Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

Abstract

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

Keywords: antipsychotic drugs; aryl hydrocarbon receptor; dopamine; naturally occurring antipsychotics; senotherapeutics.

Figure 1

In the cytosol, the AhR is stabilized by two HSP90 molecules. DA, oxidized lipids (and toxic ceramide), clozapine, serotonin, melatonin, and vitamin D3 are AhR ligands [95,96]. Pollutants, such as phthalate and bisphenol A (BPA), are also AhR ligands. In contrast, aripiprazole binds to the AhR chaperone, HSP90. HSP90 prevents AhR’s entry into the nucleus where it drives the transcription of genes, including those for cellular senescence.

Figure 2

Glial cells, including astrocytes, supply neurons with healthy mitochondria via tunneling nanotubules, preventing apoptosis [137,138]. In addition, astrocytes prevent neuronal ferroptosis by transferring antioxidants, including GPX-4. Astrocytes uptake cystine via the cystine/glutamate antiporter (Xc⁻). Cysteine can also be obtained from methionine via glutathione. Fe²⁺ enters neurons through the transferrin receptor-1 (TRF-1), which is stored in ferritin and requires ferritinophagy to be released. Excess Fe²⁺ exits the neurons via ferroportin (FPT) channels.

Figure 3

The AhR is represented in the cytosol and mitochondria (mitoAhR). Akt negatively phosphorylates GSK-3β, inhibiting its function. Toxic ceramides and iron activate GSK-3β, resulting in excessive mitochondrial ROS (mtROS) levels, which activate the mitoAhR, triggering organelle death. mtROS can also cause mitochondrial demise by activating cytochrome-C and caspase-3. The natural compounds berberine and kaempferol inhibit GSK-3β, averting organelle death.

Figure 4

The lipid bilayer of neuronal membranes is easily oxidated when intracellular iron is upregulated [182]. Oxysterols, including 7-ketocholesterol (a toxic oxide), and oxidated phospholipids alter the biophysical properties of cell membranes, disrupting neurotransmission [183]. In addition, oxidized lipids activate the AhR, triggering premature neuronal senescence. Phenazines, phenothiazines, and their derivatives intercalate themselves into the lipid bilayer, repairing the lipids in cellular and/or mitochondrial membranes.

Figure 5

Phenazine vs. phenothiazine: similarities and differences.

Figure 6

Membrane lipid replacement (MLR) replenishes oxidized lipids from the plasma and mitochondrial membrane, such as oxysterols, ceramide, and oxidized phospholipids (OxPLs) with natural glycerophospholipids. Oxidized lipids inhibit AKT (by serine-9 phosphorylation), activating GSK-3β, an enzyme associated with SCZ, SLDs, and cancer (by p53 inhibition). Berberine and kaempferol inhibit GSK-3β activation by different mechanisms, generating beneficial effects. Ceramide activates GSK-3β by the dephosphorylation of serine-9.

Figure 7

AhR agonists and antagonists relevant for neuropsychiatry [74,213,214,215,216,217,218,219,220,221,222].