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Pharmaceuticals
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Discovery of Novel Antidepressants and Anxiolytics
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Discovery of Novel Antidepressants and Anxiolytics

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

Deadline for manuscript submissions: 25 November 2025 | Viewed by 8069

Special Issue Editors

Prof. Dr. James Oluwagbamigbe Fajemiroye

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Guest Editor
Department of Pharmacology, Institute of Biological Sciences,Federal University of Goias, Goiania, Brazil
Interests: anxiety; antidepressants; anxiolytics; depression
Dr. Gunnar P. H. Dietz

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Guest Editor
University of Göttingen Medical School, Göttingen, Germany
Interests: neurobiology; phytopharmacology; neurodegenerative diseases

Special Issue Information

Dear Colleagues,

Depression and anxiety are common psychiatric illnesses of global impact. Novel therapeutics are desirable among patients who continue to experience delayed or low responses, adverse effects, and unsatisfactory remission rates with the available drugs. Understanding the complex neurobiology of these psychiatric illnesses is among the prerequisites to the comprehensive assessments of biomarkers or molecular targets, pharmacokinetics, and the clinical efficacy, safety, acceptability, and tolerability of novel antidepressants and anxiolytics. This Special Issue accepts contributions covering new compound/drug candidates, research results, current understandings of depression and anxiety, and updates on pharmacotherapy options and other related topics.

Prof. Dr. James Oluwagbamigbe Fajemiroye
Dr. Gunnar P. H. Dietz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biomarkers
  • depression
  • anxiety
  • anxiolytics
  • antidepressants
  • preclinical or clinical overview
  • experimental data
  • adverse effects
  • pharmacotherapy options
  • novel drugs

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Published Papers (5 papers)

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Research

14 pages, 1201 KiB  
Article
α1 Adrenergic Receptors Mediate Panic-like Defensive Behavior in Alcohol-Drinking but Not Alcohol-Naïve Rats
by Thatiane De Oliveira Sergio, Jacob Kellner, Sarah Wean and Frederic W. Hopf
Pharmaceuticals 2025, 18(4), 484; https://doi.org/10.3390/ph18040484 - 28 Mar 2025
Viewed by 267
Abstract
Background: Most animals display different defensive behavioral strategies during imminent or potential threats. These responses are relevant for understanding human behavioral disorders. In addition, α1 adrenergic receptors (α1ARs) are blocked by prazosin and regulate a diverse set of behaviors, including alcohol drinking related [...] Read more.
Background: Most animals display different defensive behavioral strategies during imminent or potential threats. These responses are relevant for understanding human behavioral disorders. In addition, α1 adrenergic receptors (α1ARs) are blocked by prazosin and regulate a diverse set of behaviors, including alcohol drinking related to anxiety in humans, alcohol intake in rats, responses to strong acute stresses (like restraint), and several forms of cognitive flexibility. However, the role of α1ARs in regulating panic-like escape behavior remains unexplored. Methods: Male and female Wistar rats were chronic alcohol drinkers and age-matched alcohol naïves. Animals received an injection of 0.75 mg/kg of prazosin or vehicle and then were exposed to the elevated T maze (ETM) to evaluate avoidance and escape behavior. One week later, animals underwent the light-dark test (LDT) and open field test. Results: α1AR inhibition with prazosin increased latency for escape in male and female alcohol drinkers, with no significant effects in alcohol-naïve controls. There were also interesting impacts from alcohol drinking, including a decrease in ETM avoidance in female but not male drinkers. In addition, prazosin increased latency to enter the dark in LDT in female drinkers and male naïves. Although prazosin also decreased the number of transitions in males, no differences were found in open-field locomotion. Conclusions: These results suggest that α1ARs mediate escape-like behavior in male and female alcohol drinkers, shedding light on a novel therapy for alcohol problems related to panic and anxiety. Full article
(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)
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15 pages, 1115 KiB  
Article
The Effects of Echinacea (EP107TM) on Anxiety: A Comparison of Anxiety Measures in a Randomized, Double Blind, Placebo-Controlled Study
by József Haller, Gábor Faludi, Gábor Kovacs, György Purebl, Zoltán Füzesi and Tamás F. Freund
Pharmaceuticals 2025, 18(2), 264; https://doi.org/10.3390/ph18020264 - 17 Feb 2025
Viewed by 838
Abstract
Background/Objectives: Echinacea extracts with unique alkamide profiles (EP107™) have been shown to affect upper respiratory tract infections and reduce anxiety in both animals and humans. However, a recent study found that a similar extract did not reduce anxiety more than a placebo, [...] Read more.
Background/Objectives: Echinacea extracts with unique alkamide profiles (EP107™) have been shown to affect upper respiratory tract infections and reduce anxiety in both animals and humans. However, a recent study found that a similar extract did not reduce anxiety more than a placebo, although it did enhance well-being and produced antidepressant-like effects. We hypothesized that the discrepancy arose from the differences in the anxiety assessment methods used. The study that observed no effects used the Clinically Useful Anxiety Outcome Scale, which focuses on physical symptoms, while earlier studies used the State-Trait Anxiety Inventory, which focuses on psychic symptoms. Methods: To investigate the influence of the anxiety measure on the detectability of anxiolytic effects, we examined the effects of Echinacea EP107TM using the Hospital Anxiety and Depression Scale–anxiety subscale (HADS-A), which focuses on psychic symptoms, and the Hamilton Anxiety Rating Scale (HAM-A), most items of which involve physical symptoms. The study was placebo-controlled, double-blind, and multicenter. Results: The extract significantly alleviated anxiety compared to placebo when measured with HADS-A. HAM-A total scores did not show significant treatment effects. However, Echinacea was superior to placebo in three psychic anxiety items on the HAM-A. Conclusions: These findings suggest that Echinacea EP107TM reduces psychic anxiety without affecting somatic symptoms. This indicates that the extract may be useful in mild or early-phase anxiety when somatic symptoms are not prominent. Full article
(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)
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26 pages, 6218 KiB  
Article
Revealing the Mechanism of Hemerocallis citrina Baroni in Depression Treatment Through Integrated Network Pharmacology and Transcriptomic Analysis
by Shan Gao, Jihui Lu, Yixiao Gu, Yaozhi Zhang, Cheng Wang, Feng Gao, Ziqi Dai, Shujing Xu, Jindong Zhang, Yuqin Yang and Haimin Lei
Pharmaceuticals 2024, 17(12), 1704; https://doi.org/10.3390/ph17121704 - 17 Dec 2024
Cited by 1 | Viewed by 924
Abstract
Background/Objectives: Hemerocallis citrina Baroni (HCB) is a traditional herb for the treatment of depression in China. However, the active constituents and the underlying mechanisms of its antidepressant effects remain unclear. The aim of this study was to identify the bioactive constituents of [...] Read more.
Background/Objectives: Hemerocallis citrina Baroni (HCB) is a traditional herb for the treatment of depression in China. However, the active constituents and the underlying mechanisms of its antidepressant effects remain unclear. The aim of this study was to identify the bioactive constituents of HCB and elucidate its underlying mechanism for the treatment of depression. Methods: The constituents of HCB were systematically analyzed using UHPLC-Q-Orbitrap HRMS. Its antidepressant effect was evaluated by chronic unpredictable mild stress (CUMS)-induced depression. The mechanism of HCB in treating depression was investigated through network pharmacology and molecular docking. Subsequently, its potential mechanism for the treatment of depression was carried out by RNA sequencing. Finally, the mechanism was further verified by Western blot. Results: A total of 62 chemical constituents were identified from HCB using UHPLC-Q-Orbitrap HRMS, including 17 flavonoids, 11 anthraquinones, 11 alkaloids, 10 caffeoylquinic acid derivatives, five phenolic acids, five triterpenoids, and three phenylethanosides, 13 of which were identified as potential active constituents targeting 49 depression-associated proteins. Furthermore, HCB was found to significantly reduce cognitive impairment, anxiety-like behavior, and anhedonia-like behavior. The expression levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and brain-derived neurotrophic factor (BDNF) were elevated in the hippocampal CA3 region. Results from network pharmacology and transcriptomics indicated that the PI3K/Akt/CREB signaling pathway is essential for the therapeutic effects of HCB on depression. Research in the field of molecular biology has conclusively demonstrated that HCB is associated with an increase in the expression levels of several important proteins. Specifically, there was a notable upregulation of phosphorylated PI3K (p-PI3K) relative to its unphosphorylated form PI3K, as well as an elevation in the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, the study observed increased levels of phosphorylated CREB (p-CREB) compared to its unphosphorylated CREB. Conclusions: This study provides compelling evidence that HCB possesses the ability to mitigate the symptoms of depression through its influence on the PI3K/Akt/CREB signaling pathway. HCB could be developed as a promising therapeutic intervention for individuals struggling with depression, offering new avenues for treatment strategies that target this particular signaling mechanism. Full article
(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)
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14 pages, 2109 KiB  
Article
Effects of Ketamine vs. Midazolam in Adolescent Treatment Resistant Depression
by Andrea Macejova, Veronika Kovacova, Ingrid Tonhajzerova, Zuzana Visnovcova, Nikola Ferencova, Zuzana Mlyncekova, Tomas Kukucka and Igor Ondrejka
Pharmaceuticals 2024, 17(12), 1627; https://doi.org/10.3390/ph17121627 - 4 Dec 2024
Viewed by 1319
Abstract
Background: Adolescent treatment resistant depression (TRD) is increasing in recent years. While ketamine showed rapid antidepressant effects in adult TRD studies, research on its effectiveness in adolescents is limited. Methods: This study examines the effects of intravenous ketamine vs. midazolam on depressive and [...] Read more.
Background: Adolescent treatment resistant depression (TRD) is increasing in recent years. While ketamine showed rapid antidepressant effects in adult TRD studies, research on its effectiveness in adolescents is limited. Methods: This study examines the effects of intravenous ketamine vs. midazolam on depressive and anxiety symptomatology assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and Children’s Depression Inventory (CDI) at two time points—2 h after initial infusion (T0+2h) and 24 h after the end of the treatment (Te+24h) in a sample of 55 adolescent TRD females (27 receiving ketamine, 28 midazolam). Results: At T0+2h, within-group comparisons revealed a significant reduction in MADRS and HAM-A scores compared to baseline in the ketamine and midazolam groups. At Te+24h, both groups demonstrated similar significant reductions in MADRS, HAM-A, and CDI scores compared to baseline. The MADRS assessment in the ketamine group showed 33% and 59% responders, and in the midazolam group, 14% and 46% responders at T0+2h and Te+24h, respectively. HAM-A evaluation in the ketamine group revealed 33% and 56% responders, and in the midazolam group, 11% and 39% responders at T0+2h and at Te+24h, respectively. CDI rating discovered 11% and 44% responders in the ketamine group and 4% and 21% responders in the midazolam group at T0+2h and Te+24h, respectively. Moreover, inner tension significantly decreased in ketamine compared to the midazolam group at Te+24h. Conclusions: Ketamine showed a reduction in depressive and anxiety symptoms during a short-term period with particular efficacy in alleviating inner tension over midazolam, suggesting its potential advantages in specific symptom relief in rarely studied adolescent TRD. Full article
(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)
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12 pages, 1817 KiB  
Article
Sexual Dysfunction Induced by Antidepressants—A Pharmacovigilance Study Using Data from VigiBaseTM
by Rene Zeiss, Kathrin Malejko, Bernhard Connemann, Maximilian Gahr, Verena Durner and Heiko Graf
Pharmaceuticals 2024, 17(7), 826; https://doi.org/10.3390/ph17070826 - 24 Jun 2024
Cited by 3 | Viewed by 3868
Abstract
Sexual dysfunction is a common side effect of antidepressants, significantly impacting patients’ quality of life and treatment adherence. This study investigates the relationship between sexual dysfunction and antidepressants by analyzing data from VigiBase™, the World Health Organization’s global database of individual case safety [...] Read more.
Sexual dysfunction is a common side effect of antidepressants, significantly impacting patients’ quality of life and treatment adherence. This study investigates the relationship between sexual dysfunction and antidepressants by analyzing data from VigiBase™, the World Health Organization’s global database of individual case safety reports. In this study, we examined, for the first time, reports related to sexual response—desire, arousal, and orgasm—by grouping appropriate side effect terms and calculated the reporting odds ratios (RORs) for various antidepressants. The findings of this study highlight a high disproportional reporting of sexual dysfunction, particularly with selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors. In contrast, agents such as agomelatine, bupropion, and mirtazapine showed a lower association. Furthermore, we investigated the correlation between reporting odds ratios and the binding affinities of antidepressants to specific neurotransmitter receptors and transporters, unveiling significant relationships that provide insights into the pharmacodynamic pathways underlying these adverse effects. For instance, a positive correlation was observed between the serotonin transporter and side effects in the category desire: r (19) = 0.67, p = 0.001 These insights underscore the necessity for clinicians to consider sexual side effects when prescribing antidepressants and to monitor and address these issues to improve patient outcomes. Full article
(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)
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