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February 19, 2020

Is This Where We Stand After Decades of Research to Develop More Personalized Treatments for Depression?

Author Affiliations
  • 1Yale University School of Medicine, Department of Psychiatry, New Haven, Connecticut
  • 2Yale–New Haven Health System, New Haven, Connecticut
JAMA Psychiatry. 2020;77(6):560-562. doi:10.1001/jamapsychiatry.2019.4764

Almost every clinician that has treated patients with major depressive disorder (MDD) will boldly proclaim that depression is not a single illness with a common causative mechanism, pathophysiology, prognosis, or response to treatment. Yet, despite decades of effort, it has been nearly impossible to delineate subgroupings within the disorder, beyond major depression with psychotic features, that can reliably add greater clinical meaning to the general diagnosis subsumed under the rubric of MDD. The inability to achieve what would appear to be such a simple task has frustrated the field for generations.

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Heterogeneity of Major Depressive Disorder: An Opportunity to Bring Suicide to the Forefront
Jack Lennon, M.A. | Adler University; Rush University Medical Center
Major Depressive Disorder (MDD) generally exists as a diagnosis comprised of qualitative symptoms. While these symptoms are expected to be clinically significant in those who are diagnosed, the required number of symptoms to meet criteria actually limits the diagnostic heterogeneity of the diagnosis. This point is interesting, as Sanacora[1] provides an important discussion of the significant heterogeneity of MDD, such that dramatic differences arise in MDD in response to antidepressants. This is supported by a meta-analysis[2] illuminating our lack of understanding of MDD variants. We question the degree to which this heterogeneity may hold a place for those who eventually die by suicide.

MDD is a concept that fails to sufficiently describe a given patient’s complaints and subsequent responses to first-line treatments. This becomes clearer when variability in treatment response is shown to be significantly higher with medications that target the noradrenergic system than those that target the serotonergic system. Given the role of the noradrenergic system in mood, arousal, and stress, this may point toward an MDD variant that is highly susceptible to fluctuations in subcortical structures. A genetic study determined that SLC6A2 variants, including rs2242446 or rs8836840 alleles, increased the likelihood of suicide attempts in MDD.[3] A vast body of literature suggests that the serotonergic system is implicated in both MDD and suicide attempts, with endophenotypes of impulsivity, anxiety, and poor decision-making,[4] each of which comprise the behavioral and psychological symptoms of dementia.

Our understanding of suicide biomarkers has not resulted in a comprehensive understanding of its constituents. Suicide is generally considered a resultant cause of death. We see a problem with this current paradigm. If suicide was not viewed in a fashion similar to death with Alzheimer’s disease, we may break novel ground. Suicide is more common in most neurologic disorders than the general public, in spite of often unremarkable self-reports of mood. Therefore, it is reasonable to question the direction future research could take if suicide were to be viewed in terms of its pathogenesis rather than a discrete event following depression and eventual acquired capacity. Instead, those who will attempt and die by suicide may walk a trajectory of their own, which would validate our ability to consistently detect differences between depressed patients, ideators, attempters, and those who die by suicide.[5] Rather than an act, we speculate an early path that may very well be an MDD variant deviating from those with different end results.

[1] Sanacora G. Is this where we stand after decades of research to develop more personalized treatments for depression? [published online February 19, 2020]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.4764
[2] Maslej MM, Furukawa TA, Cipriani A, Andrews PW, Mulsant BH. Individiual differences in response to antidepressants: A meta-analysis of placebo-controlled randomized clinical trials [published online Feburary 19, 2020]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.4815
[3] Sudol K, Mann JJ. Biomarkers of suicide attempt behavior: Towards a biological model of risk. Curr Psychiatry Rep 2017;19:31.
[4] Gould TD, Georgiou P, Brenner LA, et al. Animal models to improve our understanding and treatmenet of suicidal behavior. Transl Psychiatry 2017;7(4):e1092.
[5] Menon V, Kattimani S. Suicide and serotonin: Making sense of evidence. Indian J Psychol Med 2015;37:377-378.