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Recent Advances in Psychopharmacology
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Recent Advances in Psychopharmacology

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

Deadline for manuscript submissions: closed (25 May 2025) | Viewed by 15049

Special Issue Editors

Prof. Dr. Roos Van Westrhenen

E-Mail Website1 Website2
Guest Editor
1. Parnassia Psychiatric Institute, Amsterdam, The Netherlands
2. Institute of Psychiatry, Psychology and Neuroscience (IoPPN) Kings College, London, UK
3. Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
4. St. John’s National Academy of Health Sciences, Bangalore, India
Interests: psychiatry; (psycho)pharmacology; pharmacogenetics; pharmacogenomics; genetics; pharmacokinetics; pharmacodynamics; pharmacovigilance; drug interactions; phenoconversion
Prof. Dr. Allan H. Young

grade E-Mail Website
Guest Editor
1. Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
2. South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BX, UK
Interests: psychopharmacology; bipolar disorder; major depressive disorder; novel treatments; cognition

Special Issue Information

Dear Colleagues,

Performing clinical trials in psychiatry is a challenge as it is difficult to include a sufficient number of patients and assess reliable outcome parameters, and due to the fact that drug companies as Astra Zeneca, Pfizer, Glaxo Smith Kline and Eli Lilly have stopped almost all psychopharmaca discoveries [1]. Nevertheless, in a recent overview of all the recent and current phase 2 or phase 3 clinical trials, n=43 were described for schizophrenia medication, n=11 for bipolar disorder, n=56 for major depressive disorder, n=29 for anxiety disorder and trauma related disorders, and n=17 for medication for treatment of substance disorders [2]. One has to bear in mind that, in general, the availability of new psychopharmaca to patients takes nearly nine years, and the likelihood of drug approval in psychiatry is only 6.2%. Thus, novel strategies in psychiatry are urgently needed [3].

We would like to add enhancing medication prescription with pharmacogenetics as another strategy. In general, only one-third of the patients respond to treatment with available medication in psychiatry [4,5]. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians’ experience [4,5]. Pharmacogenetic testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets [4–8].

In this Special Issue, some exciting examples of newly registered medications in psychiatry will be described, in addition to recent pharmacogenetic advances including the start of a clinical trial implementing pharmacogenetics in people with mood, anxiety, and psychotic disorders.

  1. Howes OD, Baxter L. The drug treatment deadlock in psychiatry and the route forward. World Psychiatry 2023;22(1): 2-4
  2. Correll, M. Solmi, S. Cortese, M. Fava, M. Højlund, HC. Kraemer, RS. McIntyre, DS. Pine, LS. Schneider, JM. Kane- The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents, World Psychiatry 2023;22(1): 48-74
  3. Yatham LM All levels of the translational spectrum must be targeted to advance psychopharmacology and improve patient outcomes, World Psychiatry 2023;22(1): 75-76
  4. van Westrhenen& M. Ingelman-Sundberg. Editorial: From Trial and Error to Individualised Pharmacogenomics-Based Pharmacotherapy in Psychiatry. Frontiers in Pharmacology, 2021, doi: 10.3389/fphar.2021.725565
  5. Dutch Pharmacogenetics Working Group (DPWG) Guideline for the Gene-Drug Interaction between CYP2D6, CYP3A4 and CYP1A2 and Antipsychotics, L. Beunk, M Nijenhuis, B Soree,  de Boer-Veger, AM Buunk, H J Guchelaar, EJF Houwink, A Risselada, GAPJM. Rongen, RHN van Schaik, JJ Swen, D Touw, R van Westrhenen, VHM Deneer, J van der Weide Eur J Hum Gen 2023, https://doi.org/10.1038/s41431-023-01347-3
  6. Dutch Pharmacogenetics Working Group (DPWG) Guideline for the Gene-Drug Interaction between CYP2C19 and CYP2D6 and SSRIs" M. Nijenhuis, J. Brouwer, B. Soree, HJ. Guchelaar, J. Swen, R. van Schaik, J. van der Weide, G. Rongen, AM. Buunk, N. de Boer-Veger, E. Houwink, van Westrhenen, B. Wilffert, V. Deneer, and Hans Mulder. Eur J of Human Gen nov 2021, /doi.org/10.1038/s41431-021-01004-7
  7. Brown e.a. Pharmacogenomic Testing and Depressive Symptom Remission: A Systematic Review and Meta-Analysis of Prospective, Controlled Clinical Trials, Clin Pharm&Ther 2022; 112(6): 1303-1317
  8. Swen J, e.a. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet 2023;400(10374): 347-356

Prof. Dr. Roos Van Westrhenen
Prof. Dr. Allan H. Young
Guest Editors

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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

  • psychopharmaca
  • pharmacogenomics
  • pharmacogenetics
  • psychedelics
  • dementia drugs

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Published Papers (7 papers)

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Research

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24 pages, 341 KiB  
Article
Long-Term Cognitive Outcomes of Esketamine Nasal Spray in Treatment-Resistant Depression: A Preliminary Report
by Matildes de Freitas Menezes Sobreiro, Paulo Sergio Panse Silveira, Vitor Breseghello Cavenaghi, Leandro Paulino da Costa, Bruno Pinatti Ferreira de Souza, Rachel Emy Straus Takahashi, Renato Vianna Marotta Starek, José Oliveira Siqueira and Renerio Fraguas
Pharmaceuticals 2025, 18(2), 173; https://doi.org/10.3390/ph18020173 - 27 Jan 2025
Viewed by 1374
Abstract
Background/Objectives: Ketamine/esketamine has a rapid/robust antidepressant effect on treatment-resistant depression (TRD). However, its long-term cognitive effects remain unclear. In this study, we investigated the potential cognitive effects of an esketamine spray on a series of TRD patients. Methods: We evaluated the [...] Read more.
Background/Objectives: Ketamine/esketamine has a rapid/robust antidepressant effect on treatment-resistant depression (TRD). However, its long-term cognitive effects remain unclear. In this study, we investigated the potential cognitive effects of an esketamine spray on a series of TRD patients. Methods: We evaluated the cognitive performance of eight TRD patients subjected to an esketamine nasal spray as an adjunct treatment for six months. Cognitive assessments were performed before treatment initiation (T0) and at three (T3) and six (T6) months by an experienced neuropsychologist using a comprehensive neuropsychological battery. Depression severity was assessed by the Montgomery–Åsberg Depression Rating Scale. Changes in cognitive performance were analyzed by determining the bias between time points. To investigate the association between the severity of depression and performance on cognitive tests, we used correlation with correction for repeated measures and regression analysis with a general linear mixed model. We used the Tukey method to compare three estimates and the Dunnett method to compare two estimates. Results: Improvements in at least one test from T0 to T6 were found for attention, memory, and the executive functions of working memory, set-shifting, and inhibitory control. Most of the improvements had occurred by T3, but working memory and set-shifting improvements were significant only at T6. The severity of depression decreased significantly from T0 to T6, and most cognitive improvements were correlated with an improvement in depression severity. No test indicated a worsening of cognitive performance from T0 to T6. Conclusions: Our results suggest that the cognitive performance of TRD patients improved with long-term adjunct treatment with an esketamine nasal spray. Confirmatory studies are necessary. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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17 pages, 1665 KiB  
Article
The Effects of CYP2C19 Genotype on Proxies of SSRI Antidepressant Response in the UK Biobank
by Win Lee Edwin Wong, Chiara Fabbri, Benjamin Laplace, Danyang Li, Roos van Westrhenen, Cathryn M. Lewis, Gavin Stewart Dawe and Allan H. Young
Pharmaceuticals 2023, 16(9), 1277; https://doi.org/10.3390/ph16091277 - 11 Sep 2023
Cited by 11 | Viewed by 4146
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychopharmaceutical treatment for major depressive disorder (MDD), but individual responses to SSRIs vary greatly. CYP2C19 is a key enzyme involved in the metabolism of several drugs, including SSRIs. Variations in the CYP2C19 gene [...] Read more.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychopharmaceutical treatment for major depressive disorder (MDD), but individual responses to SSRIs vary greatly. CYP2C19 is a key enzyme involved in the metabolism of several drugs, including SSRIs. Variations in the CYP2C19 gene are associated with differential metabolic activity, and thus differential SSRI exposure; accordingly, the CYP2C19 genotype may affect the therapeutic response and clinical outcomes, though existing evidence of this link is not entirely consistent. Therefore, we analysed data from the UK Biobank, a large, deeply phenotyped prospective study, to investigate the effects of CYP2C19 metaboliser phenotypes on several clinical outcomes derived from primary care records, including multiple measures of antidepressant switching, discontinuation, duration, and side effects. In this dataset, 24,729 individuals were prescribed citalopram, 3012 individuals were prescribed escitalopram, and 12,544 individuals were prescribed sertraline. Consistent with pharmacological expectations, CYP2C19 poor metabolisers on escitalopram were more likely to switch antidepressants, have side effects following first prescription, and be on escitalopram for a shorter duration compared to normal metabolisers. CYP2C19 poor and intermediate metabolisers on citalopram also exhibited increased odds of discontinuation and shorter durations relative to normal metabolisers. Generally, no associations were found between metabolic phenotypes and proxies of response to sertraline. Sensitivity analyses in a depression subgroup and metabolic activity scores corroborated results from the primary analysis. In summary, our findings suggest that CYP2C19 genotypes, and thus metabolic phenotypes, may have utility in determining clinical responses to SSRIs, particularly escitalopram and citalopram, though further investigation of such a relationship is warranted. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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Review

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42 pages, 789 KiB  
Review
New Agents in the Treatment of Psychiatric Disorders: What Innovations and in What Areas of Psychopathology?
by Paola Bozzatello, Roberta Novelli, Rebecca Schisano, Claudio Brasso, Paola Rocca and Silvio Bellino
Pharmaceuticals 2025, 18(5), 665; https://doi.org/10.3390/ph18050665 - 30 Apr 2025
Viewed by 546
Abstract
Psychiatric disorders are a major cause of illness in the world. Unfortunately, many patients are resistant to treatment and present serious complications. Schizophrenia is refractory to treatment in about one-third of patients. Antidepressants are effective in about half of patients. Suicidal ideation is [...] Read more.
Psychiatric disorders are a major cause of illness in the world. Unfortunately, many patients are resistant to treatment and present serious complications. Schizophrenia is refractory to treatment in about one-third of patients. Antidepressants are effective in about half of patients. Suicidal ideation is an increasing issue in patients with mixed features in bipolar disorder (BD). Therefore, there is a need to develop and test new drugs or new indications of available medications for the treatment of psychiatric disorders through evidence-based investigations. This narrative review aims to present the molecules approved by the main drug agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), from 2018 to date, along with new indications and new formulations of existing medications. We searched PubMed for new drugs approved for schizophrenia, BD, major depressive disorder (MDD), anxiety disorders, and obsessive-compulsive disorder (OCD). We evaluated their clinical benefits, safety, and tolerability profiles. Finally, we considered studies on the main molecules that have shown initial evidence of efficacy and are in the process of obtaining approval. Our search suggested that a new antipsychotic, lumateperone, and two drug combinations, olanzapine/samidorphan (OLZ/SAM) and xanomeline/trospium (KarXT), were approved for schizophrenia. In addition, some new methods of administration—monthly risperidone administration, subcutaneous risperidone administration, and transdermal asenapine administration—obtained approval from the main drug agencies. Lumateperone and OLZ/SAM were also approved in BD. Esketamine, a compound that modulates glutamatergic transmission, was approved to treat treatment-resistant depression and acute suicidal ideation. The dextromethorphan/bupropion combination was approved for MDD. Two new agents, brexanolone and zuranolone, were approved for treatment of postpartum depression. On the other hand, no new drugs received approval for anxiety disorders or OCD. In summary, some new psychotropic medications have been developed, in particular with the aim to improve the symptoms of resistant patients and to decrease the incidence of adverse effects. It is necessary to continue testing the effectiveness of new compounds in methodologically rigorous studies. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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15 pages, 1702 KiB  
Review
Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor
by John E. Donello, Roger S. McIntyre, Donald B. Pickel and Stephen M. Stahl
Pharmaceuticals 2025, 18(2), 157; https://doi.org/10.3390/ph18020157 - 24 Jan 2025
Cited by 1 | Viewed by 2052
Abstract
Plastogens are a class of therapeutics that function by rapidly promoting changes in neuroplasticity. A notable example, ketamine, is receiving great attention due to its combined rapid and long-term antidepressant effects. Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, and, in addition to its [...] Read more.
Plastogens are a class of therapeutics that function by rapidly promoting changes in neuroplasticity. A notable example, ketamine, is receiving great attention due to its combined rapid and long-term antidepressant effects. Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, and, in addition to its therapeutic activity, it is associated with psychotomimetic and dissociative side effects. Stinels—rapastinel, apimostinel, and zelquistinel—are also plastogens not only with rapid and long-term antidepressant effects but also with improved safety and tolerability profiles compared to ketamine. Previous descriptions of the mechanism by which stinels modulate NMDAR activity have been inconsistent and, at times, contradictory. The purpose of this review is to clarify the mechanism of action and contextualize stinels within a broader class of NMDAR-targeting therapeutics. In this review, we present the rationale behind targeting NMDARs for treatment-resistant depression and other psychiatric conditions, describe the various mechanisms by which NMDAR activity is regulated by different classes of therapeutics, and present evidence for the stinel mechanism. In contrast with previous descriptions of glycine-like NMDAR partial agonists, we define stinels as positive allosteric modulators of NMDAR activity with a novel regulatory binding site. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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29 pages, 3069 KiB  
Review
N-methyl-D-aspartate Receptors and Depression: Linking Psychopharmacology, Pathology and Physiology in a Unifying Hypothesis for the Epigenetic Code of Neural Plasticity
by Stefano Comai, Sara De Martin, Andrea Mattarei, Clotilde Guidetti, Marco Pappagallo, Franco Folli, Andrea Alimonti and Paolo L. Manfredi
Pharmaceuticals 2024, 17(12), 1618; https://doi.org/10.3390/ph17121618 - 30 Nov 2024
Cited by 2 | Viewed by 1907
Abstract
Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into [...] Read more.
Uncompetitive NMDAR (N-methyl-D-aspartate receptor) antagonists restore impaired neural plasticity, reverse depressive-like behavior in animal models, and relieve major depressive disorder (MDD) in humans. This review integrates recent findings from in silico, in vitro, in vivo, and human studies of uncompetitive NMDAR antagonists into the extensive body of knowledge on NMDARs and neural plasticity. Uncompetitive NMDAR antagonists are activity-dependent channel blockers that preferentially target hyperactive GluN2D subtypes because these subtypes are most sensitive to activation by low concentrations of extracellular glutamate and are more likely activated by certain pathological agonists and allosteric modulators. Hyperactivity of GluN2D subtypes in specific neural circuits may underlie the pathophysiology of MDD. We hypothesize that neural plasticity is epigenetically regulated by precise Ca2+ quanta entering cells via NMDARs. Stimuli reach receptor cells (specialized cells that detect specific types of stimuli and convert them into electrical signals) and change their membrane potential, regulating glutamate release in the synaptic cleft. Free glutamate binds ionotropic glutamatergic receptors regulating NMDAR-mediated Ca2+ influx. Quanta of Ca2+ via NMDARs activate enzymatic pathways, epigenetically regulating synaptic protein homeostasis and synaptic receptor expression; thereby, Ca2+ quanta via NMDARs control the balance between long-term potentiation and long-term depression. This NMDAR Ca2+ quantal hypothesis for the epigenetic code of neural plasticity integrates recent psychopharmacology findings into established physiological and pathological mechanisms of brain function. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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Other

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35 pages, 1145 KiB  
Systematic Review
The Role of Vitamin D in the Management of Major Depressive Disorder: A Systematic Review
by Andreea Roșian, Mihaela Zdrîncă, Luciana Dobjanschi, Laura Grațiela Vicaș, Mariana Eugenia Mureșan, Camelia Maria Dindelegan, Rita Ioana Platona and Eleonora Marian
Pharmaceuticals 2025, 18(6), 792; https://doi.org/10.3390/ph18060792 - 25 May 2025
Viewed by 436
Abstract
Background/Objective: Depression is a widespread and complex disorder, constituting a major public health concern due to its significant impact on mental health. Because of the limitations of major depressive disorder (MDD) treatment, recent research on depression management has focused on identifying new therapeutic [...] Read more.
Background/Objective: Depression is a widespread and complex disorder, constituting a major public health concern due to its significant impact on mental health. Because of the limitations of major depressive disorder (MDD) treatment, recent research on depression management has focused on identifying new therapeutic strategies. The effects of vitamin D on the brain, mediated through various mechanisms, suggest the potential implication of vitamin D in the pathophysiology of depression. In this systematic review, our objective was to evaluate the correlation between serum levels of 25-hydroxyvitamin D (25(OH)D) and depression based on evidence from cross-sectional and cohort studies. Furthermore, we also assessed the effect of vitamin D supplementation in relation to depressive symptoms, using data from randomised controlled trials (RCTs). Methods: To achieve the proposed objective, we have compiled a report that includes a selection of empirical evidence necessary to review the relationship between vitamin D and depression. In this regard, relevant articles were searched on platforms such as PubMed, MDPI, ResearchGate, Springer Link, Springer Open, and ScienceDirect. A total of 13,976 records, published between 2008 and 2024, were initially identified through database searches. After the study selection process, performed according to the PRISMA guidelines, 70 articles were included in the systematic review. Results: According to most cross-sectional and cohort studies, the results highlight an inverse relationship between serum 25(OH)D levels and the risk of depression, as well as the severity of depressive symptoms. An increase in serum 25(OH)D concentration is associated with an improvement in depression test scores, with vitamin D supplementation exerting a beneficial effect on both the incidence and the prognosis of depression. Conclusions: Based on current evidence which indicates the implications of vitamin D in the neurobiological mechanisms associated with depression, and the results obtained in most of the studies, which demonstrate an inverse relationship between serum 25(OH)D levels and the beneficial effect of vitamin D supplementation on depressive symptoms, vitamin D could represent an adjunctive therapy in the management of MDD. More rigorous studies, without methodological errors, are needed to correctly and definitively assess the impact of vitamin D in relation to depression. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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25 pages, 2147 KiB  
Systematic Review
CYP2C19 Genetic Variants and Major Depressive Disorder: A Systematic Review
by Larissa Sousa Silva Bonasser, Calliandra Maria de Souza Silva, Caroline Ferreira Fratelli, Bruna Rodrigues Gontijo, Juliana Moura Alves Seixas, Livia Cristina Lira de Sá Barreto and Izabel Cristina Rodrigues da Silva
Pharmaceuticals 2024, 17(11), 1461; https://doi.org/10.3390/ph17111461 - 31 Oct 2024
Cited by 2 | Viewed by 2585
Abstract
Major depressive disorder (MDD) affects over 300 million people globally and has a multifactorial etiology. The CYP2C19 enzyme, involved in metabolizing certain antidepressants, can influence treatment response. Following the PRISMA protocol and PECOS strategy, this systematic review assessed the variation in common CYP2C19 [...] Read more.
Major depressive disorder (MDD) affects over 300 million people globally and has a multifactorial etiology. The CYP2C19 enzyme, involved in metabolizing certain antidepressants, can influence treatment response. Following the PRISMA protocol and PECOS strategy, this systematic review assessed the variation in common CYP2C19 gene variants’ frequencies across populations with MDD, evaluating their impact on clinical characteristics and treatment response. We comprehensively searched five databases, identifying 240 articles, of which only nine within the last decade met our inclusion criteria. Except for one study that achieved 74.28% of STROPS items, the rest met at least 75% of GRIPS and STROPS guidelines for quality and bias risk assessment. The CYP2C19’s *1 allele, the *1/*1 genotype, and the NM phenotype, considered as references, were generally more frequent. Other CYP2C19 polymorphism frequencies exhibit significant variability across different populations. Some studies associated variants with MDD development, a more extended history of depression, prolonged depressive episodes, and symptom severity, while others reported no such association. Some studies confirmed variants’ effects on escitalopram and citalopram metabolism but not that of other drugs, such as sertraline, venlafaxine, and bupropion. Treatment tolerability and symptom improvement also varied between studies. Despite some common findings, inconsistencies highlight the need for further research to clarify the role of these polymorphisms in MDD and optimize treatment strategies. Full article
(This article belongs to the Special Issue Recent Advances in Psychopharmacology)
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