The treatment of depression - searching for new ideas

Abstract

Depression is a severe mental health problem that affects people regardless of social status or education, is associated with changes in mood and behavior, and can result in a suicide attempt. Therapy of depressive disorders is based mainly on drugs discovered in the 1960s and early 1970s. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are frontline pharmacological strategies for the medical treatment of depression. In addition, approved by FDA in 2019, esketamine [as nasal spray; N-methyl-D-aspartate (NMDA) receptors antagonist with additional effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, L-type voltage-dependent calcium channel (L-VDCC), opioid receptors, and monoaminergic receptors] is an essential compound in suicide and drug-resistant depression. However, the treatment of depression is burdened with severe side effects, and in many cases, it is ineffective. An equally important issue is the choice of antidepressant therapy in people with comorbid somatic diseases, for example, due to possible interactions with the patient's other drugs. Therefore, there is a great need for new antidepressants with different mechanisms of action and the need to refine the search for new substances. The purpose of this review was to discuss new research directions and new trends that dominate laboratories worldwide. We have reviewed the literature to present new points on the pharmacological target of substances with antidepressant activity. In addition, we propose a new perspective on depressive therapies.

Keywords: DSCAM; antidepressants; depression; glutamate receptors; new target.

FIGURE 1

The classification of depression according to the American Psychiatric Association (APA). (DSM-5, 2013; Uher et al., 2014; Abdel-Bakky et al., 2021).

FIGURE 2

Selected examples of antidepressants by groups. MAO, Mono Amino Oxidase; SSRIs, Selective Serotonin Reuptake Inhibitors; TADs, Tricyclic Antidepressants; S-NRIs, Serotonin-Norepinephrine Reuptake Inhibitors; SAs and RIs, Serotonin Antagonist and Reuptake Inhibitors; NRIs, Norepinephrine Reuptake Inhibitors; N/DRIs, Noradrenaline and Dopamine Reuptake Inhibitors.

FIGURE 3

Selected examples of antidepressant compounds in clinical trials (Phase I-IV). Glu, glutamate; NMDA, N-methyl-D-aspartate; NR2B, NMDA receptor subunit 2B; mGluRs, metabotropic glutamate receptors, GABAA, gamma-aminobutyric acid receptors A; COX-2, cyclooxygenase 2; MAP-2, microtubule-associated protein 2.

FIGURE 4

Examples of combined therapy in the treatment of depression. AD, antidepressant; COX-2, cyclooxygenase 2.