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Sfera, A. Non-Dopaminergic Antipsychotic Mechanisms of Neuroleptic Drugs. Encyclopedia. Available online: https://encyclopedia.pub/entry/53892 (accessed on 30 June 2024).
Sfera A. Non-Dopaminergic Antipsychotic Mechanisms of Neuroleptic Drugs. Encyclopedia. Available at: https://encyclopedia.pub/entry/53892. Accessed June 30, 2024.
Sfera, Adonis. "Non-Dopaminergic Antipsychotic Mechanisms of Neuroleptic Drugs" Encyclopedia, https://encyclopedia.pub/entry/53892 (accessed June 30, 2024).
Sfera, A. (2024, January 16). Non-Dopaminergic Antipsychotic Mechanisms of Neuroleptic Drugs. In Encyclopedia. https://encyclopedia.pub/entry/53892
Sfera, Adonis. "Non-Dopaminergic Antipsychotic Mechanisms of Neuroleptic Drugs." Encyclopedia. Web. 16 January, 2024.
Non-Dopaminergic Antipsychotic Mechanisms of Neuroleptic Drugs
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This entry is adapted from the peer-reviewed paper 10.3390/reports6030036

In 1957, Arvid Carlsson discovered that dopamine, at the time believed to be nothing more than a norepinephrine precursor, was a brain neurotransmitter in and of itself. By 1963, postsynaptic dopamine blockade had become the cornerstone of psychiatric treatment as it appeared to have deciphered the “chlorpromazine enigma”, a 1950s term, denoting the action mechanism of antipsychotic drugs.

microbial translocation antipsychotic drugs autophagy

1. Introduction

The dopamine hypothesis (DH) of schizophrenia (SCZ), launched by Carlsson and Lindqvist in 1963, surmises that the postsynaptic blockade of dopamine (DA) receptors is responsible for the beneficial effect of antipsychotic drugs in SCZ and SCZ-like disorders [1]. Arvid Carlson’s experiments with DA depletion by reserpine, followed by chlorpromazine inhibition of dopaminergic transmission, led to a better understanding of the pathology at work in Parkinson’s disease (PD) and acute psychosis [2]. Carlsson and Lindqvist surmised that excessive DA activation of the postsynaptic DA type 2 receptors (D2R) in the central nervous system (CNS) triggered psychotic symptoms, while dopaminergic blockade of these receptors comprised the remedy [3]. This model was further substantiated by the 1970s observation that amphetamine enhanced dopaminergic signaling, often exacerbating psychotic symptoms [4]. However, the realization that antipsychotic drugs exert properties, seemingly unrelated to DA, such as antimicrobial, antiviral, antiproliferative, cell cycle arrest, autophagy activation, alteration of iron metabolism, DNA methylation, and telomere elongation, led to the third DH revision, which emphasized genetic and epigenetic input in dopaminergic transmission [5][6][7][8][9][10].
Aside from the antipsychotic drugs, several characteristics of SCZ itself may be incongruous with the DH, including increased prevalence in industrialized countries and urban areas, variance with latitude, autoantibodies, and high comorbidity with inflammatory bowel disease (IBD) and human immunodeficiency virus 1 (HIV-1) (Table 1). Moreover, excessive DA in the CNS would likely promote euphoria, motivation, and heightened alertness instead of hallucinations or delusions. Furthermore, DH equates acute psychosis with SCZ, an assumption not always shared by clinicians, many of whom conceptualize positive symptoms of SCZ as epiphenomena of this pathology [11].
Table 1. DA-unrelated SCZ characteristics explained by translocated microbes/AhR activation.
DH-Discordant SCZ Features Non-DA Mechanisms References
Negative symptoms Translocation of Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Pseudomonas putida, and Klebsiella pneumoniae [12][13][14]
Comorbidity with IBD AhR/STAT3/IL-22-regulated intestinal permeability and microbiota translocation [11][15][16]
Comorbidity with HIV AhR/STAT3/IL22-regulateted
gut barrier permeability		 [12][17][18]
Poor insight (anosognosia) IC activation by gut Prevotella and Bacteroides abundance [19][20][21][22][23][24][25]
Higher prevalence in urban areas Pollutants are AhR ligands associated with SCZ and are more prevalent in industrialized countries and urban areas [26][27][28][29][30][31][32][33][34]
Increasing prevalence with the distance from the equator Sunlight-driven vitamin D derivatives and tryptophan light metabolites are AhR ligands [35][36][37][38][39]
Autoantibodies Gut microbes express molecules, including GABA and NMDA, which can elicit formation of antibodies upon translocation [40][41][42]
Aryl hydrocarbon receptor (AhR), a cytosolic transcription factor, initially described as the dioxin receptor, responds to numerous exogenous and endogenous ligands, inducing both immune tolerance of gut microbes as well as their prompt elimination upon translocation into host tissues [43][44]. In the cytosol, AhR is bound by two heat shock protein 90 (HSP90) chaperones, molecules recently identified as both SCZ and Parkinson’s disease (PD) targets [45][46][47][48][49][50][51][52]. Other AhR ligands significant for SCZ include DA, carbidopa, clozapine, melatonin, serotonin, microbial phenazines, and various pollutants, linking endogenous and exogenous molecules to this pathology [53][54][55][56].
Several properties of antipsychotic agents appear difficult to reconcile with the DH, even when taking into consideration environmental and genetic factors [57]. For example, the antimicrobial properties of these drugs could alleviate psychosis by eliminating translocated microbes and subsequent inflammation [58]. The non-dopaminergic, therapeutic properties of antipsychotic drugs are likely driven by AhR, a protein involved in the regulation of antimicrobial, antiviral, and antiproliferative host defenses as well as pathogen clearance via reactive oxygen species (ROS), or autophagy [59][60][61]. For example, AhR-induced ROS can ameliorate psychotic symptoms by clearing intracellular pathogens, including Toxoplasma gondii, a SCZ-associated parasite [62]. In addition, neuroleptic drug-activated autophagy and clearance of molecular debris and damaged cells lower the organismal inflammatory burden, likely generating antipsychotic effects [63][64]. Conversely, dysfunctional autophagy and accumulation of cellular remains at the gut barrier and BBB may promote inflammation and microbial translocation into the host systemic circulation [65]. This may explain elevated translocation markers and the more diverse blood microbiome documented in SCZ patients [65][66][67].
Gut commensals enjoy immunological tolerance in the GI tract; however, this protection ceases upon migration outside the intestinal barrier, where they can be vehemently attacked by the host immune defenses [68]. Bactericidal antipsychotic drugs likely facilitate the clearance of both translocated microbes and damaged cells (by autophagy activation), lowering the odds of neuroinflammation and psychosis [69][70]. Other non-dopaminergic beneficial effects of antipsychotic drugs, such as telomere elongation, microglial de-escalation, and inhibition of ferroptosis, may likely be explained by the agonist/antagonist AhR binding [6][71][72][73]. For example, AhR antagonists and some partial agonists, including resveratrol, quercetin, or the synthetic compound HBU651, were demonstrated to elongate telomeres, reverse microglial activation, and avert ferroptosis, placing AhR at the epicenter of SCZ pathology [74][75][76][77] (Table 2).
Taken together, the clinical efficacy of antipsychotic drugs may be mediated by both dopaminergic and non-dopaminergic pathways, the latter including lowering neuroinflammation, ferroptosis inhibition, telomere lengthening, and deactivation of microglia [72][78][79][80].

2. Antipsychotics as Antibacterials

First- and second-generation antipsychotic drugs possess antibacterial properties, suggesting that the elimination of translocated microbes may drive symptomatic relief in psychosis [81]. This is further substantiated by the current efforts to repurpose several antipsychotic drugs as antibiotics [82]. Conversely, antibiotics such as doxycycline and minocycline exert antipsychotic properties, indicating that postsynaptic DA blockade may not be the only mechanism for alleviating psychotic symptoms [83][84].
Other antipsychotic drugs with antimicrobial properties include phenothiazines, compounds capable of eliminating E. coli, a bacterium previously associated with SCZ [85][86]. Moreover, haloperidol exerts fungicidal action against Candida albicans (C. albicans), a BBB-crossing fungus, linked by previous studies to SCZ [87][88][89]. Furthermore, both antipsychotic drugs and IL-22, including the recombinant form, inhibit IFN-γ, a cytokine with established antifungal properties [90][91]. Interestingly, IL-22 exhibits fungicidal action against C. albicans as well as antipsychotic-like properties [88][92][93][94][95] (Table 2).
Table 2. Antipsychotic-like properties of IL22 (or recombinant IL22).
Antipsychotic Drugs Recombinant IL-22 References
JAK-STAT activation JAK-STAT activation [96][97]
Neuroprotective Neuroprotective [98][99]
IFN-γ inhibitor IFN-γ inhibitor [100][101]
Activate autophagy Activate autophagy [102][103][104]
Antibacterial/antiviral Antibacterial/antiviral [87][105][106][107]

3. Antipsychotics as Antivirals

Many antipsychotic drugs possess antiviral properties inherited from their parent compound and phenothiazine dye, methylene blue (MB) [108]. For example, chlorpromazine exerts antiviral properties against SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, and is currently in clinical trials (NCT04366739) for this viral infection [109]. Other viruses enter host cells via clathrin-dependent endocytosis (CDE) and are inhibited by several neuroleptics, including chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine, emphasizing an alternative, DA-independent mechanisms of action, likely mediated by AhR (functioning as an E3 ubiquitin ligase) [110][111][112].
Several antipsychotic drugs alter the biophysical properties of cell membranes by intercalating themselves into the lipid bilayer, blocking viral fusion with host cells. At the same time, this process may comprise an antipsychotic mechanism by depolarizing neuronal membranes, lowering pathological connectivity and likely calcium entry [113][114]. Moreover, several antipsychotics, including haloperidol, are cationic, amphiphilic compounds that accumulate in lysosomes, likely sabotaging viral replication as well as SCZ-associated lysosomal dysfunction [115][116].

4. Antipsychotics as Anticancer Drugs

Several first- and second-generation antipsychotic drugs can arrest the cell cycle at the G2/M point, explaining their beneficial effects against some cancers [117][118]. In patients with SCZ, antipsychotic drugs were found to block the paradoxical attempt of mature neurons to re-enter the cell cycle, emphasizing another possible DA-independent mechanism of alleviating psychosis [119][120][121][122][123].

5. Microbial Phenazines vs. Antipsychotic Phenothiazines

Phenazines are ubiquitous nitrogen-based AhR ligands, released by a wide variety of bacteria, including gut commensals Pseudomonas spp. [124][125]. Like phenothiazine antipsychotics, phenazines exhibit anti-inflammatory, anticancer, antimicrobial, and neuroprotective properties, suggesting that they likely bind AhR [126]. Microbial phenazines are natural phenothiazines, generated by the gut commensals to eliminate pathogenic bacteria and malignant cells by ROS production [127][128][129] (Figure 1).
Reports 06 00036 g003 550
Figure 1. Structural similarity between microbial phenazines and phenothiazines. In the gut, Pseudomonas aeruginosa is the main producer of phenazines. Phenazines upregulate ACh by inhibiting its degrading enzymes, acetylcholinesterase (AChE) and butyryl acetylcholinesterase (BChE), enhancing cholinergic transmission.
Phenothiazines are MB derivatives which led to the development of the first marketed antipsychotic drug, chlorpromazine, which in 1954 ushered in the era of psychopharmacology [130][131]. Since microbial phenazines are AhR ligands, phenothiazines very likely attach to AhR, suggesting an alternative antipsychotic mechanism [132][133].

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