Multicenter retrospective study on effectiveness, reported side effects, and cognitive outcomes of SSRIs in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11DS) markedly increases risk of psychiatric disorders, including anxiety and mood disorders, and is associated with a spectrum of cognitive impairment, from borderline functioning to intellectual disability, with cognitive decline frequently reported. Despite widespread use of selective serotonin reuptake inhibitors (SSRIs) in 22q11DS, evidence regarding their safety, effectiveness, and potential effects on cognitive trajectories remains limited. We conducted a retrospective, observational multicenter study across nine international sites, including cross-sectional and longitudinal parts. In the cross-sectional part, 190 SSRI-treated participants with 22q11DS (6–56 years) were included to characterize indication, perceived effectiveness, and side effects. In the longitudinal part, intellectual quotient (IQ) trajectories were compared between 101 SSRI-treated and 214 SSRI-untreated participants (4–34 years) using mixed-models regression analyses. SSRIs were mainly prescribed for mood and/or anxiety disorders (91%) and were mostly effective or very effective (71%), with minimal reported side effects for the majority (75%). SSRI-treated participants exhibited stable or modestly improving IQ trajectories, compared with SSRI-untreated participants. Combined SSRI + psychostimulant treatment was associated with the largest improvements. Treatment duration, but not dosage, was positively associated with IQ change. SSRIs appear safe and effective for mood and anxiety disorders in 22q11DS and are associated with a modest improvement in cognitive functioning, particularly with sustained use. Concomitant psychostimulant treatment was linked to the greatest cognitive gains. These findings highlight the importance of screening and treatment of psychiatric symptoms to optimize long-term cognitive outcomes. Controlled prospective studies are needed to confirm the findings and determine underlying mechanisms.