Editorial: Enhancing Therapeutic Strategies: A Focus on Pharmacovigilance in New Wave Antidepressants and Antipsychotics

Octavian Vasiliu^1,2*Mirko Manchia^3,4*Yoshihiro Noguchi^5*Georgios Mikellides^6,7

• ¹Neurosciences Department, Universitatea de Medicina si Farmacie Carol Davila din Bucuresti, Bucharest, Romania
• ²Psychiatry Department, Spitalul Universitar de Urgenta Militar Central Dr Carol Davila, Bucharest, Romania
• ³Section of Psychiatry, Department of Public Health and Medical Services, University of Cagliari, Cagliari, Italy
• ⁴Department of Pharmacology, Dalhousie University, Halifax, Canada
• ⁵Gifu Pharmaceutical University, Gifu, Japan
• ⁶Department of Basic and Clinical Sciences, Medical School, University of Nicosia, Nicosia, Cyprus
• ⁷Centre for Repetitive Transcranial Magnetic Stimulation, Cyprus rTMS, Nicosia, Cyprus

Psychopharmacology has undergone transformative advancements, particularly with the development of next-generation antidepressants and antipsychotics. Such progress was required, and still is, due to the challenges in the clinical domain, where almost one-third of patients living with severe mental disorders (SMD) experience some degree of resistance to treatment [1][2][3]. The limited efficacy of antipsychotic treatment may be detected from the first episode of psychosis (FEP), with meta-analytical research reporting pooled rates of remission of 58% and pooled prevalence of recovery no higher than 38% [3]. When referring to Major Depressive Disorder (MDD), the learnings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial highlight that only 33% of the patients recovered after the first trial of antidepressants, and many patients required multiple trials, with the rates of responsiveness decreasing as the number of trials increased [4,5].The consequences of these limitations on the treatment efficacy, when schizophrenia spectrum disorders (SSD) and MDD are approached, are reported on multiple, relevant outcomes, such as quality of life, daily functionality and disability rates, frequency of hospitalisation and relapse, and risk of complications and mortality [6][7][8]. Based on the negative consequences of treatment resistance in SMD, significant efforts are invested in developing new pharmacological agents that could address the unmet need for better interventions starting from the very first episode of a mental disorder. However, evolution in the field of psychopharmacology should not be understood as the creation of other "me too" drugs, that can only perpetuate the illusion of a therapeutic solution, but the exploration of new pathogenic models for SMD [9][10][11].In the last decade, new generation antidepressants, i.e., esketamine, zuranolone, brexanolone, toludesvenlafaxine, gepirone, and dextromethorphan plus bupropion combo, and new generation antipsychotics, such as lumateperone, cariprazine, blonanserin, or pimavanserin, have received approvals from drug regulatory authorities (e.g., U.S. Food and Drug Administration -FDA, European Medicines Agency -EMA, the Japanese Pharmaceuticals and Medical Devices Agency-PMDA, or the Chinese National Medical Products Administration -NMPA) [12][13][14]. Some of these innovative therapies are characterized by novel mechanisms of action -such as glutamatergic modulation in the case of esketamine, or serotonin 5HT2A and 2C receptors antagonism without significant action on dopamine D2 receptors for pimavanserin-and offer new hope for addressing the persistent challenges of depressive and psychotic disorders. Beyond novel antidepressants and antipsychotics, psychedelics are being revisited as promising alternatives in treatment-resistant depression [15], heralding yet another class of agents for which post-approval monitoring of safety, identity effects, and adverse events will be essential.Despite this progress, significant gaps regarding the real-life efficacy and tolerability of these agents remain; therefore, the purpose of this topic was to gather new data on the pharmacovigilance studies regarding the new wave of antidepressants and antipsychotics (Fig. 1). Pejušković et al. presented, in a well-structured manner, the motives for using cariprazine as a treatment for varied depression symptom clusters, which is a topic with significant clinical implications from the perspective of partial or lack of responsiveness to currently available antidepressants. Cariprazine is a new-generation antipsychotic with selective action on the dopamine D3 receptors, a mechanism that deserves more attention for its potential as an add-on strategy for antidepressant therapy. The authors showed that cariprazine may be particularly beneficial for patients with MDD exhibiting anhedonia, cognitive deficits, and possibly fatigue and hypersomnia. Also, evaluating cariprazine's efficacy across these symptom domains could reveal patterns that support more personalized treatment approaches for depression.Zeng et al. published a study regarding the antidepressant effect and inflammatory profile of Sini San, a formula from the traditional Chinese medicine, composed of Radix Bupleuri, Paeoniae Radix Alba, Aurantii Fructus Immaturus, and Glycyrrhizae Radix et Rhizoma (licorice), on the treatment of chronic unpredictable mild stress (CUMS) in rats, highlighting the need to find translational models of MDD. Sini San was able to modulate the gut-brain axis by inhibition of the NLPR3 inflammasome, thus decreasing the CUMS-induced inflammation and gut microbiota dysbiosis in this preclinical model. Such an effect could be useful due to the potential significance of regulating the Brain-Derived Neurotrophic Factor (BDNF)/ Tropomyosin receptor kinase B(TrkB)/ Phosphatidylinositol 3-kinase (PI3K)/ Proteinkinase B (AKT) signaling pathway in treating depressive symptoms.Huang et al. explored the post-marketing safety of zuranolone, a neuroactive steroid that acts as a positive allosteric modulator of the gamma-amino-butyric acid (GABA) A receptors, by searching the FDA Adverse Event Reporting System (FAERS) database from the third quarter of 2023 until the second quarter of 2024. Based on an analysis of 154 reports primarily suspecting zuranolone and 426 adverse events from a total of 1,626,204 adverse event (AE) reports, zuranolone administration was associated mainly with AE in the domain of "Nervous system disorders and Psychiatric disorders". Specific AEs included in this report were somnolence, dizziness, fatigue, sedation, suicidal ideation, tremor, feeling abnormal, headache, anxiety, and nausea.Fig. 1 The need to develop new wave psychotropic drugs and pharmacovigilance studies MDD= major depressive disorder, SSD= schizophrenia spectrum disorder Antidepressants -e.g., esketamine nasal spray, i.v. brexanolone etc.Antipsychotics -e.g., pimavanserin, blonanserin, cariprazine In the pipelineglutamatergic, cholinergic, orexinergic, immune mechanisms etc. Alsfouk et al. conducted a cross-sectional study (N=220 patients) to investigate the pharmacokinetic and pharmacodynamic interactions between antipsychotics and concomitant drugs using electronic Lexicomp®, and assessed their risk rating, severity, and reliability. Antidepressants (20%), anticonvulsants (18%), and cardiovascular agents (15%) were the most frequently administered concomitant drugs, and the rate of potential drug-drug interactions was 71%. There was a "fair" level of scientific evidence in 64% of the cases and "good" in 36% of interactions. The most frequent potential adverse effects were increased sedation (36%), hyperglycemia (15%) and decreased blood pressure (14%). This study illustrates convincingly the importance of understanding the potential pharmacologic interactions between antipsychotics and concomitant drugs, and also considering the use of AI machines as helpers for this endeavour.The retrospective study of Cavanah et al. was focused on patterns in (es)citalopram, a selective serotonin reuptake inhibitor, prescriptions to Medicaid and Medicare patients in the United States (between 2015 and 2020) through the perspective of the "evergreening" effect, a phenomenon which refers to a strategy of the pharmaceutical companies for extending their patent of a drug by making minor modifications to the original product, formulation, or delivery method. A decreasing tendency for citalopram and an increasing one for escitalopram prescription rates were noted in both medical insurance databases during the researched interval. There were reported differences between generic and brand products for both substances, with generic forms being less expensive than the brand-name version. The authors showed that the noticeable decline in the use of citalopram that co-occurred with an increase in escitalopram prescribing is an argument to support the "evergreening" hypothesis.Zhang et al. authored a pharmacovigilance study that consisted of collecting data from FAERS, starting the third quarter of 2013, up to the first quarter of 2024, regarding the relevant AE associated with vortioxetine, a serotonin multimodal antidepressant. A total of 11,298 cases were analysed as "primary suspected" for vortioxetine hydrobromide, with AE for this agent involved 27 systemic organoid classes. A total of 150 significantly disproportionate preferred terms meeting all four predefined algorithms.Furutani N and Nagoshi Y showed in their case report that two patients diagnosed with somatic symptom disorder could benefit from treatment with vortioxetine, regardless of their age (one patient was aged 88, and the other 29) and specific clinical manifestations. The rapid effect of this multimodal serotonergic antidepressant was accompanied by good tolerance, highlighting its efficacy, especially in patients who had an insufficient response to serotonin reuptake inhibitors. This collection stands as an argument for the need for pharmacovigilance studies in the case of new wave antidepressants and antipsychotics that appeared in clinical use in the last decade. Large databases like FAERS are extremely useful for researchers investigating the newly reported AEs, and based on the synthesis of such reports, periodic revisions of these products' summary of characteristics are granted (Zhang et al., Huang et al.). Also, the need to investigate new pathogenetic hypotheses for MDD and SSD is a constant challenge for researchers (Zeng et al.) who want to develop new, innovative therapeutic agents, avoiding pitfalls such as the "me too" phenomenon, or "evergreening" (Cavanah et al.). New indications for the drugs in this new wave, such as vortioxetine for somatic symptom disorder, or cariprazine as an add-on for MDD, are certainly worthy of further investigations (Furutani N and Nagoshi Y, Pejušković et al.). Also, a thorough investigation of drug-drug interactions when co-prescribing antipsychotics and other pharmacological agents is a clinical necessity, if AEs, early discontinuation, lack of efficacy, or toxicity are to be avoided (Alsfouk et al.).Articles published on this topic suggest that pharmacovigilance studies in the field of MDD and SSD are strongly needed, in order to completely configure their clinical and pharmacological profile, beyond the pivotal trials required by drug regulatory agencies.