The Depressed Frail Phenotype: The Clinical Manifestation of Increased Biological Aging

Am J Geriatr Psychiatry. 2016 Nov;24(11):1084-1094. doi: 10.1016/j.jagp.2016.06.005. Epub 2016 Jun 23.


Depression in later life is a severe public health problem, associated with higher rates of mortality, suicide, and dementia. Effectiveness of treatment is limited by the failure to deconstruct the heterogeneity of the illness and because diagnostic criteria, pathophysiological models, and treatment algorithms for depression are primarily based on studies of younger adults even though symptoms of the illness and physiology of the patient change with age. Thus, understanding how aging interacts with depressive illness may elucidate endophenotypes of late-life depression with different clinical manifestations and underlying mechanisms that can then be targeted with more personalized approaches to treatment. This paper proposes a model for the critical confluence between depression and frailty, a high-risk morbidity and mortality syndrome of later life. This model hypothesizes that characteristics of frailty in adults with late life depression represent the clinical manifestation of greater biological aging and their presence in the context of a depressive illness exposes elders to deleterious trajectories. Potential common biological substrates that may result in the manifestation of the depressed frail phenotype including mitochondrial functioning, dopaminergic neurotransmission, and inflammatory processes and implications for the assessment and treatment of adults with late-life depression are discussed. As society continues to live longer, the preservation of the quality of these added years becomes paramount, and the combined impact of depression and frailty on the preservation of this quality warrants the attention of clinical researchers and physicians.

Keywords: Depression; dopamine; frailty; inflammation; mitochondria.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / immunology
  • Aging / metabolism*
  • Depressive Disorder / immunology
  • Depressive Disorder / metabolism*
  • Dopamine / metabolism
  • Frailty / immunology
  • Frailty / metabolism*
  • Humans
  • Inflammation
  • Mitochondria / metabolism
  • Oxidative Stress
  • Phenotype
  • Synaptic Transmission


  • Dopamine