Antidepressants: 70 Years

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 9442

Special Issue Editors


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Guest Editor
1. Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologique, Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 860, 45, rue des Saints Peres, 75006 Paris, France
2. CQM-Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal
Interests: medicinal chemistry; drug discovery; drug development; nanotechnology; drug delivery
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Special Issue Information

Dear Colleagues,

The 1950s were the most prolific in the last century in terms of novel psychotropic class agents. These same years that witnessed the introduction of neuroleptics in clinics also registered the serendipitous discovery of the first two classes of antidepressants: monoamine oxidase A (MAO-A) inhibitors (MAOIs) and tricyclic antidepressants (TCAs).

Current antidepressants are effective in about two-thirds of patients suffering from affective disorders. However, while newer-generation antidepressants present fewer adverse effects than seen with TCAs and MAOIs, bothersome side effects remain prevalent. While the short-term treatment of depressive disorders may be considered satisfactory, the prevention of relapse and recurrence, both in cases of unipolar depression and bipolar illness, is still challenging. More tolerable and efficacious treatments need to be developed to improve medication adherence and management of antidepressant adverse effects. On the other hand, antidepressants are effective in a vast range of psychic disorders and may act as antimigraine and adjuvant analgesics. Finally, antidepressants display pleiotropic activities that may be exploited in therapeutic areas besides psychiatric and neurological diseases (e.g., chemotherapy), thus indicating possible repurposing strategies.

While the monoaminergic hypothesis may serve as a starting point for interpreting most of the major psychiatric signs in affective disorders, we are now aware that severe mental diseases, including affective disorders, are the expression of complex pathological mechanisms. While we lack a thorough understanding of the neurobiology of most mental disorders, we can confirm that numerous neurotransmitters and hormones are involved. Thus, polypharmacology is generally adopted to treat the most severe forms of affective disorders, meaning the multi-target approach for drug discovery should be fruitfully pursued, and emerging therapeutic targets should be further investigated.

This commemorative Special Issue on antidepressants was conceived as an opportunity to take stock of the situation, obtain an up-to-date landscape on the most recent developments, and promote advances and collaborative endeavors in the challenging area of some of the most prevalent and life-threatening forms of mental illnesses and the major causes of morbidity worldwide.

Dr. Giovanni Lentini
Prof. Dr. Serge Mignani
Guest Editors

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Keywords

  • polypharmacology
  • multi-target drugs
  • emerging therapeutic targets
  • repurposing
  • unipolar depression
  • bipolar disorder

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Published Papers (4 papers)

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Research

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12 pages, 731 KiB  
Article
Comparative Short- and Long-Term Effectiveness and Safety of Pramipexole and Aripiprazole Augmentation in Treatment-Resistant Unipolar Depression: An Observational Study
by Antonio Tundo, Sophia Betrò, Rocco de Filippis, Roberto Felici, Chiara Lucangeli and Marica Iommi
Biomedicines 2024, 12(9), 2064; https://doi.org/10.3390/biomedicines12092064 - 10 Sep 2024
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Abstract
Background: This study compares the short- and long-term effectiveness and safety of pramipexole augmentation (PA) and aripiprazole augmentation (AA) for unipolar treatment-resistant depression (TRD). Methods: Patients were recruited in a private out-patients clinic specializing in mood disorders. At intake and at each visit, [...] Read more.
Background: This study compares the short- and long-term effectiveness and safety of pramipexole augmentation (PA) and aripiprazole augmentation (AA) for unipolar treatment-resistant depression (TRD). Methods: Patients were recruited in a private out-patients clinic specializing in mood disorders. At intake and at each visit, depressive and (hypo)manic symptoms, clinical status, and level of functioning were evaluated with appropriate scales. The trend of outcomes was analyzed using mixed-effect linear regression models. Results: The study includes 81 patients with unipolar TRD treated with PA and 51 with AA. After 12 and 24 weeks of treatment with PA, the predicted response (64.1% and 76.2%) and remission rates (49.7% and 72.7%) were significantly higher than the predicted response (32.2% and 38.0%) and remission rates (18.9% and 28.1%) for AA. The improvement in psychosocial functioning was significantly greater and faster in PA than in AA. PA showed significant superiority over AA as a maintenance strategy (time spent ill and psychosocial functioning) up to 12 months. No difference in safety was found at each time point. Conclusions: PA could be an alternative option for the short- and long-term treatment of unipolar TRD, more effective than AA and similar in safety. These preliminary results need confirmation from randomized clinical trials. Full article
(This article belongs to the Special Issue Antidepressants: 70 Years)
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Review

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25 pages, 436 KiB  
Review
Exploring the Complex Relationship Between Antidepressants, Depression and Neurocognitive Disorders
by Monica Neațu, Iulia Ioniță, Ana Jugurt, Eugenia Irene Davidescu and Bogdan Ovidiu Popescu
Biomedicines 2024, 12(12), 2747; https://doi.org/10.3390/biomedicines12122747 - 30 Nov 2024
Cited by 1 | Viewed by 1358
Abstract
The coexistence of dementia and depression in older populations presents a complex clinical challenge, with each condition often exacerbating the other. Cognitive decline can intensify mood disturbances, and untreated or recurring depression accelerates neurodegenerative processes. As depression is a recognized risk factor for [...] Read more.
The coexistence of dementia and depression in older populations presents a complex clinical challenge, with each condition often exacerbating the other. Cognitive decline can intensify mood disturbances, and untreated or recurring depression accelerates neurodegenerative processes. As depression is a recognized risk factor for dementia, it is crucial to address both conditions concurrently to prevent further deterioration. Antidepressants are frequently used to manage depression in dementia patients, with some studies suggesting they offer neuroprotective benefits. These benefits include promoting neurogenesis, enhancing synaptic plasticity, and reducing neuroinflammation, potentially slowing cognitive decline. Additionally, antidepressants have shown promise in addressing Alzheimer’s-related pathologies by reducing amyloid-beta accumulation and tau hyperphosphorylation. However, treatment-resistant depression remains a significant challenge, particularly in older adults with cognitive impairment. Many do not respond well to standard antidepressant therapies due to advanced neurodegenerative changes. Conflicting findings from studies add to the uncertainty, with some research suggesting that antidepressants may increase dementia risk, especially when used in patients with undiagnosed early-stage dementia. This article aims to explore the intricate relationship between depression and dementia, examining the benefits and risks of antidepressant use. We highlight the urgent need for personalized, comprehensive treatment strategies that balance mental health improvement with cognitive protection. Full article
(This article belongs to the Special Issue Antidepressants: 70 Years)
27 pages, 1640 KiB  
Review
Neuroplasticity and Mechanisms of Action of Acute and Chronic Treatment with Antidepressants in Preclinical Studies
by Gilberto Uriel Rosas-Sánchez, León Jesús Germán-Ponciano, Gabriel Guillen-Ruiz, Jonathan Cueto-Escobedo, Ana Karen Limón-Vázquez, Juan Francisco Rodríguez-Landa and César Soria-Fregozo
Biomedicines 2024, 12(12), 2744; https://doi.org/10.3390/biomedicines12122744 - 29 Nov 2024
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Abstract
Pharmacotherapy for depression includes drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors (NaSSAs), and atypical antidepressants; these drugs exert differentially beneficial effects on symptoms of depression after acute and [...] Read more.
Pharmacotherapy for depression includes drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors (NaSSAs), and atypical antidepressants; these drugs exert differentially beneficial effects on symptoms of depression after acute and chronic treatment in animal models. Said effects are established through neuroplastic mechanisms involving changes in neurogenesis and synaptogenesis as result of the activation of intracellular signaling pathways associated with neurochemical and behavioral changes. Antidepressants increase the synaptic availability of monoamines (monoaminergic hypothesis) such as 5-HT, NA, and gamma-aminobutyric acid (GABA) by inhibiting their reuptake or degradation and activating intracellular signaling pathways such as the responsive element binding protein (cAMP-CREB) cascade, which regulates the expression of genes related to neuroplasticity and neurogenesis, such as brain-derived neurotrophic factor (BDNF), in various brain structures implicated in depression. The aim of this review is to analyze the mechanisms of action of different antidepressants and to compare the effects of acute and chronic treatment on neuroplasticity in animal models of depression. A thorough search was conducted in PubMed, Scopus, and Web of Science, focusing on studies since 1996 with keywords like antidepressants, acute and chronic treatment, neuroplasticity, and experimental depression. Studies included had to investigate antidepressant effects experimentally, with full-text access, while excluding those that did not. Data extraction focused on study design, findings, and relevance to understanding treatment differences. Only high-quality, peer-reviewed studies were considered to ensure a comprehensive synthesis of current knowledge. Full article
(This article belongs to the Special Issue Antidepressants: 70 Years)
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18 pages, 4618 KiB  
Review
Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms
by Piotr Kawczak, Igor Feszak and Tomasz Bączek
Biomedicines 2024, 12(10), 2283; https://doi.org/10.3390/biomedicines12102283 - 9 Oct 2024
Cited by 2 | Viewed by 3437
Abstract
Research over the past years has compared the enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine) of the previously known racemic mixture called ketamine (R/S-ketamine). Esketamine has been found to be more potent, offering three times stronger analgesic effects and 1.5 times greater anesthetic efficacy [...] Read more.
Research over the past years has compared the enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine) of the previously known racemic mixture called ketamine (R/S-ketamine). Esketamine has been found to be more potent, offering three times stronger analgesic effects and 1.5 times greater anesthetic efficacy than arketamine. It provides smoother anesthesia with fewer side effects and is widely used in clinical settings due to its neuroprotective, bronchodilatory, and antiepileptic properties. Approved by the FDA and EMA in 2019, esketamine is currently used alongside SSRIs or SNRIs for treatment-resistant depression (TRD). On the other hand, arketamine has shown potential for treating neurological disorders such as Alzheimer’s, Parkinson’s, and multiple sclerosis, offering possible antidepressant effects and anti-inflammatory benefits. While esketamine is already in clinical use, arketamine’s future depends on further research to address its safety, efficacy, and optimal dosing. Both enantiomers hold significant clinical value, with esketamine excelling in anesthesia, and arketamine showing promise in neurological and psychiatric treatments. Full article
(This article belongs to the Special Issue Antidepressants: 70 Years)
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