Abstract
The messenger RNA (mRNA) vaccines for COVID-19, Pfizer-BioNTech and Moderna, were authorized in the US on an emergency basis in December of 2020. The rapid distribution of these therapeutics around the country and the world led to millions of people being vaccinated in a short time span, an action that decreased hospitalization and death but also heightened the concerns about adverse effects and drug-vaccine interactions. The COVID-19 mRNA vaccines are of particular interest as they form the vanguard of a range of other mRNA therapeutics that are currently in the development pipeline, focusing both on infectious diseases as well as oncological applications. The Vaccine Adverse Event Reporting System (VAERS) has gained additional attention during the COVID-19 pandemic, specifically regarding the rollout of mRNA therapeutics. However, for VAERS, absence of a reporting platform for drug-vaccine interactions left these events poorly defined. For example, chemotherapy, anticonvulsants, and antimalarials were documented to interfere with the mRNA vaccines, but much less is known about the other drugs that could interact with these therapeutics, causing adverse events or decreased efficacy. In addition, SARS-CoV-2 exploitation of host cytochrome P450 enzymes, reported in COVID-19 critical illness, highlights viral interference with drug metabolism. For example, patients with severe psychiatric illness (SPI) in treatment with clozapine often displayed elevated drug levels, emphasizing drug-vaccine interaction.
1 Introduction
In 2021, the Centers for Disease Control and Prevention prioritized vaccination for mentally ill individuals as psychiatric illness was added to the list of COVID-19 risk factors (Mazereel et al., 2021). Currently, there are very few studies on mRNA vaccine efficacy in patients with SPI in treatment with psychotropic drugs. However, increased breakthrough infections and limited vaccine responses were reported by a recent epidemiological study on veterans with SPI, highlighting possible drug-vaccine interaction (Nishimi et al., 2022). This study is in line with earlier data, showing that, in general, patients with SPI exhibit suboptimal vaccine effectiveness, a phenomenon also documented in the geriatric population (Solomon et al., 1970; Hussar et al., 1971; Della Bella et al., 2007; Derhovanessian and Pawelec, 2012; Wang et al., 2016). Indeed, immunological similarities, but also differences, exist between the SPI patients and older individuals. For example, persons with SPI exhibit a shorter-than-average lifespan and high comorbidity with age-related diseases, implicating premature cellular senescence in this pathology (Lindqvist et al., 2015; Lee et al., 2021; Pousa et al., 2021). In addition, SPIs were associated with lower counts of regulatory T cells (Tregs) that are often reversed by the treatment with psychotropic drugs (Hwang et al., 2009; Laursen, 2011; Papanastasiou et al., 2011; Kelly et al., 2018; Solana et al., 2018; Corsi-Zuelli et al., 2021). On the other hand, unlike older individuals, SPI patients display an increased number of natural killer cell (NKC) that are unaffected by the psychotropic drugs, probably explaining the low prevalence of malignancy as well as COVID-19 critical illness in this population (Yovel et al., 2000; Bao et al., 2021; Tarantino et al., 2021). Indeed, immune malfunction may account for both limited vaccine responses and protection from COVID-19 critical illness in medicated SPI patients (Nishimi et al., 2022), (Sfera et al., 2021; Nemani et al., 2022). For example, upregulated NKCs may promptly eliminate not only virus-infected but also mRNA-transfected cells, disrupting translation at the ribosomal level as well as antibody production (Arai et al., 1983; Brieva et al., 1984; Mason et al., 1988). In addition, psychotropic drugs’ anti-inflammatory and immunosuppressant actions may protect against virus-induced “cytokine storm” but at the same time lower immune reactivity necessary for adequate vaccine responses (Gobin et al., 2014; Baumeister et al., 2016; Wei and Hui, 2022).
2 Messenger RNA vaccines
The novel mRNA COVID-19 vaccines were inspired by the similarity between extracellular vesicles (EVs) and liposomes, a characteristic exploited in the treatment of hereditary transthyretin-mediated amyloidosis, a therapy comprised of small interfering ribonucleic acids (siRNAs) embedded in LNPs (Antimisiaris et al., 2018; Urits et al., 2020). Replacing siRNA content with mRNA led to the concept of LNP therapeutics encoding for the SARS-CoV-2 spike (S) protein to elicit neutralizing antibodies against it (Manjunath et al., 2005; Suzuki and Ishihara, 2021). Compared to other methods of exogenous nucleic acid introduction into cells, such as viral vectors, LNPs are better tolerated, although their transfection efficacy is less robust (Settanni et al., 2022).
To effectively deliver the synthetic mRNA to host ribosomes, LNPs must avoid several obstacles, including hydrolysis by extracellular RNases, activation of intracellular immune sensors, and degradation by the enzymes of the endosomal lysosomal system (ELS) (Cullis and Hope, 2017) (Sahay et al., 2013; Maugeri et al., 2019). Modifying and hiding mRNAs in LNPs can overcome the first two barriers, while ionizable lipids SM-102 (Moderna) and ALC-0315 (Pfizer BioNTech) may conquer the last one (Hou et al., 2021).
The mRNA-containing LNPs are comprised of four lipids: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), PEG, an alternative cholesterol, and ionizable lipids SM-102 or ALC-0315 (Benne et al., 2018; Aldosari et al., 2021). The SM-102, ALC-0315, and the alternative cholesterol are proprietary molecules and have not been revealed up to the present time. However, interrogating siRNA platforms, it is reasonable to conclude that ionizable lipids may resemble DLin-MC3-DMA and that a phytosterol may replace the cholesterol (Tam et al., 2013; Xia et al., 2020).
LNPs enter cells by endocytosis or phagocytosis (immune cell uptake) (Birge et al., 2016) (Battistelli and Falcieri, 2020). Entry by the endocytic pathway (EP) can take place via clathrin-dependent or independent routes. Regardless of the ingress modality, LNPs travel from the early to late endosomes and can withstand an environmental pH of 5.5 or higher (Paliwal et al., 2015; Baranov et al., 2019). As exposure to the lysosomal pH of 4.5–5.0, could degrade the LNPs, endosomal-lysosomal system (ELS) exit must take place in the late endosomes (Paliwal et al., 2015). However, as late endosomes can also release their cargo via EVs, LNPs may be expulsed into the extracellular space instead of the cytosol (Gurung et al., 2021). Indeed, studies with split green fluorescence proteins (GFPs) have found that endosomal escape in general is an inefficient process as only about 2% of ELS content reaches the cytosol (Teo et al., 2021). This ratio can be increased with the help of negatively charged phospholipids, such as phosphatidylserine (PS) or analogs. For example, externalized PS (ePS) on ELS membranes generates an electrostatic imbalance between the cationic lipids and anionic phospholipids, enabling LNP to escape (Brock et al., 2019; ur Rehman et al., 2013; Wojnilowicz et al., 2019).
Taken together, the successful delivery of LNP to the host translation machinery depends on overcoming several key obstacles. A major bottleneck that must be successfully negotiated to ensure cargo delivery involves LNP lysosomal evasion as well as the premature expulsion into the extracellular compartment.
2.1 The lipid nanoparticles in the cytosol and potential drug-interactions
There is a paucity of studies discussing the fate of LNP-mRNA in the cytosol. It is generally assumed that once released from the liposome, mRNA can find its way to the ribosomes where the S antigen is translated (Wu and Li, 2021) (Figure 1). However, the modified vaccine mRNA may be perceived by the cell as defective or damaged, holding back translation by ribosomal stalling (Baker and Coller, 2006; Karamyshev and Karamysheva, 2018; Chandrasekaran et al., 2019; Kow et al., 2021; Brest et al., 2022; Deb et al., 2021). Interestingly, several psychotropic drugs, including aripiprazole, clozapine, and lithium, were demonstrated to alter ribosomal function and protein synthesis, highlighting possible interference with the vaccine mRNA (Bayraktar et al., 2021; Liu et al., 2022).
FIGURE 1
LNPs enter host cells via endocytosis or phagocytosis (immune cell endocytosis). LNP is trafficked through the ELS, traveling from early to late endosomes. Progressing from late endosome to lysosomes would risk LNP degradation by the hydrolyzing enzymes; therefore, ELS escape must take place in late endosome. However, late endosomes may expulse their cargo into the extracellular compartment via EVs (not shown). This is a major hurdle that LNPs must negotiate. Under ideal circumstances, ribosomes translate the exogenous mRNA into the S protein. For this to occur, it must be assumed that the human translation machinery does not differentiate between endogenous (nucleus-derived) and exogenous mRNA.
Single molecule tracking studies have found that cytosolic mRNA can access cellular cytoskeleton and to travel throughout the cytosol from where it can diffuse into cytoplasmic organelles, including the nucleus (Yamagishi et al., 2013) (Vargas et al., 2005) (Fusco et al., 2003) (Siwaszek et al., 2014). For example, a recent study found that upon entering the host nuclear compartment, Pfizer BioNTech mRNA could be retrotranscribed into DNA by the long interspersed nuclear element-1 (LINE-1), emphasizing vaccine-genome interactions (Zhang et al., 2021; Aldén et al., 2022). Interestingly, upregulated LINE-1, a marker of SPI, can be lowered by psychotropic drugs (via DNA methylation), likely reducing, or averting the transcription of RNA to DNA (Houtepen et al., 2016; Doyle et al., 2017) (Table 1).
TABLE 1
Psychotropic drugs compound some LNP effects, altering cell entry, endosomal release, and exit of mRNA vaccines and their responses.
EP, endosomal pathway; LNP, lipid nanoparticle; ApoE, apolipoprotein E; PEG, polyethylene glycol; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine.
In the following sections, we take a closer look at the four LNP lipids and their interaction with psychotropic drugs.
2.1.1 PEGylated lipids
PEGylated lipids extend the duration of mRNA action and facilitate LNP endocytosis, while lowering aggregation and opsonization during the circulation (Yang and Shen, 2006; Li et al., 2014). However, despite these advantages, PEGylation raises the so-called “PEG dilemma”: prolongation of both LNP uptake and ELS escape, risking vaccine-mRNA degradation by the lysosomal enzymes (Fang et al., 2017). Given that the LNP composition is proprietary, it is unknown how the mRNA-based vaccines overcome the “PEG dilemma” however, linking PEG oxygen to the head group of SM-102 or ALC-0315 is a previously documented solution (Park et al., 2021). In addition, CHARMM-GUI membrane builder (http://www.charmm-gui.org/input/membrane), an in-silico lipid simulation platform, highlights PEG oxygen bond as the likely overcomer of the “PEG dilemma” (Lee et al., 2019).
2.2 Psychotropic drugs and PEGylated lipids
Several classes of psychotropic drugs, including phenothiazines were demonstrated to inhibit the EP by binding to adaptor protein 2 (AP2), a cell membrane protein that plays a crucial role in clathrin-mediated endocytosis (CME) (Hussar et al., 1971; Inoue et al., 2007; Kovtun et al., 2020). As CME is a major LNP intake mechanism, psychotropic drugs-inhibited AP2 likely disrupt vaccine transfection (Wang et al., 1993; Chang et al., 2014). Moreover, psychotropic medications were demonstrated to accumulate in lysosomes (lysosomotropism) and increase the ELS pH, likely delaying LNP escape thus, lowering the vaccine efficacy (Daniel, 2003; Canfrán-Duque et al., 2016). Along this line, the antipsychotic drug pimozide was shown to disrupt the LNP exit from ELS, emphasizing a drug-vaccine interaction that can inactivate the mRNA vaccines (Popova et al., 2013; Meyer et al., 2021). Interestingly, PEGylated liposomes were previously shown to induce cytochrome P450, especially CYP3A1, CYP2C6, and CYP1A2, causing accelerated blood clearance (ABC), a phenomenon that reduces the efficacy of PEGylated nanocarriers, emphasizing a less discussed LNP weakness (Su et al., 2018; Liu et al., 2020).
2.2.2 1,2-distearoyl-sn-glycero-3-phosphocholine
DSPC is a non-pyrogenic, neutral phospholipid that plays a key role in cell apoptosis and immune regulation (Chaurio et al., 2009). DSPC was added to the LNP to prevent immune detection by the cytosolic sensors, including toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) (Zhang et al., 2022). DSPC plays a major role in stealthy LNP entry into the cells without alerting the host immune defenses. This is accomplished by altering the lipid asymmetry of plasma membranes, mimicking ePS, a global immunosuppressive signal (Birge et al., 2016). In addition, DSPC increases regulatory T cells (Tregs), further lowering host immune surveillance (Lin et al., 2006; Benne et al., 2020). Tregs upregulation is a double-edged sword as these lymphocytes can lower both virus-mediated inflammation (cytokine storm) and vaccine-evoked neutralizing antibodies, emphasizing that antiviral and pro-viral actions are highly intertwined (Batista-Duharte et al., 2021; Galván-Peña et al., 2021).
2.3 Potential interaction with psychotropic drugs
Psychotropic drugs may lower the robustness of vaccine responses by direct mechanisms, interaction with LNPs, or indirectly by the anti-inflammatory and anti-immunogenic properties of these agents (Baumeister et al., 2016), (Stapel et al., 2018; Lin et al., 2022). For example, the immunosuppressant properties of clozapine, haloperidol, risperidone, and antidepressant drugs are well-established, emphasizing likely interference with the vaccine-associated immunogenicity (Gobin et al., 2014) (Leykin et al., 1997; May et al., 2019; Ponsford et al., 2019). Indeed, biophysical studies show that antipsychotic drugs can insert themselves between the lipid molecules of plasma membrane, triggering anti-inflammatory responses that can impair vaccine efficacy (Jutila et al., 2001; Al-Amin et al., 2013; May et al., 2019; Pandurangi and Buckley, 2020). Moreover, leukopenia and decreased immunoglobulins, well-established properties of psychotropic drugs, may directly lower vaccine-elicited neutralizing antibodies (Ponsford et al., 2019) (Sherman et al., 1986; Goldsmith, 2002; Lozano et al., 2015). Interestingly, chlorpromazine, was found to also inhibit mRNA expression in human thymocytes, likely disrupting vaccine efficacy at the translation level (Schleuning et al., 1989) (Ficarra et al., 2016). Vaccine effectiveness can be further decreased by antipsychotic drugs-upregulated Tregs, an established defense mechanism against autoimmunity (Kelly et al., 2018) (Himmerich et al., 2010).
2.3.3 Ionizable lipids
Ionizable lipids added to the LNP, SM-102 and ALC-0315, are pH-sensitive molecules, positively charged in an acidic environment and neutral at physiological pH (Paloncýová et al., 2021). This characteristic supports protonation, an event that facilitates LNP escape from the late endosomes (Maugeri et al., 2019), (Gao and Huang, 1996; Han et al., 2021).
Ionizable lipids likely contain synthetic polyamines as amine groups accumulate in the ELS, increasing membrane permeability that in turn promotes LNP transport into the cytosol (Figure 1) (Soulet et al., 2004; Goldman et al., 2009; Jiang et al., 2020). In addition, as polyamines play a key role in mRNA translation and stability, they may be key components of SM-102/ALC-0315 lipids (Li et al., 2017). Among the polyamines, spermine has demonstrated superior cellular uptake and endosomal escape ability, suggesting that LNPs may contain this molecule (Ding et al., 2021). In addition, spermine was shown to increase vaccine efficacy by upregulating autophagy in human T cells and enhancing antigen responses (Merkley et al., 2018; Alsaleh et al., 2020).
Novel studies attributed antipsychotic properties to spermine, while its dysfunction was associated with the pathogenesis of SPI, particularly suicidal behavior (Squassina et al., 2013; Yadav et al., 2018). Moreover, as spermine plays a major role in male and female reproductive physiology, disruption of this polyamine may contribute to infertility and decreased birth rates (Lefèvre et al., 2011). Indeed, epidemiological studies from several countries have reported lower 2021 natality rates compared to the previous year, as demonstrated by Italy (−9.1%), Spain (−8.4%), Portugal (−6.6%), and New York (−19.8%) that might reflect dysfunctional polyamine signaling (Aassve et al., 2021; McLaren et al., 2021). Although it is difficult to trace the source of any potential infertility to mRNA vaccines as dysfunctional polyamines were also documented in SARS-CoV-2 infection and several psychiatric disorders, it is important to investigate these biomolecules further (Fiori and Turecki, 2008; Zhao et al., 2008; Gross and Turecki, 2013; Bourgin et al., 2021; Firpo et al., 2021).
2.4 Potential interference with psychotropic drugs
Several psychotropic drugs were shown to alter the integrity of membrane phospholipids, suggesting possible interference with the LNP ingress and ELS escape (Daniel, 2003). In addition, psychotropic drugs were demonstrated to alkalinize the ELS that in turn could disrupt the pH-dependent polyamines (Canfrán-Duque et al., 2016). Moreover, accumulating evidence suggests that polyamines, including putrescine, spermidine, and spermine, are not only involved in the pathogenesis of SPI but are also modulated by the antipsychotic drugs, suggesting possible interference with the mRNA vaccines (Squassina et al., 2013) (Fiori and Turecki, 2008). For example, spermidine, a spermine derivative, was found protective of the GABAergic and dopaminergic systems, suggesting that LNPs may interfere with this signaling (Yadav et al., 2018). This is significant as dopamine is not only involved in psychiatric disorders but is also an established fertility promoter, and dopamine agonists are frequently prescribed as part of assisted reproduction technology (ART) (Heiczman and Tóth, 1995; Tang et al., 2016).
2.4.1 Cholesterol analog
The cholesterol analog utilized in LNP is likely a phytosterol, as these molecules display high transfection capability by binding to apolipoprotein E (ApoE), followed by rapid endocytosis (Eygeris et al., 2020; Sebastiani et al., 2021). However, phytosterols have a major disadvantage as they suppress phagocytosis, probably limiting the LNP uptake in immune cells and therefore, mRNA translation (Yuan et al., 2019; Guo et al., 2022). In addition, unlike cholesterol, phytosterols cross the blood–brain barrier (BBB) and accumulate in the brain where their oxidation may precipitate the development of neurodegenerative disorders (Gamba et al., 2015; Sharma and Tan, 2021).
Several sterols, including desmosterol, were associated with both major depressive disorder and antidepressant medication, possibly accounting for the rare post-vaccination psychiatric symptoms recorded in VAERs (Cenik et al., 2017) (Balasubramanian et al., 2022; Chen et al., 2022). Moreover, cholesterol and other sterols can interact directly with dopamine transporters (DAT), possibly accounting for the post-vaccination dyskinesia noted in some patients with Parkinson’s disease (Sharma and Tan, 2021) (Jones et al., 2012; Erro et al., 2021).
2.5 Potential interference with psychotropic drugs
Several psychotropic drugs, including clozapine, olanzapine, haloperidol, and imipramine, were shown to up-regulate ApoE, a cholesterol transporter disrupted in SPI, suggesting possible interference with LNP transfection (Barroso et al., 2015; Dean et al., 2003; Digney et al., 2005; Miatmoko et al., 2021; Vik-Mo et al., 2009). As psychotropic medications upregulate the ATP-binding cassette transporter A1 (ABCA1), increasing cholesterol egress from cells, a process that may compromise vaccine efficacy by flushing LNPs into the extracellular compartment prior to mRNA release (Luquain-Costaz et al., 2020). In addition, several psychotropic drugs, including aripiprazole, haloperidol, and trazodone, were reported to increase the levels of cholesterol precursor, desmosterol, that in turn upregulates the expression of cholesterol efflux genes, likely removing LNPs from cells prematurely (Korade et al., 2017).
3 Limitations
This study has potential limitations. Firstly, it refers to a new technology within the clinical standard of care, which even though has a considerable body of literature in the scientific and preparatory phases, it is still developing the breadth of scientific observations from a clinical perspective. Secondly, it is likely that some of the potential drug-immunization interactions in the latest pandemics might be masked by the vaccine escape properties attributed to newly emerging SARS-CoV-2 variants, and as such an even more careful approach of the subject would be required to distinguish these compounding factors of lower than anticipated immune efficacy. Thirdly, it is presumed that some of the above observed interactions would have similarities in the future provision of mRNA therapeutics for non-communicable diseases, such as different cancer types. However, this remains a working hypothesis that requires further testing.
4 Discussion and conclusion
We opine that more studies are needed to assess the interaction between the major classes of psychotropic drugs, including antipsychotics, antidepressants, and mood stabilizers with the mRNA therapeutics. As the polyethylene glycol (PEG) component of lipid nanoparticles (LNPs) increases the permeability of BBB for a short interval, we anticipate that LNPs will be rapidly adopted by neuropsychiatry as vehicles for drug transport and delivery to the select CNS networks. For this reason, it is important to develop a VAERS-like system for recording the interaction of psychotropic drugs with current and future mRNA therapeutics.
Up to date, the exact LNP composition has not been released therefore, we analyze earlier data and virtual screening research, attempting to “fill-in” the blanks. For this reason, our assumptions and evidence may seem circumstantial, however, we believe, provide a foundation worth of further investigation.
LNPs are crucial for transporting exogenous mRNA to the host translational machinery where the S antigen is synthesized, eliciting neutralizing antibodies. The four LNP lipids guide the mRNA-loaded particle through the maze of extra and intracellular compartments, releasing its cargo into the cytosol. However, several bottlenecks on this journey, including ingress failure, delayed ELS escape, or premature expulsion from cells, may lower vaccine efficacy.
Treatment with psychotropic drugs may decrease the mRNA vaccine effectiveness by lowering inflammation/immunogenicity, inhibiting virus/LNP endocytosis, delaying ELS escape, or directly downregulating neutralizing antibodies.
Statements
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/WHO.
References
1
AassveA.CavalliN.MencariniL.PlachS.SandersS. (2021). Early assessment of the relationship between the COVID-19 pandemic and births in high-income countries. Proc. Natl. Acad. Sci. U. S. A.118 (36), e2105709118. 10.1073/pnas.2105709118
2
Al-AminM. M.Nasir UddinM. M.Mahmud RezaH. (2013). Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clin. Psychopharmacol. Neurosci.11 (3), 144–151. Epub 2013 Dec 24. PMID: 24465251. 10.9758/cpn.2013.11.3.144
3
AldénM.Olofsson FallaF.YangD.BarghouthM.LuanC.RasmussenM.et al (2022). Intracellular reverse transcription of pfizer BioNTech COVID-19 mRNA vaccine BNT162b2 in vitro in human liver cell line. Curr. Issues Mol. Biol.44 (3), 1115–1126. 10.3390/cimb44030073
4
AldosariB. N.AlfagihI. M.AlmurshediA. S. (2021). Lipid nanoparticles as delivery systems for RNA-based vaccines. Pharmaceutics13 (2), 206. 10.3390/pharmaceutics13020206
5
AlsalehG.PanseI.SwadlingL.ZhangH.RichterF. C.MeyerA.et al (2020). Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. Elife9, e57950. 10.7554/eLife.57950
6
AntimisiarisS. G.MourtasS.MaraziotiA. (2018). Exosomes and exosome-inspired vesicles for targeted drug delivery. Pharmaceutics10 (4), 218. 10.3390/pharmaceutics10040218
7
AraiS.YamamotoH.ItohK.KumagaiK. (1983). Suppressive effect of human natural killer cells on pokeweed mitogen-induced B cell differentiation. J. Immunol.131 (2), 651–657. PMID: 6223088.
8
BakerK. E.CollerJ. (2006). The many routes to regulating mRNA translation. Genome Biol.7 (12), 332. PMID: 17176455; PMCID: PMC1794424. 10.1186/gb-2006-7-12-332
9
BalasubramanianI.FaheemA.PadhyS. K.MenonV. (2022). Psychiatric adverse reactions to COVID-19 vaccines: A rapid review of published case reports. Asian J. Psychiatr.71, 103129. 10.1016/j.ajp.2022.103129
10
BaoC.TaoX.CuiW.HaoY.ZhengS.YiB.et al (2021). Natural killer cells associated with SARS-CoV-2 viral RNA shedding, antibody response and mortality in COVID-19 patients. Exp. Hematol. Oncol.10, 5. 10.1186/s40164-021-00199-1
11
BaranovM. V.OleaR. A.van den BogaartG. (2019). Chasing uptake: Super-resolution microscopy in endocytosis and phagocytosis. Trends Cell Biol.29 (9), 727–739. 10.1016/j.tcb.2019.05.006
12
BarrosoR. P.BassoL. G.Costa-FilhoA. J. (2015). Interactions of the antimalarial amodiaquine with lipid model membranes. Chem. Phys. Lipids186, 68–78. 10.1016/j.chemphyslip.2014.12.003
13
Batista-DuharteA.PeraA.AliñoS. F.SolanaR. (2021). Regulatory T cells and vaccine effectiveness in older adults. Challenges and prospects. Int. Immunopharmacol.96, 107761. 10.1016/j.intimp.2021.107761
14
BattistelliM.FalcieriE. (2020). Apoptotic bodies: Particular extracellular vesicles involved in intercellular communication. Biol. (Basel)9 (1), 21. 10.3390/biology9010021
15
BaumeisterD.CiufoliniS.MondelliV. (2016). Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?Psychopharmacol. Berl.233 (9), 1575–1589. 10.1007/s00213-015-4044-5
16
Bayraktarİ.YalçınN.DemirkanK. (2021). The potential interaction between COVID-19 vaccines and clozapine: A novel approach for clinical trials. Int. J. Clin. Pract.75 (8), e14441. PMID: 34289643; PMCID: PMC8420459. 10.1111/ijcp.14441
17
BenneN.LebouxR. J. T.GlandrupM.van DuijnJ.Lozano VigarioF.NeustrupM. A.et al (2020). Atomic force microscopy measurements of anionic liposomes reveal the effect of liposomal rigidity on antigen-specific regulatory T cell responses. J. Control. Release318, 246–255. 10.1016/j.jconrel.2019.12.003
18
BenneN.van DuijnJ.Lozano VigarioF.LebouxR. J. T.van VeelenP.KuiperJ.et al (2018). Anionic 1, 2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG) liposomes induce antigen-specific regulatory T cells and prevent atherosclerosis in mice. J. Control. Release291, 135–146. 10.1016/j.jconrel.2018.10.028
19
BirgeR. B.BoeltzS.KumarS.CarlsonJ.WanderleyJ.CalianeseD.et al (2016). Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ.23 (6), 962–978. 10.1038/cdd.2016.11
20
BourginM.DerosaL.SilvaC. A. C.GoubetA. G.DubuissonA.DanlosF. X.et al (2021). Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients. Aging (Albany NY)13 (17), 20860–20885. 10.18632/aging.203525
21
BrestP.MograbiB.HofmanP.MilanoG. (2022). COVID-19 vaccination and cancer immunotherapy: should they stick together?Br. J. Cancer126 (1), 1–3. 10.1038/s41416-021-01618-0
22
BrievaJ. A.TarganS.StevensR. H. (1984). NK and T cell subsets regulate antibody production by human in vivo antigen-induced lymphoblastoid B cells. J. Immunol.132 (2), 611–615. PMID: 6228592.
23
BrockD. J.Kondow-McConaghyH. M.HagerE. C.PelloisJ. P. (2019). Endosomal escape and cytosolic penetration of macromolecules mediated by synthetic delivery agents. Bioconjug. Chem.30 (2), 293–304. 10.1021/acs.bioconjchem.8b00799
24
Canfrán-DuqueA.BarrioL. C.LermaM.de la PeñaG.SernaJ.PastorO.et al (2016). First-Generation antipsychotic haloperidol alters the functionality of the late endosomal/lysosomal compartment in vitro. Int. J. Mol. Sci.17 (3), 404. 10.3390/ijms17030404
25
CenikB.CenikC.SnyderM. P.BrownE. S. (2017). Plasma sterols and depressive symptom severity in a population-based cohort. PLoS One12 (9), e0184382. 10.1371/journal.pone.0184382
26
ChandrasekaranV.JuszkiewiczS.ChoiJ.PuglisiJ. D.BrownA.ShaoS.et al (2019). Mechanism of ribosome stalling during translation of a poly(A) tail. Nat. Struct. Mol. Biol.26 (12), 1132–1140. 10.1038/s41594-019-0331-x
27
ChangC. C.WuM.YuanF. (2014). Role of specific endocytic pathways in electrotransfection of cells. Mol. Ther. Methods Clin. Dev.1, 14058. 10.1038/mtm.2014.58
28
ChaurioR. A.JankoC.MuñozL. E.FreyB.HerrmannM.GaiplU. S. (2009). Phospholipids: key players in apoptosis and immune regulation. Molecules14 (12), 4892–4914. 10.3390/molecules14124892
29
ChenS.AruldassA. R.CardinalR. N. (2022). Mental health outcomes after SARS-CoV-2 vaccination in the United States: A national cross-sectional study. J. Affect. Disord.298, 396–399. 10.1016/j.jad.2021.10.134
30
Corsi-ZuelliF.DeakinB.de LimaM. H. F.QureshiO.BarnesN. M.UpthegroveR.et al (2021). T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives. Brain Behav. Immun. Health17, 100330. 10.1016/j.bbih.2021.100330
31
CullisP. R.HopeM. J. (2017). Lipid nanoparticle systems for enabling gene therapies. Mol. Ther.25 (7), 1467–1475. 10.1016/j.ymthe.2017.03.013
32
DanielW. A. (2003). Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions. Prog. Neuropsychopharmacol. Biol. Psychiatry27 (1), 65–73. PMID: 12551728. 10.1016/s0278-5846(02)00317-2
33
DeanB.LawsS. M.HoneE.TaddeiK.ScarrE.ThomasE. A.et al (2003). Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia. Biol. Psychiatry54 (6), 616–622. 10.1016/s0006-3223(03)00075-1
34
DebS.ArrighiS. (2021). Potential effects of COVID-19 on cytochrome P450-mediated drug metabolism and disposition in infected patients. Eur. J. Drug Metab. Pharmacokinet.46 (2), 185–203. 10.1007/s13318-020-00668-8
35
Della BellaS.BiertiL.PresicceP.ArientiR.ValentiM.SaresellaM.et al (2007). Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin. Immunol.122 (2), 220–228. 10.1016/j.clim.2006.09.012
36
DerhovanessianE.PawelecG. (2012). Vaccination in the elderly. Microb. Biotechnol.5 (2), 226–232. 10.1111/j.1751-7915.2011.00283.x
37
DigneyA.KeriakousD.ScarrE.ThomasE.DeanB. (2005). Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. Biol. Psychiatry57 (7), 711–715. 10.1016/j.biopsych.2004.12.028
38
DingF.ZhangH.CuiJ.LiQ.YangC. (2021). Boosting ionizable lipid nanoparticle-mediated in vivo mRNA delivery through optimization of lipid amine-head groups. Biomater. Sci.9 (22), 7534–7546. 10.1039/d1bm00866h
39
DoyleG. A.CristR. C.KaratasE. T.HammondM. J.EwingA. D.FerraroT. N.et al (2017). Analysis of LINE-1 elements in DNA from postmortem brains of individuals with schizophrenia. Neuropsychopharmacology42 (13), 2602–2611. 10.1038/npp.2017.115
40
ErroR.BuonomoA. R.BaroneP.PellecchiaM. T. (2021). Severe dyskinesia after administration of SARS-CoV2 mRNA vaccine in Parkinson's disease. Mov. Disord.36 (10), 2219. 10.1002/mds.28772
41
EygerisY.PatelS.JozicA.SahayG. (2020). Deconvoluting lipid nanoparticle structure for messenger RNA delivery. Nano Lett.20 (6), 4543–4549. 10.1021/acs.nanolett.0c01386
42
FangY.XueJ.GaoS.LuA.YangD.JiangH.et al (2017). Cleavable PEGylation: a strategy for overcoming the "PEG dilemma" in efficient drug delivery. Drug Deliv.24, 22–32. 10.1080/10717544.2017.1388451
43
FicarraS.RussoA.BarrecaD.GiuntaE.GaltieriA.TelloneE. (2016). Short-Term effects of chlorpromazine on oxidative stress in erythrocyte functionality: Activation of metabolism and membrane perturbation. Oxid. Med. Cell. Longev.2016, 2394130. 10.1155/2016/2394130
44
FioriL. M.TureckiG. (2008). Implication of the polyamine system in mental disorders. J. Psychiatry Neurosci.33 (2), 102–110. PMID: 18330456; PMCID: PMC2265312.
45
FirpoM. R.MastrodomenicoV.HawkinsG. M.ProtM.LevillayerL.GallagherT.et al (2021). Targeting polyamines inhibits coronavirus infection by reducing cellular attachment and entry. ACS Infect. Dis.7 (6), 1423–1432. 10.1021/acsinfecdis.0c00491
46
FuscoD.AccorneroN.LavoieB.ShenoyS. M.BlanchardJ. M.SingerR. H.et al (2003). Single mRNA molecules demonstrate probabilistic movement in living mammalian cells. Curr. Biol.13 (2), 161–167. 10.1016/s0960-9822(02)01436-7
47
Galván-PeñaS.LeonJ.ChowdharyK.MichelsonD. A.VijaykumarB.YangL.et al (2021). Profound Treg perturbations correlate with COVID-19 severity. Proc. Natl. Acad. Sci. U. S. A.118 (37), e2111315118. 10.1073/pnas.2111315118
48
GambaP.TestaG.GargiuloS.StaurenghiE.PoliG.LeonarduzziG. (2015). Oxidized cholesterol as the driving force behind the development of Alzheimer's disease. Front. Aging Neurosci.7, 119. 10.3389/fnagi.2015.00119
49
GaoX.HuangL. (1996). Potentiation of cationic liposome-mediated gene delivery by polycations. Biochemistry35 (3), 1027–1036. 10.1021/bi952436a
50
GobinV.Van SteendamK.DenysD.DeforceD. (2014). Selective serotonin reuptake inhibitors as a novel class of immunosuppressants. Int. Immunopharmacol.20 (1), 148–156. 10.1016/j.intimp.2014.02.030
51
GoldmanS. D.FunkR. S.RajewskiR. A.KriseJ. P. (2009). Mechanisms of amine accumulation in, and egress from, lysosomes. Bioanalysis1 (8), 1445–1459. 10.4155/bio.09.128
52
GoldsmithS. K. (2002). Haloperidol reduces IgG immunoreactivity in the rat brain. Int. J. Neuropsychopharmacol.5 (4), 309–313. 10.1017/s146114570200305x
53
GrossJ. A.TureckiG. (2013). Suicide and the polyamine system. CNS Neurol. Disord. Drug Targets12 (7), 980–988. 10.2174/18715273113129990095
54
GuoS. J.MaC. G.HuY. Y.BaiG.SongZ. J.CaoX. Q. (2022). Solid lipid nanoparticles for phytosterols delivery: The acyl chain number of the glyceride matrix affects the arrangement, stability, and release. Food Chem.394, 133412. 10.1016/j.foodchem.2022.133412
55
GurungS.PerocheauD.TouramanidouL.BaruteauJ. (2021). The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun. Signal.19, 47. 10.1186/s12964-021-00730-1
56
HanX.ZhangH.ButowskaK.SwingleK. L.AlamehM. G.WeissmanD.et al (2021). An ionizable lipid toolbox for RNA delivery. Nat. Commun.12, 7233. 10.1038/s41467-021-27493-0
57
HeiczmanA.TóthM. (1995). Effect of chlorpromazine on the synthesis of neutral lipids and phospholipids from [3H]glycerol in the primordial human placenta. Placenta16 (4), 347–358. 10.1016/0143-4004(95)90092-6
58
HimmerichH.MilenovićS.FuldaS.PlümäkersB.SheldrickA. J.MichelT. M.et al (2010). Regulatory T cells increased while IL-1β decreased during antidepressant therapy. J. Psychiatr. Res.44 (15), 1052–1057. 10.1016/j.jpsychires.2010.03.005
59
HouX.ZaksT.LangerR.DongY. (2021). Lipid nanoparticles for mRNA delivery. Nat. Rev. Mat.6, 1078–1094. 10.1038/s41578-021-00358-0
60
HoutepenL. C.van BergenA. H.VinkersC. H.BoksM. P. (2016). DNA methylation signatures of mood stabilizers and antipsychotics in bipolar disorder. Epigenomics8 (2), 197–208. 10.2217/epi.15.98
61
HussarA. E.CradleJ. L.BeiserS. M. (1971). A study of the immunologic and allergic responsiveness of chronic schizophrenics. Br. J. Psychiatry118 (542), 91–92. 10.1192/bjp.118.542.91
62
HwangK. A.KimH. R.KangI. (2009). Aging and human CD4(+) regulatory T cells. Mech. Ageing Dev.130 (8), 509–517. 10.1016/j.mad.2009.06.003
63
InoueY.TanakaN.TanakaY.InoueS.MoritaK.ZhuangM.et al (2007). Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J. Virol.81 (16), 8722–8729. 10.1128/JVI.00253-07
64
JiangY.LuQ.WangY.XuE.HoA.SinghP.et al (2020). Quantitating endosomal escape of a library of polymers for mRNA delivery. Nano Lett.20 (2), 1117–1123. 10.1021/acs.nanolett.9b04426
65
JonesK. T.ZhenJ.ReithM. E. (2012). Importance of cholesterol in dopamine transporter function. J. Neurochem.123 (5), 700–715. 10.1111/jnc.12007
66
JutilaA.SöderlundT.PakkanenA. L.HuttunenM.KinnunenP. K. (2001). Comparison of the effects of clozapine, chlorpromazine, and haloperidol on membrane lateral heterogeneity. Chem. Phys. Lipids112 (2), 151–163. 10.1016/s0009-3084(01)00175-x
67
KaramyshevA. L.KaramyshevaZ. N. (2018). Lost in translation: Ribosome-associated mRNA and protein quality controls. Front. Genet.9, 431. 10.3389/fgene.2018.00431
68
KellyD. L.LiX.KildayC.FeldmanS.ClarkS.LiuF.et al (2018). Increased circulating regulatory T cells in medicated people with schizophrenia. Psychiatry Res.269, 517–523. 10.1016/j.psychres.2018.09.006
69
KoradeŽ.LiuW.WarrenE. B.ArmstrongK.PorterN. A.KonradiC. (2017). Effect of psychotropic drug treatment on sterol metabolism. Schizophr. Res.187, 74–81. Epub 2017 Feb 12. PMID: 28202290; PMCID: PMC555446. 10.1016/j.schres.2017.02.001
70
KovtunO.DicksonV. K.KellyB. T.OwenD. J.BriggsJ. A. G. (2020). Architecture of the AP2/clathrin coat on the membranes of clathrin-coated vesicles. Sci. Adv.6 (30), eaba8381. 10.1126/sciadv.aba8381
71
KowC. S.HasanS. S. (2021). Potential interactions between COVID-19 vaccines and antiepileptic drugs. Seizure86, 80–81. 10.1016/j.seizure.2021.01.021
72
LaursenT. M. (2011). Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophr. Res.131 (1-3), 101–104. 10.1016/j.schres.2011.06.008
73
LeeJ.PatelD. S.StåhleJ.ParkS. J.KernN. R.KimS..et al (2019). CHARMM-GUI membrane builder for complex biological membrane simulations with glycolipids and lipoglycans. J. Chem. Theory Comput.15 (1), 775–786. 10.1021/acs.jctc.8b01066
74
LeeS.YuY.TrimpertJ.BenthaniF.MairhoferM.Richter-PechanskaP..et al (2021). Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature599 (7884), 283–289. 10.1038/s41586-021-03995-1
75
LefèvreP. L.PalinM. F.MurphyB. D. (2011). Polyamines on the reproductive landscape. Endocr. Rev.32 (5), 694–712. Epub 2011 Jul 26. PMID: 21791568. 10.1210/er.2011-0012
76
LeykinI.MayerR.ShinitzkyM. (1997). Short and long-term immunosuppressive effects of clozapine and haloperidol. Immunopharmacology37 (1), 75–86. 10.1016/s0162-3109(97)00037-4
77
LiJ.HeY.WangW.WuC.HongC.HammondP. T. (2017). Polyamine-mediated stoichiometric assembly of ribonucleoproteins for enhanced mRNA delivery. Angew. Chem. Int. Ed. Engl.56 (44), 13709–13712. 10.1002/anie.201707466
78
LiY.KrögerM.LiuW. K. (2014). Endocytosis of PEGylated nanoparticles accompanied by structural and free energy changes of the grafted polyethylene glycol. Biomaterials35 (30), 8467–8478. 10.1016/j.biomaterials.2014.06.032
79
LinD. Y.GuY.WheelerB.YoungH.HollowayS.SunnyS. K.et al (2022). Effectiveness of covid-19 vaccines over a 9-month period in North Carolina. N. Engl. J. Med.386 (10), 933–941. 10.1056/NEJMoa2117128
80
LinW. C.BlanchetteC. D.RattoT. V.LongoM. L. (2006). Lipid asymmetry in DLPC/DSPC-supported lipid bilayers: a combined AFM and fluorescence microscopy study. Biophys. J.90 (1), 228–237. 10.1529/biophysj.105.067066
81
LindqvistD.EpelE. S.MellonS. H.PenninxB. W.RévészD.VerhoevenJ. E.et al (2015). Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging. Neurosci. Biobehav. Rev.55, 333–364. 10.1016/j.neubiorev.2015.05.007
82
LiuM.ChuY.LiuH.SuY.ZhangQ.JiaoJ.et al (2020). Accelerated blood clearance of nanoemulsions modified with PEG-cholesterol and PEG-phospholipid derivatives in rats: The effect of PEG-lipid linkages and PEG molecular weights. Mol. Pharm.17 (4), 1059–1070. 10.1021/acs.molpharmaceut.9b00770
83
LiuZ. S. J.TruongT. T. T.BortolasciC. C.SpoldingB.PanizzuttiB.SwintonC.et al (2022). Effects of psychotropic drugs on ribosomal genes and protein synthesis. Int. J. Mol. Sci.23 (13), 7180. 10.3390/ijms23137180
84
LozanoR.MarinR.SantacruzM. J.PascualA. (2015). Selective immunoglobulin M deficiency among clozapine-treated patients: A nested case-control study. Prim. Care Companion CNS Disord.17 (4). 10.4088/PCC.15m01782
85
Luquain-CostazC.KockxM.AnastasiusM.ChowV.KontushA.JessupW.et al (2020). Increased ABCA1 (ATP-Binding cassette transporter a1)-specific cholesterol efflux capacity in schizophrenia. Arterioscler. Thromb. Vasc. Biol.40 (11), 2728–2737. 10.1161/ATVBAHA.120.314847
86
ManjunathK.ReddyJ. S.VenkateswarluV. (2005). Solid lipid nanoparticles as drug delivery systems. Methods Find. Exp. Clin. Pharmacol.27 (2), 127–144. 10.1358/mf.2005.27.2.876286
87
MasonP. D.WeetmanA. P.SissonsJ. G.BorysiewiczL. K. (1988). Suppressive role of NK cells in pokeweed mitogen-induced immunoglobulin synthesis: effect of depletion/enrichment of leu 11b+ cells. Immunology65 (1), 113–118. PMID: 3053423; PMCID: PMC1385028.
88
MaugeriM.NawazM.PapadimitriouA.AngerforsA.CamponeschiA.NaM.et al (2019). Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells. Nat. Commun.10, 4333. 10.1038/s41467-019-12275-6
89
MayM.BeaucheminM.VaryC.BarlowD.HouseknechtK. L. (2019). The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice. PLoS One14 (6), e0218937. 10.1371/journal.pone.0218937
90
MazereelV.Van AsscheK.DetrauxJ.De HertM. (2021). COVID-19 vaccination for people with severe mental illness: why, what, and how?Lancet Psychiatry8 (5), 444–450. 10.1016/S2215-0366(20)30564-2
91
McLarenR. A.JrTrejoF. E.BlitzM. J.BiancoA.LimayeM.BrustmanL.et al (2021). COVID-related "lockdowns" and birth rates in New York. Am. J. Obstet. Gynecol. MFM3 (6), 100476. 10.1016/j.ajogmf.2021.100476
92
MerkleyS. D.ChockC. J.YangX. O.HarrisJ.CastilloE. F. (2018). Modulating T cell responses via autophagy: The intrinsic influence controlling the function of both antigen-presenting cells and T cells. Front. Immunol.9, 2914. 10.3389/fimmu.2018.02914
93
MeyerN.HenkelL.LinderB.ZielkeS.TascherG.TrautmannS.et al (2021). Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death. Autophagy17 (11), 3424–3443. 10.1080/15548627.2021.1874208
94
MiatmokoA.NurjannahI.NehruN. F.RositaN.HendradiE.SariR.et al (2021). Interactions of primaquine and chloroquine with PEGylated phosphatidylcholine liposomes. Sci. Rep.11 (1), 12420. 10.1038/s41598-021-91866-0
95
NemaniK.WilliamsS. Z.OlfsonM.Leckman-WestinE.FinnertyM.KammerJ.et al (2022). Association between the use of psychotropic medications and the risk of COVID-19 infection among long-term inpatients with serious mental illness in a New York state-wide psychiatric hospital system. JAMA Netw. Open5 (5), e2210743. 10.1001/jamanetworkopen.2022.10743
96
NishimiK.NeylanT. C.BertenthalD.SealK. H.O'DonovanA. (2022). Association of psychiatric disorders with incidence of SARS-CoV-2 breakthrough infection among vaccinated adults. JAMA Netw. Open5 (4), e227287. 10.1001/jamanetworkopen.2022.7287
97
PaliwalS. R.PaliwalR.VyasS. P. (2015). A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery. Drug Deliv.22 (3), 231–242. 10.3109/10717544.2014.882469
98
PaloncýováM.ČechováP.ŠrejberM.KührováP.OtyepkaM. (2021). Role of ionizable lipids in SARS-CoV-2 vaccines as revealed by molecular dynamics simulations: From membrane structure to interaction with mRNA fragments. J. Phys. Chem. Lett.12 (45), 11199–11205. 10.1021/acs.jpclett.1c03109
99
PandurangiA. K.BuckleyP. F. (2020). Inflammation, antipsychotic drugs, and evidence for effectiveness of anti-inflammatory agents in schizophrenia. Curr. Top. Behav. Neurosci.44, 227–244. 10.1007/7854_2019_91
100
PapanastasiouE.GaughranF.SmithS. (2011). Schizophrenia as segmental progeria. J. R. Soc. Med.104 (11), 475–484. 10.1258/jrsm.2011.110051
101
ParkS.ChoiY. K.KimS.LeeJ.ImW. (2021). CHARMM-GUI membrane builder for lipid nanoparticles with ionizable cationic lipids and PEGylated lipids. J. Chem. Inf. Model.61 (10), 5192–5202. 10.1021/acs.jcim.1c00770
102
PonsfordM. J.PecoraroA.JollesS. (2019). Clozapine-associated secondary antibody deficiency. Curr. Opin. Allergy Clin. Immunol.19 (6), 553–562. PMID: 31567398. 10.1097/ACI.0000000000000592
103
PopovaN. V.DeyevI. E.PetrenkoA. G. (2013). Clathrin-mediated endocytosis and adaptor proteins. Acta Naturae5, 62–73. 10.32607/20758251-2013-5-3-62-73
104
PousaP.SouzaR.MeloP.CorreaB.MendonçaT.Simões-E-SilvaA.et al (2021). Telomere shortening and psychiatric disorders: A systematic review. Cells10, 1423. 10.3390/cells10061423
105
SahayG.QuerbesW.AlabiC.EltoukhyA.SarkarS.ZurenkoC.et al (2013). Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol.31 (7), 653–658. 10.1038/nbt.2614
106
SchleuningM. J.DugganA.ReemG. H. (1989). Inhibition by chlorpromazine of lymphokine-specific mRNA expression in human thymocytes. Eur. J. Immunol.19 (8), 1491–1495. 10.1002/eji.1830190822
107
SebastianiF.Yanez ArtetaM.LercheM.PorcarL.LangC.BraggR. A.et al (2021). Apolipoprotein E binding drives structural and compositional rearrangement of mRNA-containing lipid nanoparticles. ACS Nano15 (4), 6709–6722. 10.1021/acsnano.0c10064
108
SettanniG.BrillW.HaasH.SchmidF. (2022). pH-dependent behavior of ionizable cationic lipids in mRNA-carrying lipoplexes investigated by molecular dynamics simulations. Macromol. Rapid Commun.43 (12), e2100683. 10.1002/marc.202100683
109
SferaA.OsorioC.AfzaalJ.Del CampoZ-M.KozlakidisZ. “COVID-19: A catalyst for novel psychiatric paradigms may 2021,” in In book: Biotechnology to combat COVID-19 (London: Intechopen). 202110.5772/intechopen.96940
110
SharmaN.TanM. A. (2021). An SSA. Phytosterols: Potential metabolic modulators in neurodegenerative diseases. Int. J. Mol. Sci.22 (22), 12255. 10.3390/ijms222212255
111
ShermanM. A.LinthicumD. S.BolgerM. B. (1986). Haloperidol binding to monoclonal antibodies: conformational analysis and relationships to D-2 receptor binding. Mol. Pharmacol.29 (6), 589–598. PMID: 2423865.
112
SiwaszekA.UklejaM.DziembowskiA. (2014). Proteins involved in the degradation of cytoplasmic mRNA in the major eukaryotic model systems. RNA Biol.11 (9), 1122–1136. PMID: 25483043; PMCID: PMC4615280. 10.4161/rna.34406
113
SolanaC.PereiraD.TarazonaR. (2018). Early senescence and leukocyte telomere shortening in SCHIZOPHRENIA: A role for cytomegalovirus infection?Brain Sci.8 (10), 188. 10.3390/brainsci8100188
114
SolomonG. F.RubboS. D.BatchelderE. (1970). Secondary immune response to tetanus toxoid in psychiatric patients. J. Psychiatr. Res.7 (3), 201–207. 10.1016/0022-3956(70)90007-5
115
SouletD.GagnonB.RivestS.AudetteM.PoulinR. (2004). A fluorescent probe of polyamine transport accumulates into intracellular acidic vesicles via a two-step mechanism. J. Biol. Chem.279 (47), 49355–49366. 10.1074/jbc.M401287200
116
SquassinaA.ManchiaM.ChillottiC.DeianaV.CongiuD.ParibelloF.et al (2013). Differential effect of lithium on spermidine/spermine N1-acetyltransferase expression in suicidal behaviour. Int. J. Neuropsychopharmacol.16 (10), 2209–2218. 10.1017/S1461145713000655
117
StapelB.SieveI.FalkC. S.BleichS.Hilfiker-KleinerD.KahlK. G. (2018). Second generation atypical antipsychotics olanzapine and aripiprazole reduce expression and secretion of inflammatory cytokines in human immune cells. J. Psychiatr. Res.105, 95–102. 10.1016/j.jpsychires.2018.08.017
118
SuY.LiuM.LiangK.LiuX.SongY.DengY. (2018). Evaluating the accelerated blood clearance phenomenon of PEGylated nanoemulsions in rats by intraperitoneal administration. AAPS PharmSciTech19 (7), 3210–3218. 10.1208/s12249-018-1120-2
119
SuzukiY.IshiharaH. (2021). Difference in the lipid nanoparticle technology employed in three approved siRNA (Patisiran) and mRNA (COVID-19 vaccine) drugs. Drug Metab. Pharmacokinet.41, 100424. 10.1016/j.dmpk.2021.100424
120
TamY. Y.ChenS.CullisP. R. (2013). Advances in lipid nanoparticles for siRNA delivery. Pharmaceutics5 (3), 498–507. 10.3390/pharmaceutics5030498
121
TangH.MouradS.ZhaiS. D.HartR. J. (2016). Dopamine agonists for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst. Rev.11 (11), CD008605. 10.1002/14651858.CD008605.pub3
122
TarantinoN.LeboyerM.BouleauA.HamdaniN.RichardJ. R.BoukouaciW..et al (2021). Natural killer cells in first-episode psychosis: an innate immune signature?Mol. Psychiatry26 (9), 5297–5306. 10.1038/s41380-020-01008-7
123
TeoS. L. Y.RennickJ. J.YuenD.Al-WassitiH.JohnstonA. P. R.PoutonC. W. (2021). Unravelling cytosolic delivery of cell penetrating peptides with a quantitative endosomal escape assay. Nat. Commun.12, 3721. 10.1038/s41467-021-23997-x
124
ur RehmanZ.HoekstraD.ZuhornI. S. (2013). Mechanism of polyplex- and lipoplex-mediated delivery of nucleic acids: real-time visualization of transient membrane destabilization without endosomal lysis. ACS Nano7 (5), 3767–3777. 10.1021/nn3049494
125
UritsI.SwansonD.SwettM. C.PatelA.BerardinoK.AmgalanA.et al (2020). A review of patisiran (ONPATTRO®) for the treatment of polyneuropathy in people with hereditary transthyretin amyloidosis. Neurol. Ther.9 (2), 301–315. 10.1007/s40120-020-00208-1
126
VargasD. Y.RajA.MarrasS. A.KramerF. R.TyagiS. (2005). Mechanism of mRNA transport in the nucleus. Proc. Natl. Acad. Sci. U. S. A.102 (47), 17008–17013. 10.1073/pnas.0505580102
127
Vik-MoA. O.FernøJ.SkredeS.SteenV. M. (2009). Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells. BMC Pharmacol.9, 10. 10.1186/1471-2210-9-10
128
WangL. H.RothbergK. G.AndersonR. G. (1993). Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J. Cell Biol.123, 1107–1117. 10.1083/jcb.123.5.1107
129
WangY.YuL.ZhouH.ZhouZ.ZhuH.LiY.et al (2016). Serologic and molecular characteristics of hepatitis B virus infection in vaccinated schizophrenia patients in China. J. Infect. Dev. Ctries.10 (4), 427–431. 10.3855/jidc.7377
130
WeiJiaoHuiAi-Min (2022). The paradigm shift in treatment from Covid-19 to oncology with mRNA vaccines. Cancer Treat. Rev.107, 102405. 10.1016/j.ctrv.2022.102405
131
WojnilowiczM.GlabA.BertucciA.CarusoF.CavalieriF. (2019). Super-resolution imaging of proton sponge-triggered rupture of endosomes and cytosolic release of small interfering RNA. ACS Nano13 (1), 187–202. 10.1021/acsnano.8b05151
132
WuZ.LiT. (2021). Nanoparticle-mediated cytoplasmic delivery of messenger RNA vaccines: Challenges and future perspectives. Pharm. Res.38 (3), 473–478. 10.1007/s11095-021-03015-x
133
XiaY.MihaiC.GriffithJ. P.HouS.EspositoA. A.KetovaT.et al (2020). Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA. Nat. Commun.11 (1), 983. 10.1038/s41467-020-14527-2
134
YadavM.ParleM.JindalD. K.SharmaN. (2018). Potential effect of spermidine on GABA, dopamine, acetylcholinesterase, oxidative stress and proinflammatory cytokines to diminish ketamine-induced psychotic symptoms in rats. Biomed. Pharmacother.98, 207–213. 10.1016/j.biopha.2017.12.016
135
YamagishiM.ShirasakiY.FunatsuT. (2013). Single-molecule tracking of mRNA in living cells. Methods Mol. Biol.950, 153–167. PMID: 23086875. 10.1007/978-1-62703-137-0_10
136
YangJ.ShenM. H. (2006). Polyethylene glycol-mediated cell fusion. Methods Mol. Biol.325, 59–66. PMID: 16761719. 10.1385/1-59745-005-7:59
137
YovelG.SirotaP.MazehD.ShakharG.RosenneE.Ben-EliyahuS. (2000). Higher natural killer cell activity in schizophrenic patients: the impact of serum factors, medication, and smoking. Brain Behav. Immun.14 (3), 153–169. 10.1006/brbi.1999.0574
138
YuanL.ZhangF.ShenM.JiaS.XieJ. (2019). Phytosterols suppress phagocytosis and inhibit inflammatory mediators via ERK pathway on LPS-triggered inflammatory responses in RAW264.7 macrophages and the correlation with their structure. Foods8 (11), 582. 10.3390/foods8110582
139
ZhangH.HanX.AlamehM. G.ShepherdS. J.PadillaM. S.XueL.et al (2022). Rational design of anti-inflammatory lipid nanoparticles for mRNA delivery. J. Biomed. Mat. Res. A110 (5), 1101–1108. 10.1002/jbm.a.37356
140
ZhangL.RichardsA.BarrasaM. I.HughesS. H.YoungR. A.JaenischR. (2021). Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues. Proc. Natl. Acad. Sci. U. S. A.118 (21), e2105968118. 10.1073/pnas.2105968118
141
ZhaoY. C.ChiY. J.YuY. S.LiuJ. L.SuR. W.MaX. H.et al (2008). Polyamines are essential in embryo implantation: expression and function of polyamine-related genes in mouse uterus during peri-implantation period. Endocrinology149 (5), 2325–2332. 10.1210/en.2007-1420
Summary
Keywords
LNP, psychotropic drugs, cell-cell fusion, PEGylated lipids, DSPC, ionizable lipids, cholesterol analogs
Citation
Sfera A, Hazan S, Anton JJ, Sfera DO, Andronescu CV, Sasannia S, Rahman L and Kozlakidis Z (2022) Psychotropic drugs interaction with the lipid nanoparticle of COVID-19 mRNA therapeutics. Front. Pharmacol. 13:995481. doi: 10.3389/fphar.2022.995481
Received
19 July 2022
Accepted
09 August 2022
Published
09 September 2022
Volume
13 - 2022
Edited by
Simona Pichini, National Institute of Health (ISS), Italy
Reviewed by
Maria Rosaria Varì, National Institute of Health (ISS), Italy
Annagiulia Di Trana, Marche Polytechnic University, Italy
Updates
Copyright
© 2022 Sfera, Hazan, Anton, Sfera, Andronescu, Sasannia, Rahman and Kozlakidis.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Adonis Sfera, dr.sfera@gmail.com
This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology
Disclaimer
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