Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

AIMS: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. METHODS: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. RESULTS: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. CONCLUSIONS: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells.

The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5-20 µM) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30-40% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival.

The effect of olanzapine on spatial memory impairment, depressive-like behavior, pain perception, and BDNF and synaptophysin expression following childhood chronic unpredictable mild stress in adult male and female rats.

Chronic unpredictable mild stress (CUMS) method has been introduced as a rodent model of depression. On the other hand, olanzapine, as an antipsychotic, can induce antidepressant and antipsychotic effects. Also, olanzapine may improve cognitive functions. Both CUMS and olanzapine can also affect the expression level of brain-derived neurotrophic factor (BDNF) and synaptophysin, the molecular factors involved in synaptic function, and learning and memory. In this study, we investigated the effect of olanzapine on locomotor activity (using open field test), pain threshold (using hot plate), depressive-like behavior (using forced swim test), spatial learning and memory (using Morris water maze), and BDNF and synaptophysin hippocampal expression (using real-time PCR) in both male and female CUMS rats. CUMS was performed for three consecutive weeks. Olanzapine was also injected intraperitoneally at the dose of 5 mg/kg. Our data showed that olanzapine can reverse the effects of CUMS on behavioral functions and BDNF and synaptophysin expression levels in the hippocampus of both males and females. It was also shown that olanzapine effects on spatial memory, pain perception, and BDNF and synaptophysin level were stronger in females than males. In conclusion, we suggested that the therapeutic effects of olanzapine in CUMS rats may be closely related to the function of BDNF and synaptophysin. Also, the therapeutic effects of olanzapine may be stronger in females. Therefore, and for the first time, we showed that there may be a sex difference in the effects of olanzapine on behavioral and molecular changes following CUMS.

Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Fractional amplitude of low-frequency fluctuations in sensory-motor networks and limbic system as a potential predictor of treatment response in patients with schizophrenia.

BACKGROUND: Previous investigations have revealed substantial differences in neuroimaging characteristics between healthy controls (HCs) and individuals diagnosed with schizophrenia (SCZ). However, we are not entirely sure how brain activity links to symptoms in schizophrenia, and there is a need for reliable brain imaging markers for treatment prediction. METHODS: In this longitudinal study, we examined 56 individuals diagnosed with 56 SCZ and 51 HCs. The SCZ patients underwent a three-month course of antipsychotic treatment. We employed resting-state functional magnetic resonance imaging (fMRI) along with fractional Amplitude of Low Frequency Fluctuations (fALFF) and support vector regression (SVR) methods for data acquisition and subsequent analysis. RESULTS: In this study, we initially noted lower fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, coupled with higher fALFF values in the left hippocampus and right putamen in SCZ patients compared to the HCs at baseline. However, when comparing fALFF values in brain regions with abnormal baseline fALFF values for SCZ patients who completed the follow-up, no significant differences in fALFF values were observed after 3 months of treatment compared to baseline data. The fALFF values in the right postcentral/precentral gyrus and left postcentral gyrus, and the left postcentral gyrus were useful in predicting treatment effects. CONCLUSION: Our findings suggest that reduced fALFF values in the sensory-motor networks and increased fALFF values in the limbic system may constitute distinctive neurobiological features in SCZ patients. These findings may serve as potential neuroimaging markers for the prognosis of SCZ patients.

The antipsychotic agent sulpiride microinjected into the ventral pallidum restores positive symptom-like habituation disturbance in MAM-E17 schizophrenia model rats.

Dysfunction of subcortical D2-like dopamine receptors (D2Rs) can lead to positive symptoms of schizophrenia, and their analog, the increased locomotor activity in schizophrenia model MAM-E17 rats. The ventral pallidum (VP) is a limbic structure containing D2Rs. The D2R antagonist sulpiride is a widespread antipsychotic drug, which can alleviate positive symptoms in human patients. However, it is still not known how sulpiride can influence positive symptoms via VP D2Rs. We hypothesize that the microinjection of sulpiride into the VP can normalize hyperactivity in MAM-E17 rats. In addition, recently, we showed that the microinjection of sulpirid into the VP induces place preference in neurotypical rats. Thus, we aimed to test whether intra-VP sulpiride can also have a rewarding effect in MAM-E17 rats. Therefore, open field-based conditioned place preference (CPP) test was applied in neurotypical (SAL-E17) and MAM-E17 schizophrenia model rats to test locomotor activity and the potential locomotor-reducing and rewarding effects of sulpiride. Sulpiride was microinjected bilaterally in three different doses into the VP, and the controls received only vehicle. The results of the present study demonstrated that the increased locomotor activity of the MAM-E17 rats was caused by habituation disturbance. Accordingly, larger doses of sulpiride in the VP reduce the positive symptom-analog habituation disturbance of the MAM-E17 animals. Furthermore, we showed that the largest dose of sulpiride administered into the VP induced CPP in the SAL-E17 animals but not in the MAM-E17 animals. These findings revealed that VP D2Rs play an important role in the formation of positive symptom-like habituation disturbances in MAM-E17 rats.

Determining Ideal Management for Patients With Coexisting Prolactinomas and Psychiatric Symptoms: A Systematic Review.

OBJECTIVE: Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin pathway, making them the first-line treatment for prolactinomas. However, the main side effect of DA treatment, hyperdopaminergia, is an explicit etiology for psychiatric side effects. Psychiatric conditions are often treated with dopamine antagonists, which can induce hyperprolactinemia. This presents a challenge for patients with both a prolactinoma and a preexisting psychiatric condition, as treatment of one condition could worsen the other. This review seeks to identify an adequate therapeutic regimen for patients with coexisting prolactinomas and psychiatric symptoms. METHODS: This review examined PubMed citations from 1960 to 2023 published in English and involving human subjects. Case reports, case series, and cohort studies involving patients with concomitant prolactinomas and psychiatric symptoms, as validated by brain imaging, serologic prolactin levels, and medical history or chart reports of psychiatric symptoms, were included. RESULTS: Thematic analysis included 23 reports involving 42 participants; 27 of the 42 patients experienced a significant reduction in prolactin levels and psychiatric symptoms (64%). Treatment of those 42 patients included discontinuing or altering antipsychotic/dopamine antagonist therapy or discontinuing DA therapy to reduce psychiatric symptoms, with surgery or radiation postpharmacotherapy as a last-line strategy. However, in some cases (reported in Tables 2 to 4), either psychiatric or prolactin-related symptoms recurred despite adjustment. CONCLUSIONS: Clinicians may find it beneficial to prioritize specific antipsychotics (aripiprazole, olanzapine, ziprasidone, or clozapine) over others (risperidone, thioridazine, thiothixene, and remoxipride). Discontinuing DA medication at least periodically until the patient's condition improves may also be advisable. If these 2 initial approaches do not yield a significant improvement in symptom management, surgery or radiation therapy may be considered. As patients may respond differently to these therapies, our study still recommends a patient-centered approach.

Ziprasidone triggers inflammasome signaling via PI3K-Akt-mTOR pathway to promote atrial fibrillation.

BACKGROUND: Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia. METHODS: Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes. RESULTS: The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na+/Ca2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1ß, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone. CONCLUSIONS: Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.

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.

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.

Continuous oral olanzapine or clozapine treatment initiated in adolescence has differential short- and long-term impacts on antipsychotic sensitivity than those initiated in adulthood.

One of the major discoveries in recent research on antipsychotic drugs is that antipsychotic treatment in adolescence could induce robust long-term alterations in antipsychotic sensitivity that persist into adulthood. These long-term impacts are likely influenced by various factors, including the "diseased" state of animals, sex, type of drugs, mode of drug administration, and age of treatment onset. In this study we compared the short- and long-term behavioral effects of 21-day continuous oral olanzapine (7.5 mg/kg/day) or clozapine (30.0 mg/kg/day) administration in heathy or maternal immune activated adolescent (33-53 days old) or adult (80-100 days old) rats of both sexes. We used a conditioned avoidance response model to assess the drug-induced alterations in antipsychotic sensitivity. Here, we report that while under the chronic drug treatment period, olanzapine progressively increased its suppression of avoidance responding over time, especially when treatment was initiated in adulthood. Clozapine's suppression depended on the age of drug exposure, with treatment initiated in adulthood showing a suppression while that initiated in adolescent did not. After a 17-day drug-free interval, in a drug challenge test, olanzapine treatment initiated in adolescence caused a decrease in drug sensitivity, as reflected by less avoidance suppression (a tolerance effect); whereas that initiated in adulthood appeared to cause an increase (more avoidance suppression, a sensitization effect). Clozapine treatments initiated in both adolescence and adulthood caused a similar tolerance effect. Our findings indicate that the same chronic antipsychotic treatment regimen initiated in adolescence or adulthood can have differential short- and long-term impacts on drug sensitivity.

Antipsychotic Zuclopenthixol Inhibits Melanoma Growth and Brain Metastasis by Inducing Apoptosis and Cell Cycle Arrest.

BACKGROUND: The incidence of melanoma brain metastasis (MBM) is high and significantly compromises patient survival and quality of life. Effective treatment of MBM is made difficult by the blood-brain barrier (BBB), since it restricts the entry of drugs into the brain. Certain anti-psychotic drugs able to cross the BBB have demonstrated efficacy in suppressing brain metastasis in preclinical studies. However, the activity of zuclopenthixol against MBM is not yet clear. METHODS: Cell viability assays were employed to investigate the potential of zuclopenthixol in the treatment of MBM. Subsequently, the mechanism of action was investigated by RNA-sequencing (RNAseq), flow cytometry-based cell cycle and apoptosis assays, protein expression analysis, and autophagy flux detection. Additionally, the efficacy of zuclopenthixol against tumor growth was investigated in vivo, including MBM models. RESULTS: Zuclopenthixol inhibited the proliferation of various melanoma cell lines at minimal doses by causing cell cycle arrest in the G0/G1 phase and mitochondrial-mediated intrinsic apoptosis. Zuclopenthixol also induced cytoprotective autophagy, and inhibition of autophagy enhanced the anti-melanoma effects of zuclopenthixol. Furthermore, zuclopenthixol inhibited the growth of human melanoma tumors in nude mice, as well as the growth of intracranial metastases in a mouse model of MBM. CONCLUSIONS: These results demonstrate that zuclopenthixol has significant potential as an effective therapeutic agent for MBM.

Clearing the Fog: A Review of Antipsychotics for Parkinson's-Related Hallucinations: A Focus on Pimavanserin, Quetiapine and Clozapine.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care.

Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia.

Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.

Pharmacogenetic intervention improves treatment outcomes in Chinese adult men with schizophrenia.

To investigate the clinical application value of pharmacogenetic testing in individualized drug therapy for adult male patients with schizophrenia. A total of 186 adult patients with schizophrenia were enrolled and randomised into the pharmacogenetic (PGx) intervention group and the standard care group. In the PGx intervention group, PGx testing was performed, and the medication regimen was adjusted according to the results of the pharmacogenomic analysis. In contrast, in the standard care group, patients were treated according to the physician's medication experience. Differences in the primary indicator of schizophrenia, the Positive and Negative Symptom Scale (PANSS), and the secondary efficacy measures, the Clinical Global Impressions-Severity of Illness scale (CGI-SI) and Clinical Global Impressions-Global Improvement (CGI-GI) scale, were compared between the intervention and standard care groups. At baseline, the PGx intervention group consisted of 109 individuals, while the standard care group had 77 participants. After 12 weeks of treatment, 49 individuals withdrew from the PGx group (a dropout rate of 45.0%), and 34 withdrew from the standard care group (a dropout rate of 44.2%), with no significant difference in dropout rates between the two groups. The PANSS score reduction rate in the PGx intervention group significantly exceeded that of the standard care group during weeks 3, 6, and 12 of follow-up (P < 0.05). At the 12th week, the PGx intervention group achieved a treatment response rate of 81.7%, significantly surpassing the 48.8% of the standard care group (odds ratio of 4.67, 95% confidence interval of 1.96-11.41; P = 0.001). Furthermore, the PGx intervention was significantly more effective than standard care regardless of whether the patient had a first episode or a relapse (P < 0.05). Furthermore, the Global Assessment of Functioning (GAF) scores and the Personal and Social Performance Scale (PSP) score changes in the PGx intervention group were both significantly different from those in the standard care group (P < 0.05). It is noteworthy that the PGx intervention similarly improves the prognostic outcomes for patients with and without a family history of mental disorders. In conclusion, the application of a PGx intervention treatment model based on PGx testing can significantly improve medication efficacy and shorten the time to achieve the effects of medication in schizophrenia.

Inhibition of voltage-gated potassium channel by aripiprazole in rabbit coronary arterial smooth muscle cells.

Aripiprazole, a third-generation antipsychotic, has been widely used to treat schizophrenia. In this study, we evaluated the effect of aripiprazole on voltage-gated potassium (Kv) channels in rabbit coronary arterial smooth muscle cells using the patch clamp technique. Aripiprazole reduced the Kv current in a concentration-dependent manner with a half-maximal inhibitory concentration of 0.89 ± 0.20 µM and a Hill coefficient of 1.30 ± 0.25. The inhibitory effect of aripiprazole on Kv channels was voltage-dependent, and an additional aripiprazole-induced decrease in the Kv current was observed in the voltage range of full channel activation. The decay rate of Kv channel inactivation was accelerated by aripiprazole. Aripiprazole shifted the steady-state activation curve to the right and the inactivation curve to the left. Application of a repetitive train of pulses (1 and 2 Hz) promoted inhibition of the Kv current by aripiprazole. Furthermore, the recovery time constant from inactivation increased in the presence of aripiprazole. Pretreatment of Kv1.5 subtype inhibitor reduced the inhibitory effect of aripiprazole. However, pretreatment with Kv 7 and Kv2.1 subtype inhibitors did not change the degree of aripiprazole-induced inhibition of the Kv current. We conclude that aripiprazole inhibits Kv channels in a concentration-, voltage-, time-, and use (state)-dependent manner by affecting the gating properties of the channels.

Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders.

BACKGROUND: Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. METHODS: The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. RESULTS: The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. CONCLUSIONS: In our study, patients with schizophrenia - including the drug-naïve - have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

Understanding the Therapeutic Action of Antipsychotics: From Molecular to Cellular Targets With Focus on the Islands of Calleja.

The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors, apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine, and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at the highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum.

M1/M4 receptors as potential therapeutic treatments for schizophrenia: A comprehensive study.

Muscarinic acetylcholine receptors (mAChRs) play a significant role in the pathophysiology of schizophrenia. Although activating mAChRs holds potential in addressing the full range of schizophrenia symptoms, clinical application of many non-selective mAChR agonists in cognitive deficits, positive and negative symptoms is hindered by peripheral side effects (gastrointestinal disturbances and cardiovascular effects) and dosage restrictions. Ligands binding to the allosteric sites of mAChRs, particularly the M1 and M4 subtypes, demonstrate activity in improving cognitive function and amelioration of positive and negative symptoms associated with schizophrenia, enhancing our understanding of schizophrenia. The article aims to critically examine current design concepts and clinical advancements in synthesizing and designing small molecules targeting M1/M4, providing theoretical insights and empirical support for future research in this field.