Dear Colleagues,

Major depression represents a protean psychiatric illness with heterogeneous clinical manifestations and multiple comorbidities leading to severe disability. In spite of decades of research on the pathophysiogenesis of depressive disorders, the pharmacotherapies currently used to treat major depression are mainly based on the modulation of monoamines, whose alteration has been considered the neurobiological foundation of depression. However, approximately one third to half of patients respond partially or become refractory to monoamine-based treatments, 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 glutamatergic neurotransmission. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamatergic synaptic plasticity—which is involved in cognitive functions—has been demonstrated to be involved in several psychiatric syndromes, including depression, via transsynaptic modulation of specific molecular substrates, such as mTOR, GSK3, postsynaptic scaffolding proteins, etc.

The aim of this issue is to encourage a discussion which is as thorough as possible about the most advanced knowledge on the involvement of glutamatergic system in the molecular mechanisms at the basis of major depression pathophysiogenesis, as well as the glutamate-based therapeutic strategies currently suggested to optimize depression treatment and prevent suicide (which is the most devastating depression outcome). Moreover, we would like to stimulate the acquirement of both new clinical and “neurobiological targeted” strategies, based on the glutamate system, with the purpose of promoting new avenues of investigation aiming at developing interventions that overstep the monoaminergic boundaries to improve depressive disorder therapy.

A lot of studies have been focusing on the involvement of the glutamatergic system in the therapeutic strategies against major depression, as well as suicide prevention. We would like to deepen cutting-edge research on NMDA receptor modulators (e.g., ketamine, esketamine, memantine, lanicemine), AMPA receptor modulators, metabotropic glutamate receptor modulators, and psychotherapeutic (e.g., CBT) and glutamate-based brain stimulation techniques (e.g., ECT, TMS).

We would like to solicit articles in which new glutamate-based treatments for major depression are described and future research avenues on glutamate-targeting strategies are suggested to by-pass the limiting step of monoamine-based classical treatments.

Dr. Domenico De Berardis
Dr. Carmine Tomasetti
Guest Editors

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• psychopharmacology
• dopamine–glutamate interaction
• emotions
• affective dysregulation
• suicide
• psychiatry