Rumination, worry, and other forms of negative self-referential processing (NSRP) are familiar to everyone, as reflecting on the self is perhaps our most human characteristic. However, for a substantial subgroup of patients, NSRP arises in response to intense emotionality, worsening the clinical presentation, and diminishing the treatment response. The combination of emotionality and NSRP likely reflects an endophenotype of complicated and treatment refractory patients who fail to achieve a satisfactory treatment response in our trials and our clinics. An important next step is to personalize treatments by deliberately targeting NSRPs within established treatment protocols or in as yet novel treatments. Enriching treatments with mindfulness meditation is one possible avenue for personalized care of patients with this hypothesized endophenotype.