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].

Several properties of antipsychotic agents appear difficult to reconcile with the DH, even when taking into consideration environmental and genetic factors [109]. For example, the antimicrobial properties of these drugs could alleviate psychosis by eliminating translocated microbes and subsequent inflammation [204]. 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 [205,206,207]. For example, AhR-induced ROS can ameliorate psychotic symptoms by clearing intracellular pathogens, including Toxoplasma gondii, a SCZ-associated parasite [208]. In addition, neuroleptic drug-activated autophagy and clearance of molecular debris and damaged cells lower the organismal inflammatory burden, likely generating antipsychotic effects [209,210]. 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 [66]. This may explain elevated translocation markers and the more diverse blood microbiome documented in SCZ patients [66,70,211].

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 [212]. Bactericidal antipsychotic drugs likely facilitate the clearance of both translocated microbes and damaged cells (by autophagy activation), lowering the odds of neuroinflammation and psychosis [213,214]. 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 [6,200,215,216]. 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 [217,218,219,220] (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 [215,221,222,223].

First- and second-generation antipsychotic drugs possess antibacterial properties, suggesting that the elimination of translocated microbes may drive symptomatic relief in psychosis [224]. This is further substantiated by the current efforts to repurpose several antipsychotic drugs as antibiotics [225]. 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 [226,227].

Other antipsychotic drugs with antimicrobial properties include phenothiazines, compounds capable of eliminating E. coli, a bacterium previously associated with SCZ [228,229]. Moreover, haloperidol exerts fungicidal action against Candida albicans (C. albicans), a BBB-crossing fungus, linked by previous studies to SCZ [230,231,232]. Furthermore, both antipsychotic drugs and IL-22, including the recombinant form, inhibit IFN-γ, a cytokine with established antifungal properties [233,234]. Interestingly, IL-22 exhibits fungicidal action against C. albicans as well as antipsychotic-like properties [231,235,236,237,238] (Table 2).

Many antipsychotic drugs possess antiviral properties inherited from their parent compound and phenothiazine dye, methylene blue (MB) [251]. 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 [252]. 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) [253,254,255].

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 [256,257]. Moreover, several antipsychotics, including haloperidol, are cationic, amphiphilic compounds that accumulate in lysosomes, likely sabotaging viral replication as well as SCZ-associated lysosomal dysfunction [258,259].

Several first- and second-generation antipsychotic drugs can arrest the cell cycle at the G2/M point, explaining their beneficial effects against some cancers [260,261]. 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 [262,263,264,265,266].

Phenazines are ubiquitous nitrogen-based AhR ligands, released by a wide variety of bacteria, including gut commensals Pseudomonas spp. [267,268]. Like phenothiazine antipsychotics, phenazines exhibit anti-inflammatory, anticancer, antimicrobial, and neuroprotective properties, suggesting that they likely bind AhR [269]. Microbial phenazines are natural phenothiazines, generated by the gut commensals to eliminate pathogenic bacteria and malignant cells by ROS production [270,271,272] (Figure 1).

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 [273,274]. Since microbial phenazines are AhR ligands, phenothiazines very likely attach to AhR, suggesting an alternative antipsychotic mechanism [275,276].