Caretakers of adolescents and young adults with Down syndrome (DS) may report the onset of a depressive illness in previously mentally well individuals. However, the behavioral phenomenology of these conditions has not been well characterized. We ascertained a cohort of DS patient-subjects presenting to a specialty clinic with medical and/or mental health concerns between 2002 and 2009. Caretakers completed questionnaires measuring psychopathology and maladaptive behavior on all subjects. When psychopathology was present a psychiatric diagnosis was made using "Diagnostic and Statistical Manual of Mental Disorders," 4th Edition-Revised (American Psychiatric Association, 1994) criteria. DS subjects without mental health concerns served as a control group. Cases scored significantly higher (p less than 0.0001) on the Anxiety, Attention, Autism, Depression, Psychosis, Withdrawn, Other behavior, and Total score of the Reiss Scales for Children's Dual Diagnosis (RSCDD) and the Stereotypy and Lethargy subscales of the Aberrant Behavior Checklist compared with Control subjects. Cases with major depressive illness also scored significantly higher (p less than 0.01) on the Anxiety, Depression, Somatoform, Other behavior, and Total scores of the RSCDD compared to cases without depression. The RSCDD appears useful for capturing caretaker-reported psychopathology in clinically referred subjects with DS and major depressive illness. (Contains 8 tables.)