinician to do? Should we consider divalproex before antipsychotics, hoping to avoid metabolic side effects? Does it work? This systematic review takes a look at the ­existing evidence.

The authors reviewed three RCTs, one open-label study, and six case reports of autistic children treated with oral or intravenous (IV) divalproex for aggression or irritability. Outcomes included behavioral improvement and tolerability.

IV divalproex produced striking, rapid calming in two case reports—within minutes of infusion—suggesting potential use for acute behavioral crises. Oral divalproex had mixed results. One RCT (Hollander E et al, Neuropsychopharmacology 2010; 35(4):990–998) found clear benefit (63% vs 9% of responders on placebo), but others showed minimal or no improvement. Definitions of “response” varied widely, making the data hard to interpret.

Reported side effects included sedation, fatigue, insomnia, weight gain, and behavioral activation. Both high and low serum levels caused problems—toxicity at the high end and rebound aggression when levels fell too low.

CARLAT TAKE

Divalproex may help some autistic kids with severe aggression, but consistency is the problem. IV dosing looks promising for acute outbursts when you need fast control, although it may be impractical in an acute setting. Oral treatment seems even less reliable. If you try divalproex, keep a close eye on serum levels and side effects, and in females, remember the risk of polycystic ovary syndrome. Divalproex is a reasonable step in the algorithm, but it’s not a sure thing.