All childhood and adolescent depression can be characterized as 'refractory' if the measurement used is scientific evidence of efficacious treatments. There have been a small number of systematic studies reported examining the efficacy of psychotherapy interventions for child and adolescent depression. Treatment resistance is a difficult concept to operationalize in young populations, and may apply to a substantial proportion of children and adolescents who are seen clinically. It is clearly established that pediatric major depression is a valid diagnostic entity which as clinical continuity with adult affective disorders. Potential for overdose is a significant concern in the treatment of mood disordered children and adolescents. Selective serotonin reuptake inhibitors (SSRIs) have a very low potential of lethality, while the lethality of tricyclic antidepressants (TCAs) is very high. SSRIs have potential drug-drug interactions with thioridazine, TCAs, and terfenadine.