Kristen is a 13-year-old girl with Down syndrome (DS) who was seen urgently with concerns of cognitive and developmental regression including loss of language, social, and toileting skills. The evaluation in the DS clinic focused on potential medical diagnoses including atlantoaxial joint instability, vitamin deficiency, obstructive sleep apnea (OSA), and seizures. A comprehensive medical evaluation yielded only a finding of moderate OSA. A reactive depression was considered in association with several psychosocial factors including moving homes, entering puberty/onset of menses, and classroom change from an integrated setting to a self-contained classroom comprising unfamiliar peers with behavior challenges.Urgent referrals for psychological and psychiatric evaluations were initiated. Neuropsychological testing did not suggest true regression in cognitive, language, and academic skills, although decreases in motivation and performance were noted with a reaction to stress and multiple environmental changes as a potential causative factor. Psychiatry consultation supported this finding in that psychosocial stress temporally correlated with Kristen's regression in skills.Working collaboratively, the team determined that Kristen's presentation was consistent with a reactive form of depression (DSM-IV-TR: depressive disorder, not otherwise specified). Kristen's presentation was exacerbated by salient environmental stress and sleep apnea, rather than a cognitive regression associated with a medical cause. Treatment consisted of an antidepressant medication, continuous positive airway pressure for OSA, and increased psychosocial supports. Her school initiated a change in classroom placement. With this multimodal approach to evaluation and intervention, Kristen steadily improved and she returned to her baseline function.