New Antidepressant Development in the Treatment of Depression.
Alessandro Spiti, Daniela Caldirola, Giampaolo Perna
Advances in experimental medicine and biology 2026 DOI: 10.1007/978-981-95-6872-7_23 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression |
| Keywords | Antidepressants Artificial intelligence Drug development Gabaergic system Glutamatergic system Opioid system Psychedelics |
| Citations | 1 |
| Key findings | Antidepressant research has expanded beyond monoamines to include glutamatergic, GABAergic, opioid, and psychedelic mechanisms, yet challenges such as diagnostic heterogeneity and lack of biomarkers remain. |
Abstract
Major depressive disorder (MDD) continues to pose a major therapeutic challenge due to its clinical heterogeneity. This chapter looks at the development of antidepressant treatments, starting with early interventions such as electroconvulsive therapy (ECT), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Although these treatments targeted the monoaminergic system, they had significant limitations in terms of safety and efficacy. The introduction of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) improved tolerability but left unmet needs, particularly in terms of treatment resistance and side effects. In response, research has expanded beyond monoamines and focused on new mechanisms. A breakthrough came with N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine and esketamine, which achieved fast-acting effects and shifted the focus to glutamatergic modulation. Other developments in this area include modulators such as partial agonists, positive allosteric modulators (PAMs), and negative allosteric modulators (NAMs). In addition, gamma-aminobutyric acid (GABA) modulation has gained attention, with neurosteroids such as zurolone (approved for postpartum depression [PPD]) representing a new therapeutic approach. Other new strategies target the opioid system, particularly kappa-opioid receptor (KOR) antagonism, whose role in the treatment of anhedonia and depression is being investigated. Psychedelics, including psilocybin, have come back into focus as potential treatments due to their ability to elicit rapid and sustained antidepressant effects via agonism of the serotonin 2A receptor (5-HT2A), although their efficacy and safety require further research. In addition, innovative treatments targeting orexin, trace amine-associated receptor 1 (TAAR1) and members of the Q subfamily of voltage-gated potassium channels (KCNQ) are also in development. Despite these advances, some challenges remain. These include diagnostic heterogeneity, incomplete understanding of neurobiological mechanisms, limitations of preclinical models, lack of reliable biomarkers, and economic obstacles. Future advances could be driven by artificial intelligence (AI), which has the potential to revolutionize drug discovery, optimize clinical trials, and personalize treatments for patients.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cites 21
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Single-Dose Psilocybin Treatment for Major Depressive Disorder JAMA August 31, 2023
- Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. EClinicalMedicine February 1, 2023
and 16 more in the library