Novel pathways in the treatment of major depression: Focus on the glutamatergic system

Carmine Tomasetti, Chiara Montemitro, Annastasia L.C. Fiengo, Cristina Santone, Laura Orsolini, Alessandro Valchera, Alessandro Carano, Maurizio Pompili, Gianluca Serafini, Giampaolo Perna, Federica Vellante, Giovanni Martinotti, Massimo D. Giannantonio, Yong Ku Kim, Marco D. Nicola, Antonello Bellomo, Antonio Ventriglio, Michele Fornaro, Domenico D. Berardis

Research output: Contribution to journalArticlepeer-review


Depressive disorders represent protean psychiatric illnesses with heterogeneous clinical manifestations and a multitude of comorbidities leading to severe disability. In spite of decades of research on the pathophysiogenesis of these disorders, the wide variety of pharmacotherapies currently used to treat them is based on the modulation of monoamines, whose alteration has been considered the neurobiological foundation of depression, and consequently of its treatment. However, approximately one third to a half of patients respond partially or become refractory to monoamine-based therapies, thereby jeopardizing the therapeutic effectiveness in the real world of clinical practice. Recent scientific evidence has been pointing out the essential role of other biological systems beyond monoamines in the pathophysiology of depressive disorders, in particular, the glutamatergic neurotransmission. In the present review, we will discuss the most advanced knowledge on the involvement of glutamatergic system in the molecular mechanisms at the basis of depression pathophysiology, as well as the glutamate-based therapeutic strategies currently suggested to optimize depression treatment (e.g., ketamine). Finally, we will mention further “neurobiological targeted” approaches, based on glutamate system, with the purpose of promoting new avenues of investigation aiming at developing interventions that overstep the monoaminergic boundaries to improve depressive disorders therapy.

Original languageEnglish
Pages (from-to)381-387
Number of pages7
JournalCurrent Pharmaceutical Design
Issue number4
Publication statusPublished - Jan 1 2019


  • Antidepressants
  • Antipsychotics
  • Depressive disorders
  • Glutamate
  • Ketamine
  • Mglur
  • Nmda
  • Postsynaptic density

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery


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