TY - JOUR
T1 - Personalized antidepressant selection and pathway to novel treatments
T2 - Clinical utility of targeting inflammation
AU - Jha, Manish K.
AU - Trivedi, Madhukar H.
N1 - Funding Information:
Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Pfizer Inc., SHIRE Development and Takeda. In addition, he has received grants/research support from the National Institute of Mental Health and National Institute on Drug Abuse.
Funding Information:
identify newer treatments and better strategies to personalize currently available antidepressant to identify newer treatments and better strategies to personalize currently available antidepressant treatments. In the search for biomarkers to personalize antidepressant medication selection, treatments. In the search for biomarkers to personalize antidepressant medication selection, inflammatory inflammatory biomarkers, such as CRP, have emerged as a robust and pragmatic option. However, biomarkers, such as CRP, have emerged as a robust and pragmatic option. However, as over a third of as over a third of patients with MDD are resistant to currently available medications, novel patients with MDD are resistant to currently available medications, novel antidepressants that target antidepressants that target the pathophysiology underlying depression are also needed. Anti-the pathophysiology underlying depression are also needed. Anti-cytokine treatments have emerged cytokine treatments have emerged as potentially selective agents to target proinflammatory cytokines as potentially selective agents to target proinflammatory cytokines in those patients with markers of in those patients with markers of systemic inflammation. Additional strategies include targeting of systemic inflammation. Additional strategies include targeting of the BBB to mitigate the CNS effects of the BBB to mitigate the CNS effects of peripheral inflammation. In conclusion, inflammatory markers peripheral inflammation. In conclusion, inflammatory markers present clinically useful targets for both present clinically useful targets for both personalizing antidepressant prescription and for identifying personalizing antidepressant prescription and for identifying novel antidepressants. novel antidepressants. Acknowledgments: Part of this work was supported by the National Institute of Mental Health (N01 MH-90003 tAocMknaodwhulekdagrmHe. nTrtsiv: ePdair)t. oTfhtihsiws worokrkw wasaas lssuopspuoprpteodrt ebdy itnhepNaratttihornoaul gInhstthiteuCtee onft eMr efonrtaDl eHperaelstshio (nNR01e sMeaHrc-h90a0n0d3 to Madhukar H. Trivedi). This work was also supported in part through the Center for Depression Research and Clinical Care at UT Southwestern (Principal Investigator: Madhukar H. Trivedi. MD), The Hersh Foundation, and editorial support. and The Jordan Harris Foundation. The authors would like to thank Jeremy A. Kee, M.A., for his administrative Author Contributions: Manish K. Jha and Madhukar H. Trivedi substantially contributed to the conception of work, carried out the review of literature, drafted the manuscript, approved the submitted version and agreed tAoubtehoprerCsoonnatrlilybuatcicoonusn:tMabalneifsohrKth.eJihraoawnndcMonatdrhibuuktaiornHs.aTnrdivfeodriesnusbusrtianngtitahlalyt qcuoensttriiobnusterdel taotetdhetocothneceapcctiuorna coyf work, carried out the review of literature, drafted the manuscript, approved the submitted version and agreed to be personally accountable for their own contributions and for ensuring that questions related to the accuracy Coro ninftliecgtrsitoyf oInf taenryes pt:aJrht aorfe tcheeivwedorcko,n etvraecnt roenseesa ricnhwsuhpicpho trht efryomweArec andoita pPehrasromnaalcleyuitnicvaolslv. eTdri,vaerdei aispoprrohparsiabteeelny an advisor/consultant and received fees from Alkermes, AstraZeneca, Cerecor, Eli Lilly & Company, Lundbeck,
Funding Information:
Conflicts of Interest: Jha received contract research support from Acadia Pharmaceuticals. Trivedi is or has been an advisor/consultant and received fees from Alkermes, AstraZeneca, Cerecor, Eli Lilly & Company, Lundbeck,
Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/1/12
Y1 - 2018/1/12
N2 - Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments.
AB - Major depressive disorder (MDD) is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP)-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments.
KW - Antidepressants
KW - Blood-brain barrier
KW - C-reactive protein
KW - Depression
KW - Experimental drugs
KW - Inflammation
KW - Monoamines
KW - Monoclonal antibodies
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U2 - 10.3390/ijms19010233
DO - 10.3390/ijms19010233
M3 - Review article
C2 - 29329256
AN - SCOPUS:85040940259
SN - 1661-6596
VL - 19
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 1
M1 - 233
ER -