The incidence of mental health disorders in adolescents continues to rise. The cause of the increase in mental illness is multifactorial, including both environmental and biological causes. To investigate the latter, ten adolescents at a psychiatric residential treatment center in Colorado with the DSM-5 diagnosis of major depressive disorder (MDD), of whom seven were additionally diagnosed with generalized anxiety disorder (GAD), were chosen at random for further serologic study. Testing revealed exposureto group A Streptococcus(GAS) in 2 of 10 (20%); Borrelia Burgdorferi sensulato (Bbsl)in 2 of 10 (20%); and Bartonella speciesin 3 of 10 (30%). In addition, 9 of 10 (90%) subjects had abnormal Cunningham Panels, which measures levels of antineuronal antibodies that have been associated with psychiatric disturbances. Given the degree of psychological dysfunction in these adolescents requiring intensive residential treatment, this case series lends support to the hypothesis that exposure to infectious agents may play a role, perhaps by autoimmune mechanisms, in the significant and ongoing rise in the rate of neuropsychiatric illness in adolescents. This preliminary report adds to this premise and requires further investigation.