Pharmacology of Antidepressants: Recent Advances

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (5 July 2025) | Viewed by 3285

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Department of Pharmacology and Toxicology, Medical University of Lodz, 7/9 Zeligowskiego, 90-752 Lodz, Poland
Interests: carotenoids; depression; endoplasmic reticulum stress; inflammation; oxidative stress; periodontitis
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Dear Colleagues,

Depression is a chronic, severe, and often life-threatening condition. Depression can be characterized by a diverse combination of symptoms, including changes in mood (affect), sleep, appetite, cognition, and motivation, as well as a reduced ability to experience pleasure (anhedonia) or suicidal thoughts. For decades, depressive symptoms have been treated primarily with medications that target the brain's serotonin and norepinephrine systems. These medications include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants, as well as the newer selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs), which increase levels of serotonin and/or norepinephrine in synapses. While waiting for these medications to have an effect, people continue to experience suicidal thoughts or actions, so the discovery of rapid-acting antidepressants has become an important challenge. The first example of such a drug is S-ketamine, as its introduction to therapy contributed to the search for the mechanism of action responsible for the rapid effect, and consequently targets, for other drugs.

In recent years, the relationship between inflammation and the development of depression has been studied. Peripheral inflammation can contribute to depressive symptoms by reaching the central nervous system (CNS) through various mechanisms, including the gut–microbiota–brain axis, the hypothalamic–pituitary–adrenal (HPA) axis, the glutamatergic system, and the kynurenine (KYN) pathway, as well as by impairing neuroplasticity. Therefore, we are inclined to ask whether there are natural or synthetic substances that could exhibit antidepressant effects through anti-inflammatory action?

Analyzing the role of the gut–brain axis in the development of depression is becoming very fashionable. Disorders of the bacterial flora of the gastrointestinal tract resulting from, for example, chronic stress may cause symptoms of mental disorders. The use of probiotics is a response to such a pathophysiology of depression. Is this the right direction?

In this Special Issue, titled “Pharmacology of Antidepressants; Recent Advances”, we want to consider the direction in which we are heading regarding the treatment of depression, as well as what mechanisms should characterize a new and effective antidepressant. Alternatively, the basis of depression in each patient should be examined, as each patient may have a different pathophysiology, and drugs should be selected depending on the type of depression.

Dr. Anna Wiktorowska-Owczarek
Guest Editor

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Keywords

  • new mechanisms of antidepressants action
  • new targets for antidepressant therapy
  • rapid-acting antidepressants
  • inflammation in depression
  • gut–microbiota–brain axis in depression
  • probiotic as an antidepressant
  • quo vadis pharmacology of antidepressants

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Published Papers (2 papers)

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34 pages, 1218 KiB  
Systematic Review
Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade
by Layla Bleibel, Paulina Sokołowska, Gabriela Henrykowska, Jacek Owczarek and Anna Wiktorowska-Owczarek
Pharmaceuticals 2025, 18(6), 867; https://doi.org/10.3390/ph18060867 - 10 Jun 2025
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Abstract
Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, [...] Read more.
Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, utilizing SSRIs and SNRIs, with Esketamine emerging as a supplementary option in recent times. Nevertheless, there is a growing focus on exploring the relationship between inflammation and depression, revealing a strong correlation between the two. This insight prompts consideration of the anti-inflammatory properties of current antidepressants in their therapeutic application. Methods: A systematic literature search was conducted using the PubMed database to identify randomized controlled trials (RCTs) and clinical trials (CTs) that assessed the in vivo anti-inflammatory effects of SSRIs (fluoxetine, escitalopram, sertraline, and paroxetine), the SNRI venlafaxine, and esketamine/ketamine in human subjects undergoing treatment for depression. The included studies were evaluated based on changes in levels of pro-inflammatory and anti-inflammatory markers in response to the antidepressant treatments. Results: SSRIs, SNRIs, esketamine, and ketamine (a racemic mixture of S- and R-ketamine not formally approved for the treatment of depression) exhibit anti-inflammatory effects through diverse mechanisms, such as reducing pro-inflammatory cytokines or enhancing anti-inflammatory cytokines in serum or within specific brain regions like the hippocampus and prefrontal cortex. These actions are mediated through various inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome, the glutamatergic system, the gut–brain axis, the hypothalamic–pituitary axis, impaired neuroplasticity, and the kynurenine pathway. Conclusions: In summary, SSRIs, SNRIs, esketamine, and ketamine exert an anti-inflammatory role alongside their antidepressant effects via these intricate mechanisms. Full article
(This article belongs to the Special Issue Pharmacology of Antidepressants: Recent Advances)
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27 pages, 1122 KiB  
Systematic Review
An Overview of the Systematic Reviews About the Efficacy of Fluvoxamine on Depression
by Luiz Henrique Junqueira Dieckmann, Michel Haddad, Thiago Wendt Viola, Franciele Franco Scarante, Naielly Rodrigues da Silva and Jair de Jesus Mari
Pharmaceuticals 2025, 18(5), 711; https://doi.org/10.3390/ph18050711 - 12 May 2025
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Abstract
Background: Depression is one of the leading causes of disability worldwide. Among pharmacological treatments, fluvoxamine—an early SSRI with a distinct pharmacological profile—has been recently reappraised for its broader clinical relevance. Objective: To assess the efficacy of fluvoxamine in the treatment of depression compared [...] Read more.
Background: Depression is one of the leading causes of disability worldwide. Among pharmacological treatments, fluvoxamine—an early SSRI with a distinct pharmacological profile—has been recently reappraised for its broader clinical relevance. Objective: To assess the efficacy of fluvoxamine in the treatment of depression compared to placebo and other antidepressants through a comprehensive overview of systematic reviews and meta-analyses. Methods: A systematic search was conducted in MEDLINE and the Cochrane Central Register of Controlled Trials, including systematic reviews and meta-analyses of randomized controlled trials evaluating fluvoxamine’s efficacy. Reviews were eligible if they included adults diagnosed with depressive disorders based on the DSM or ICD criteria. Reviews focusing on other psychiatric disorders, comorbidities, tolerability, or economic evaluations were excluded. Data extraction included effect size measures and methodological quality assessments using the AMSTAR-2 tool. Results were synthesized by comparing fluvoxamine to placebo, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other antidepressants. Results: A total of 74 reviews were identified, of which 14 systematic reviews met the inclusion criteria after screening and full-text analysis. These reviews, published between 1994 and 2021, predominantly involved nine pairwise meta-analyses and five network meta-analyses, comparing fluvoxamine with placebo and various antidepressants. Fluvoxamine demonstrated consistent superiority over placebo in achieving treatment response and remission outcomes. Comparisons with imipramine, clomipramine, amitriptyline, dothiepin, paroxetine, fluoxetine, citalopram, mianserin, nortriptyline, and moclobemide generally revealed no significant differences in efficacy. However, some reviews indicated that venlafaxine and mirtazapine were superior to fluvoxamine in certain outcomes, while fluvoxamine demonstrated greater efficacy than desipramine in one review. Sertraline and milnacipran showed mixed or review-quality-dependent results, with one low-quality review favoring milnacipran. Most reviews assessed outcomes over a median follow-up of six weeks using standardized depression rating scales. Conclusions: Fluvoxamine is a robust and effective antidepressant, demonstrating consistent efficacy comparable to other antidepressants and superior to placebo. While no single antidepressant was universally superior, fluvoxamine’s unique pharmacological profile and favourable safety characteristics support its clinical utility. Further research is needed to explore its role in personalized treatment strategies and emerging therapeutic contexts, such as comorbid anxiety and post-traumatic stress disorder. Full article
(This article belongs to the Special Issue Pharmacology of Antidepressants: Recent Advances)
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