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Seeking New Antidepressant Agents

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 60628

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Special Issue Editor

Dr. Karolina Pytka

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Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
Interests: depression; cognition; biased agonists; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Major depressive disorder affects more than 300 million people of all ages around the world. According to the World Health Organization, depression is a significant risk factor for suicide, accounting for up to 0.5 million suicides yearly. Moreover, the recent coronavirus disease 2019 (COVID-19) pandemic has seriously impacted public mental health and caused a rapid rise in depressed patients. Unfortunately, the available antidepressants are effective in only around one-third of depressed individuals, leaving the vast majority of patients inadequately treated. Besides, the clinical effects of most drugs appear after 2–4 weeks of treatment, which dramatically increases the risk of suicide. Thus, the development of new rapidly acting antidepressants is of utmost importance. Various compounds have proven successful in treating depression and may inspire further investigation for the development of new antidepressant molecules.

With this Special Issue, we would like to bring together experts working in the field of depression and invite them to present their recent results related to all aspects of drug discovery and development. We will also welcome review articles and short communications on the latest achievements in this field.

Dr. Karolina Pytka
Guest Editor

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Keywords

serotonin and noradrenaline reuptake inhibitors (SNRIs)
selective serotonin reuptake inhibitors (SSRIs)
tricyclic antidepressants (TCAs)
monoamine oxidase inhibitors (MAOIs)
noradrenaline and specific serotoninergic antidepressants (NASSAs)
atypical antidepressants
drug discovery
preclinical studies
clinical studies

Published Papers (14 papers)

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Research

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19 pages, 2682 KiB

Open AccessArticle

Cannabinoid CB1 Receptor Involvement in the Actions of CBD on Anxiety and Coping Behaviors in Mice

by Amaya Austrich-Olivares, María Salud García-Gutiérrez, Lucía Illescas, Ani Gasparyan and Jorge Manzanares

Pharmaceuticals 2022, 15(4), 473; https://doi.org/10.3390/ph15040473 - 13 Apr 2022

Cited by 18 | Viewed by 5016

Abstract

The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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16 pages, 2910 KiB

Open AccessArticle

Two Lignan Glycosides from Albizia julibrissin Durazz. Noncompetitively Inhibit Serotonin Transporter

by Bishan Huang, Hanhe Liu, Yingyao Wu, Chan Li, Qingfa Tang and Yuan-Wei Zhang

Pharmaceuticals 2022, 15(3), 344; https://doi.org/10.3390/ph15030344 - 11 Mar 2022

Cited by 9 | Viewed by 2470

Abstract

Albizia julibrissin Durazz. is one of the most common herbs used for depression and anxiety treatment, but its molecular basis and mechanism of action as an antidepressant or anxiolytic drug are not understood. In this study, we separated and identified two lignan glycosides that inhibit serotonin transporter (SERT) noncompetitively by decreasing V_max with little change in K_m for its fluorescence substrate. In addition, treatment with lignan glycosides did not alter total and cell surface expression levels of the transporter protein. The two compounds decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of SERT. These results are consistent with molecular docking for the association of the lignan glycosides to the allosteric site in SERT. The present work supports the proposal that these compounds act on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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14 pages, 940 KiB

Open AccessArticle

Antidepressant-like Effects of BDNF and NGF Individual Loop Dipeptide Mimetics Depend on the Signal Transmission Patterns Associated with Trk

by Armen G. Mezhlumyan, Anna V. Tallerova, Polina Y. Povarnina, Aleksey V. Tarasiuk, Nellya M. Sazonova, Tatiana A. Gudasheva and Sergey B. Seredenin

Pharmaceuticals 2022, 15(3), 284; https://doi.org/10.3390/ph15030284 - 24 Feb 2022

Cited by 2 | Viewed by 2263

Abstract

Neurotrophins are considered as an attractive target for the development of antidepressants with a novel mechanism of action. Previously, the dimeric dipeptide mimetics of individual loops of nerve growth factor, NGF (GK-6, loop 1; GK-2, loop 4) and brain-derived neurotrophic factor, BDNF (GSB-214, loop 1; GTS-201, loop 2; GSB-106, loop 4) were designed and synthesized. All the mimetics of NGF and BDNF in vitro after a 5–180 min incubation in a HT-22 cell culture were able to phosphorylate the tropomyosin-related kinase A (TrkA) or B (TrkB) receptors, respectively, but had different post-receptor signaling patterns. In the present study, we conduct comparative research of the antidepressant-like activity of these mimetics at acute and subchronic administration in the forced swim test in mice. Only the dipeptide GSB-106 that in vitro activates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and phospholipase C-gamma (PLC_γ) post-receptor pathways exhibited antidepressant-like activity (0.1 and 1.0 mg/kg, ip) at acute administration. At the same time, the inhibition of any one of these signaling pathways completely prevented the antidepressant-like effects of GSB-106 in the forced swim test. All the NGF mimetics were inactive after a single injection regardless of post-receptor in vitro signaling patterns. All the investigated dipeptides, except GTS-201, not activating PI3K/AKT in vitro unlike the other compounds, were active at subchronic administration. The data obtained demonstrate that the low-molecular weight BDNF mimetic GSB-106 that activates all three main post-receptor TrkB signaling pathways is the most promising for the development as an antidepressant. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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17 pages, 4570 KiB

Open AccessArticle

Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism

by Anna Rafało-Ulińska, Piotr Brański and Agnieszka Pałucha-Poniewiera

Pharmaceuticals 2022, 15(2), 125; https://doi.org/10.3390/ph15020125 - 21 Jan 2022

Cited by 19 | Viewed by 5349

Abstract

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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21 pages, 8816 KiB

Open AccessArticle

Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin–Paroxetine Complex

by Thammarat Aree

Pharmaceuticals 2022, 15(1), 98; https://doi.org/10.3390/ph15010098 - 14 Jan 2022

Cited by 4 | Viewed by 2200

Abstract

Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD–paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD–PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD–PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH₂–O- group bridging the A- and C–D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host–guest N–H···O5/O6 H-bonds and C/O–H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD–PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD–PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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19 pages, 2701 KiB

Open AccessArticle

Strain-, Sex-, and Time-Dependent Antidepressant-like Effects of Cannabidiol

by Gabriela P. Silote, Michelle C. Gatto, Amanda Eskelund, Francisco S. Guimarães, Gregers Wegener and Sâmia R. L. Joca

Pharmaceuticals 2021, 14(12), 1269; https://doi.org/10.3390/ph14121269 - 06 Dec 2021

Cited by 15 | Viewed by 3862

Abstract

Cannabidiol (CBD) is a non-intoxicating compound extracted from Cannabis sativa, showing antidepressant-like effects in different rodent models. However, inconsistent results have been described depending on the species and the strain used to assess depressive-like behavior. Moreover, only a few studies investigated the effect of CBD in female rodents. Therefore, we aimed to (i) investigate the effects of CBD in two different strains of mice (Swiss and C57BL/6) and a rat model of depression based on selective breeding (Flinders Sensitive and Resistant Lines, FSL and FRL) subjected to tests predictive of antidepressant-like effects and (ii) investigate the influence of sex in the effects of CBD in both mice and rats. CBD induced an antidepressant-like effect in male Swiss but not in female Swiss or C57BL/6 mice in the tail suspension test (TST). In male FSL rats, CBD produced an antidepressant-like effect 1 h post injection. However, in female FSL, CBD induced a bimodal effect, increasing the immobility time at 1 h and decreasing it at 2 h. In conclusion, strain, sex, and administration time affect CBD’s behavioral response to rodents exposed to tests predictive of antidepressant effects. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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21 pages, 4146 KiB

Open AccessArticle

Catenin Alpha 2 May Be a Biomarker or Potential Drug Target in Psychiatric Disorders with Perseverative Negative Thinking

by Nora Eszlari, Zsolt Bagyura, Andras Millinghoffer, Tamas Nagy, Gabriella Juhasz, Peter Antal, Bela Merkely and Gyorgy Bagdy

Pharmaceuticals 2021, 14(9), 850; https://doi.org/10.3390/ph14090850 - 26 Aug 2021

Cited by 3 | Viewed by 2943

Abstract

AlphaN-catenin gene CTNNA2 has been implicated in intrauterine brain development, as well as in several psychiatric disorders and cardiovascular diseases. Our present aim was to investigate CTNNA2 gene-wide associations of single-nucleotide polymorphisms (SNPs) with psychiatric and cardiovascular risk factors to test the potential mediating role of rumination, a perseverative negative thinking phenotype in these associations. Linear mixed regression models were run by FaST-LMM within a sample of 795 individuals from the Budakalasz Health Examination Survey. The psychiatric outcome variables were rumination and its subtypes, and ten Brief Symptom Inventory (BSI) scores including, e.g., obsessive-compulsive, depression, anxiety, hostility, phobic anxiety, and paranoid ideation. Cardiovascular outcome variables were BMI and the Framingham risk scores for cardiovascular disease, coronary heart disease, myocardial infarction, and stroke. We found nominally significant CTNNA2 associations for every phenotype. Rumination totally mediated the associations of CTNNA2 rs17019243 with eight out of ten BSI scores, but none with Framingham scores or BMI. Our results suggest that CTNNA2 genetics may serve as biomarkers, and increasing the expression or function of CTNNA2 protein may be a potential new therapeutic approach in psychiatric disorders with perseverative negative thinking including, e.g., depression. Generally, an antiruminative agent could be a transdiagnostic and preventive psychopharmacon. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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21 pages, 5195 KiB

Open AccessArticle

Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation

by Thammarat Aree

Pharmaceuticals 2021, 14(8), 812; https://doi.org/10.3390/ph14080812 - 18 Aug 2021

Cited by 9 | Viewed by 2748

Abstract

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (K_as) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH₂–CH₂- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔE_stbs), although the complex stability orders based on K_as and ΔE_stbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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10 pages, 832 KiB

Open AccessArticle

Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21

by Liina Laukkanen, Cassiano R. A. F. Diniz, Sebastien Foulquier, Jos Prickaerts, Eero Castrén and Plinio C. Casarotto

Pharmaceuticals 2021, 14(8), 773; https://doi.org/10.3390/ph14080773 - 06 Aug 2021

Cited by 2 | Viewed by 2379

Abstract

Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1–10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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24 pages, 2998 KiB

Open AccessArticle

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT_1A and D₂ Receptors

by Kinga Sałaciak, Natalia Malikowska-Racia, Klaudia Lustyk, Agata Siwek, Monika Głuch-Lutwin, Grzegorz Kazek, Justyna Popiół, Jacek Sapa, Henryk Marona, Dorota Żelaszczyk and Karolina Pytka

Pharmaceuticals 2021, 14(8), 744; https://doi.org/10.3390/ph14080744 - 29 Jul 2021

Cited by 4 | Viewed by 2256

Abstract

The increasing number of patients reporting depressive symptoms requires the design of new antidepressants with higher efficacy and limited side effects. As our previous research showed, 2-methoxyphenylpiperazine derivatives are promising candidates to fulfill these criteria. In this study, we aimed to synthesize a novel 2-methoxyphenylpiperazine derivative, HBK-10, and investigate its in vitro and in vivo pharmacological profile. After assessing the affinity for serotonergic and dopaminergic receptors, and serotonin transporter, we determined intrinsic activity of the compound at the 5-HT_1A and D₂ receptors. Next, we performed behavioral experiments (forced swim test, tail suspension test) to evaluate the antidepressant-like activity of HBK-10 in naïve and corticosterone-treated mice. We also assessed the safety profile of the compound. We showed that HBK-10 bound strongly to 5-HT_1A and D₂ receptors and presented antagonistic properties at these receptors in the functional assays. HBK-10 displayed the antidepressant-like effect not only in naïve animals, but also in the corticosterone-induced mouse depression model, i.e., chronic administration of HBK-10 reversed corticosterone-induced changes in behavior. Moreover, the compound’s sedative effect was observed at around 26-fold higher doses than the antidepressant-like ones. Our study showed that HBK-10 displayed a favorable pharmacological profile and may represent an attractive putative treatment candidate for depression. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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Review

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21 pages, 1557 KiB

Open AccessReview

The Potential Use of Ebselen in Treatment-Resistant Depression

by Fitri Fareez Ramli, Philip J. Cowen and Beata R. Godlewska

Pharmaceuticals 2022, 15(4), 485; https://doi.org/10.3390/ph15040485 - 16 Apr 2022

Cited by 6 | Viewed by 3947

Abstract

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere’s Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium’s anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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14 pages, 781 KiB

Open AccessReview

Rediscovering Psilocybin as an Antidepressive Treatment Strategy

by Rene Zeiss, Maximilian Gahr and Heiko Graf

Pharmaceuticals 2021, 14(10), 985; https://doi.org/10.3390/ph14100985 - 28 Sep 2021

Cited by 8 | Viewed by 12637

Abstract

There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major depressive disorder (MDD). Several state-of-the-art studies have provided new insight into the mechanisms of action of psilocybin and its therapeutic potential. Nevertheless, many questions remain unanswered. With this review, we provide an overview of the current state of research on the potential mechanisms of psilocybin, its antidepressant potential, and the associated risks and adverse effects, to provide an update on a controversial topic discussed in psychopharmacology. A database search was conducted in Medline including articles on psilocybin over the period of the last 20 years. Despite the promising progress in understanding the mechanisms of psilocybin, the exact antidepressive mechanism and the role of the psychedelic experience remain elusive. The studies included in this review found high treatment effect sizes for psilocybin as an antidepressant. However, the results must be regarded as preliminary due to several limitations. Although the current studies observed no severe adverse events, several questions regarding safety and utility remain and must be subject of future research. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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15 pages, 805 KiB

Open AccessReview

New Molecular Targets for Antidepressant Drugs

by Johannes Kornhuber and Erich Gulbins

Pharmaceuticals 2021, 14(9), 894; https://doi.org/10.3390/ph14090894 - 02 Sep 2021

Cited by 22 | Viewed by 4571

Abstract

Major depressive disorder (MDD) is a common and severe mental disorder that is usually recurrent and has a high risk of suicide. This disorder manifests not only with psychological symptoms but also multiple changes throughout the body, including increased risks of obesity, diabetes, and cardiovascular disease. Peripheral markers of oxidative stress and inflammation are elevated. MDD is therefore best described as a multisystem whole-body disease. Pharmacological treatment with antidepressants usually requires several weeks before the desired effects manifest. Previous theories of depression, such as the monoamine or neurogenesis hypotheses, do not explain these characteristics well. In recent years, new mechanisms of action have been discovered for long-standing antidepressants that also shed new light on depression, including the sphingolipid system and the receptor for brain-derived neurotrophic factor (BDNF). Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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17 pages, 882 KiB

Open AccessReview

A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity “Shati/Nat8l-BDNF System” in the Dorsal Striatum

by Hajime Miyanishi and Atsumi Nitta

Pharmaceuticals 2021, 14(9), 889; https://doi.org/10.3390/ph14090889 - 01 Sep 2021

Cited by 18 | Viewed by 6218

Abstract

Depression is one of the most common mental diseases, with increasing numbers of patients globally each year. In addition, approximately 30% of patients with depression are resistant to any treatment and do not show an expected response to first-line antidepressant drugs. Therefore, novel antidepressant agents and strategies are required. Although depression is triggered by post-birth stress, while some individuals show the pathology of depression, others remain resilient. The molecular mechanisms underlying stress sensitivity remain unknown. Brain-derived neurotrophic factor (BDNF) has both pro- and anti-depressant effects, dependent on brain region. Considering the strong region-specific contribution of BDNF to depression pathogenesis, the regulation of BDNF in the whole brain is not a beneficial strategy for the treatment of depression. We reviewed a novel finding of BDNF function in the dorsal striatum, which induces vulnerability to social stress, in addition to recent research progress regarding the brain regional functions of BDNF, including the prefrontal cortex, hippocampus, and nucleus accumbens. Striatal BDNF is regulated by Shati/Nat8l, an N-acetyltransferase through epigenetic regulation. Targeting of Shati/Nat8l would allow BDNF to be striatum-specifically regulated, and the striatal Shati/Nat8l-BDNF pathway could be a promising novel therapeutic agent for the treatment of depression by modulating sensitivity to stress. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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