Clozapine Prescripers-Dogmatic or Pragmatic?

Clozapine, amongst antipsychotics, has a unique composite mode of action that might translate into an expanded therapeutic potential on clinical grounds. Sorely, clozapine remains underutilized.

Antipsychotic drugs selectively decorrelate long-range interactions in deep cortical layers.

Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.

Cannabidiol exhibits anxiolytic-like effects and antipsychotic-like effects in mice models.

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1AR) in vitro (CHO cells expressing human 5-HT1AR) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively. Concurrently, we investigated whether WAY-100635, a typical 5-HT1AR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HT1AR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC50 = 1.75 µM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HT1AR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.

The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells.

Liver cancer annually accounts for over 800,000 cases and 700,000 deaths worldwide. Hepatocellular carcinoma is responsible for over 80% of liver cancer cases. Due to ineffective treatment options and limited surgical interventions, hepatocellular carcinoma is notoriously difficult to treat. Nonetheless, drugs utilized for other medical conditions, such as the antihypertensive medication prazosin, the neuroleptic medication chlorpromazine, and the neuroleptic medication haloperidol, have gained attention for their potential anti-cancer effects. Therefore, this study used these medications for investigating toxicity to hepatocellular carcinoma while testing the adverse effects on a noncancerous liver cell line model THLE-2. After treatment, an XTT cell viability assay, cell apoptosis assay, reactive oxygen species (ROS) assay, apoptotic proteome profile, and western blot were performed. We calculated IC50 values for chlorpromazine and prazosin to have a molar range of 35-65 µM. Our main findings suggest the capability of both of these treatments to reduce cell viability and generate oxidative stress in HepG2 and THLE-2 cells (p value < 0.05). Haloperidol, however, failed to demonstrate any reduction in cell viability revealing no antitumor effect up to 100 µM. Based on our findings, a mechanism of cell death was not able to be established due to lack of cleaved caspase-3 expression. Capable of bypassing many aspects of the lengthy, costly, and difficult cancer drug approval process, chlorpromazine and prazosin deserve further investigation for use in conjunction with traditional chemotherapeutics.

A Pilot Study to Explore the Effect of Long Acting Injectable Antipsychotics on Aggression.

Objectives: To explore the effect of switching from an oral antipsychotic to a long-acting injectable (LAI) antipsychotic on aggression, in terms of the changes of verbal and physical aggression, interventions required, self-injurious behavior, use of seclusion or restraint, antipsychotic medication refusal, and use of antipsychotics as needed (PRN). Methods: This was a retrospective chart review at a long-term state forensic psychiatric facility. Patients treated with an oral antipsychotic for at least 6 months and then switched to a LAI antipsychotic for an additional 6 months during an 80-month period were included. Results: Out of 70 patients evaluated, 18 were the study subjects. The median age of the cohort was 38 years with a majority being male. Of the seven patients who had an incident of aggression, two had an increase in aggressive incidents following the switch, three had a decrease, and two had no change. Thirty-six interventions occurred while patients were on an oral antipsychotic, which decreased by 30.6% to 25 interventions after the switch. Three patients had an incident of self-injurious behavior, and 6 patients required restraints/seclusions. Of the eight patients who had retrievable medication refusal and antipsychotic PRN use information, five had a decrease in antipsychotic medication refusals and five had an increase in PRN antipsychotic use after the switch. Conclusion: The switch from an oral antipsychotic to a LAI antipsychotic did not appear to significantly increase or decrease incidents of aggression or self-injurious behavior, but seemed to decrease the number of restraints/seclusions required.

Genotoxic and genoprotective effects of some antipsychotic drugs, methylphenidate and atomoxetine on human lymphocytes and HepG2 cells.

OBJECTIVE: Aripiprazole, risperidone, atomoxetine, and methylphenidate are drugs commonly prescribed for many psychiatric conditions and can be used alone or in combination in children and adolescents. This study aimed to investigate comparatively the possible genotoxic effects or genoprotective potentials of these drugs on human lymphocytes and HepG2 cells. MATERIALS AND METHODS: Cytotoxicity analysis was performed with the cell viability test on human lymphocytes and HepG2 cells, and half-maximal inhibitory concentration (IC50) values of the drugs were determined, and three different doses (» IC50, ½ IC50, and IC50) were applied for genetic analysis. For the determined doses, cells with and without DNA damage were examined by comet analysis. RESULTS: In lymphocytes, aripiprazole and risperidone increased DNA damage at moderate and maximum doses, whereas atomoxetine increased DNA damage only at the maximum dose. In HepG2 cells, risperidone reduced DNA damage at all doses, while atomoxetine increased DNA damage at all doses. On the other hand, in the DNA-damaged cells induced by hydrogen peroxide (H2O2), DNA damage decreased at all concentrations of all drugs in both lymphocytes and HepG2 cells. CONCLUSIONS: As a result, the genotoxicity of the drugs was found to be dose-dependent, and all drugs showed a genoprotective effect on DNA-damaged cells.

Serum S100B protein and white matter changes in schizophrenia before and after medication.

Schizophrenia patients have abnormalities in white matter (WM) integrity in brain regions. S100B has been shown to be a marker protein for glial cells. The atypical antipsychotics have neuroprotective effects on the brain. It is not clear whether antipsychotics can induce S100B changes and improve symptoms by protecting oligodendrocytes. To investigate WM and S100B changes and associations and determine the effect of quetiapine on WM and S100B in schizophrenia patients, we determined serum S100B levels with solid phase immunochromatography and fractional anisotropy（FA）values of 36 patients and 40 healthy controls. Patients exhibited significantly higher serum concentrations of S100B and decreased FA values in left postcentral，right superior frontal，right thalamus, and left inferior occipital gyrus, while higher in right temporal cortex WM compared with healthy controls. Following treatment with quetiapine, patients had decreased S100B and higher FA values in right cerebellum，right superior frontal，right thalamus, and left parietal cortex，and decreased FA values in right temporal cortex WM compared with pre-treatment values. Furthermore, S100B were negatively correlated with PANSS positive scores and positively correlated with FA values in the left postcentral cortex. In addition，the percentage change in FA values in the right temporal cortex was positively correlated with the percentage change in the S100B, percentage reduction in PANSS scores, and percentage reduction in PANSS-positive scores. Our findings demonstrated abnormalities in S100B and WM microstructure in patients with schizophrenia. These abnormalities may be partly reversed by quetiapine treatment.

Revealing receptor-ligand interactions of atypical antipsychotic drugs and screening anti-schizophrenia ingredients in Magnolia officinalis based on 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models.

Schizophrenia is a serious mental illness with unknown etiology, and shows increasing incidence and high lifetime prevalence rate. The main receptors related to the disease are DRD2 and 5-HTR2A. Thus, a comprehensive understanding of the interaction mode between antipsychotic drugs with relevant receptors is very important for developing more effective drugs. 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models constructed in this work provided a new method for studying the interaction between atypical antipsychotics and the two receptors. The results of comparative experiments showed that the new models not only met the high selectivity and specificity of the screening requirements but were also more stable and long-lasting than the traditional CMC model. Binding assays showed that the effects of three atypical antipsychotics (including clozapine, olanzapine, and quetiapine) on 5-HTR2A were stronger than their effects on DRD2. Additionally, two potentially active components, magnolol and honokiol, were screened in Magnolia officinalis methanol extract using the 5-HTR2A-SNAP-Tag/CMCHPLC-MS system. Nonlinear chromatographic analysis and molecular docking were conducted to study the interactions between screened compounds and the two receptors. The binding constants (KA) of magnolol and honokiol with 5-HTR2A were 17,854 ± 1,117 M-1 and 38,858 ± 4,964 M-1, respectively, and KA values with DRD2 were 4,872 ± 1,618 M-1 and 20,692 ± 10,267 M-1, respectively. We concluded that the established models are reliable for studying receptor-ligand interactions and screening antagonists of schizophrenia.

Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects.

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2R and mGlu3R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3R ligands in clinical trials. Studies evaluating mGlu2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2R and mGlu3R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3R, but not mGlu2R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2R, but not mGlu3R regulation observed in schizophrenia brains. mGlu2R and mGlu3R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2R and mGlu3R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3R, but not mGlu2R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3R expression are activated to counterbalance mGluR loss of function is described.

The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells.

The antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.

Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates.

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment.

Pharmacodynamic properties of lumateperone and its efficacy in acute bipolar depression: a mechanistic hypothesis based on data.

The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible mechanistic targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of lumateperone fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of lumateperone. The original model suggests that a constellation of effects on different receptors is necessary, but refinements, including the present study, suggest that the inhibition of the serotonin reuptake at the first level, the 5HT-2A blockade at the second level, and the norepinephrine alpha-1 receptors blockade at a third level in combination with D1 blockade contribute to the antidepressant effect in acute bipolar depression. The D2 blockade acts as a protective mechanism and reduces the risk of switching to mania/hypomania.

The contribution of first-episode illness characteristics and cumulative antipsychotic usage to progressive structural brain changes over a long-term follow-up in schizophrenia.

Exposure to antipsychotics as well as certain first-episode illness characteristics have been associated with greater gray matter (GM) deficits in the early phase of schizophrenia. Whether the first-episode illness characteristics affect the long-term progression of the structural brain changes remain unexplored. We therefore assessed the role of first-episode illness characteristics and life-time antipsychotic use in relation to long-term structural brain GM changes in schizophrenia. Individuals with schizophrenia (SZ, n = 29) and non-psychotic controls (n = 61) from the Northern Finland Birth Cohort 1966 underwent structural MRI at the ages of 34 (baseline) and 43 (follow-up) years. At follow-up, the average duration of illness was 19.8 years. Voxel-based morphometry was used to assess the effects of predictors on longitudinal GM changes in schizophrenia-relevant brain areas. Younger age of onset (AoO), higher cumulative antipsychotic dose and severity of symptoms were associated with greater GM deficits in the SZ group at follow-up. None of the first-episode illness characteristics were associated with longitudinal GM changes during 9-year follow-up period. We conclude that a younger AoO and high life-time antipsychotic use may contribute to progression of structural brain changes in schizophrenia. Apart from AoO, other first-episode illness characteristics may not contribute to longitudinal GM changes in midlife.

Olanzapine's effects on hypothalamic transcriptomics and kinase activity.

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.

Effects of chronic haloperidol treatment on the expression of fear memory and fear memory extinction in the cued fear-conditioned rats.

AIM: Impairments in emotional memory are frequently observed in several mental disorders, highlighting their significance as potential therapeutic targets. Recent research on the cued fear conditioning model has elucidated the neural circuits involved in fear memory processing. However, contradictory findings have been reported concerning the role of dopamine and the impact of dopamine D2 receptor (D2R) antagonists. There is notably limited knowledge regarding the clinical utility of chronic D2R antagonist treatments. This study aimed to uncover how such treatments affect fear memory processing. METHODS: We utilized a cued fear conditioning rat model and conducted chronic haloperidol treatment for 14 days. Subsequently, to investigate the effect of chronic haloperidol treatment on fear-conditioned memory expression and extinction, we observed freezing behavior under exposure to a conditioned stimulus for 14 days. RESULTS: Chronic haloperidol treatment suppressed freezing time on the fear memory expression. In contrast, a single haloperidol administration enhanced the freezing time on fear memory expression and delayed extinction. CONCLUSION: The results of this study suggest that chronic administration of antipsychotic drugs affects fear memory processing differently from single-dose administration. This indicates that the effects of chronic D2R antagonist treatment are distinct from the nonspecific effects of the drugs. This study provides fundamental insights that may contribute to our understanding of therapeutic mechanisms for fear memory disorders related to D2R in the future.

Targeting autophagy by antipsychotic phenothiazines: potential drug repurposing for cancer therapy.

Cancer is recognized as the major cause of death worldwide and the most challenging public health issues. Tumor cells exhibit molecular adaptations and metabolic reprograming to sustain their high proliferative rate and autophagy plays a pivotal role to supply the high demand for metabolic substrates and for recycling cellular components, which has attracted the attention of the researchers. The modulation of the autophagic process sensitizes tumor cells to chemotherapy-induced cell death and reverts drug resistance. In this regard, many in vitro and in vivo studies having shown the anticancer activity of phenothiazine (PTZ) derivatives due to their potent cytotoxicity in tumor cells. Interestingly, PTZ have been used as antiemetics in antitumor chemotherapy-induced vomiting, maybe exerting a combined antitumor effect. Among the mechanisms of cytotoxicity, the modulation of autophagy by these drugs has been highlighted. Therefore, the use of PTZ derivatives can be considered as a repurposing strategy in antitumor chemotherapy. Here, we provided an overview of the effects of antipsychotic PTZ on autophagy in tumor cells, evidencing the molecular targets and discussing the underlying mechanisms. The modulation of autophagy by PTZ in tumor cells have been consistently related to their cytotoxic action. These effects depend on the derivative, their concentration, and also the type of cancer. Most data have shown the impairment of autophagic flux by PTZ, probably due to the blockade of lysosome-autophagosome fusion, but some studies have also suggested the induction of autophagy. These data highlight the therapeutic potential of targeting autophagy by PTZ in cancer chemotherapy.

Effects of olanzapine on hippocampal CA3 and the prefrontal cortex local field potentials.

Olanzapine is an antipsychotic drug applied in psychiatry to treat psychoses, especially schizophrenia and schizoaffective disorders with similar or better improvement than haloperidol and risperidone in the treatment of depressive and negative symptoms. The effect of olanzapine on neural synchrony remains to be explored. We investigated the effects of olanzapine on gamma oscillations in the CA3 region of the hippocampus and frontal association cortex. Olanzapine reduced carbachol (CCh)-induced gamma oscillation power in CA3 slice and gamma oscillation power in the frontal association cortex in vivo. The power of theta oscillations was increased in the presence of olanzapine. The phase amplitude coupling of theta and gamma wave was strengthened by the administration of olanzapine in the frontal association cortex in vivo. Taken together, these results show that olanzapine modulates local field potential and the neuronal activity.

Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis.

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.