In 1961, Jean-Noël Seignot (1925-2022) published a clinical observation in the Annales Médico-Psychologiques of a patient with a severe form of Gilles de la Tourette syndrome. He included the results of his clinical test with R.1625, a new compound then in an experimental phase, developed by Janssen Laboratories in Belgium-that is, haloperidol. Seignot's article is constantly cited in the bibliographies on the treatment of this syndrome. Here, I present the first-ever complete translation of Seignot's publication, followed by his biography, based on family archives kindly made available to me. This account is accompanied by a brief history of the discovery of haloperidol. Seignot saw that Gilles de la Tourette syndrome was not just a disease but "a whole mode of being." His foresight in the care and treatment of his seriously ill patient deserves a commemorative biography.

KarXT (marketed as Cobenfy™), a fixed-dose combination of xanomeline and trospium chloride, represents the first new mechanism of action of an antipsychotic used for adult schizophrenia approved by the US Food and Drug Administration (FDA) in over 30 years. While mainstream drugs (e.g. haloperidol, chlorpromazine, risperidone, olanzapine, quetiapine, aripiprazole) mainly antagonize dopamine D2 or serotonin 5-HT2A receptors, KarXT acts through transient activation of muscarinic M1 and M4 receptors. M4 stimulation influences the functioning of mesolimbic dopaminergic pathways, providing an indirect means of regulating dopamine release that bypasses D2 blockade. Trospium, a peripherally acting muscarinic receptor antagonist, was used to reduce anticholinergic adverse effects (AEs). It does not cross the blood-brain barrier and therefore minimizes central adverse events. In a series of randomized placebo-controlled phase 2 and 3 studies, the KarXT significantly and clinically meaningfully reduced Positive and Negative Syndrome Scale (PANSS) total scores. The effect sizes were moderate to large with few extrapyramidal symptoms (EPS), minimal metabolic disturbances and no significant prolactin level increases. In this narrative review, we discuss in detail the pharmacological mechanism, basis of preclinical development, and clinical outcomes of KarXT. We also contextualize this drug within the development of a new wave of non-D2 antipsychotics, highlighting cholinergic dysfunction as one important mechanistic pathway within the broader multidimensional neurobiology of schizophrenia.

The global prevalence of mental disorders has increased considerably in recent decades. This evidence, associated with population growth and the expansion of access to medications, favors the growing global consumption of psychotropic drugs. Consequently, an increasing load of these substances is introduced into the environment, especially into water bodies, characterizing them as emerging contaminants. This scoping review study aimed to integrate data and provide a global overview of the occurrence of widely used psychotropic drugs (diazepam, fluoxetine, and haloperidol) in drinking water. The search for studies was conducted across 7 databases, with no language or publication year restrictions. We included only original studies in this review and synthesized data from the included studies for water sampled, sampling location, year of sampling, analytical method used, psychotropic drug found, and concentration found. Our review identified 13 studies published between 2000 and 2024 on the occurrence of diazepam and fluoxetine in tap water, drinking water, bottled water, and drinking well water from 7 countries, with concentrations ranging from 0.2 to 300 ng/L. No studies on the occurrence of haloperidol in drinking water were found. Our data highlight that the occurrence of psychotropic drugs in drinking water is a growing global reality and also show a significant lack of research dedicated to the topic. Furthermore, the results of this scoping review reinforce the need to expand water quality monitoring, improve analytical techniques, invest in advanced water treatment technologies, and implement public policies on the proper disposal of medication and the control of drug pollution.

Human reward processing varies along cue-centric and outcome-centric axes, but the mechanistic basis of individual variation in incentive salience attribution remains incompletely characterized. Here we show, using fMRI across five cohorts (N-total = 1251; N1 = 890; N2 = 245; N3 = 34; N4 = 48; N5 = 34), two reproducible imaging phenotypes mirroring sign- and goal-tracking (ST-like, GT-like). ST-like individuals showed dominant ventral striatal responses to reward-anticipation cues and sustained incentive salience attribution; GT-like individuals showed heightened responses to reward outcomes. This distinction was replicable across sites and independent samples. Single-dose and repeated-dose D2/D3 antagonism (risperidone, haloperidol, amisulpride) selectively reduced anticipatory ventral striatal activity in ST, with single-dose antagonism additionally producing a parallel drop in self-reported energy. Instead, D2/D3 partial agonism (aripiprazole) increased anticipatory and reduced outcome-phase responses in GT. In a psychosis cohort, antipsychotic D2 affinity was associated with blunted anticipatory signals and higher negative symptom burden, offering a neuroimaging-driven basis for stratifying patients and predicting response to dopaminergic agents.

Group-living mammals can identify stress in conspecifics. When the male subject rats were allowed to interact with a pair consisting of a naïve stimulus rat and a shocked stimulus rat that had received foot shocks immediately before testing, they showed the biased social interaction toward shocked stimulus rats. Findings in the literature suggest roles for the oxytocin and other neuromodulatory systems in this biased interaction. However, the roles of the vasopressin, dopamine, and opioid systems remain unclear. Here we examined the effects of intraperitoneal administration of atosiban (an oxytocin receptor antagonist), SR49,059 (a vasopressin V1a receptor antagonist), haloperidol (a dopamine D2 receptor antagonist), naloxone (an opioid receptor antagonist), or vehicle, on this biased interaction. The vehicle-treated subjects showed longer interaction times toward shocked stimulus rats than toward naïve stimulus rats. This bias was abolished by atosiban, SR49,059, or haloperidol, whereas the naloxone-treated subjects retained the bias. These results suggest that oxytocin, vasopressin V1a, and dopamine D2 receptors, but not opioid receptors, contribute to biased interaction toward stressed conspecifics. Moreover, the naloxone-treated subjects showed an increased total interaction time, suggesting increased sociality. These findings contribute to a more comprehensive understanding of the neuromodulatory mechanisms underlying stress identification.

Schizophrenia is still a large psychiatric problem worldwide, therefore much study into the structural, electronics and pharmacokinetic properties of therapeutic drugs used in its treatment are needed. The present study has been performed by employing Density Functional Theory (DFT) calculations, molecular electrostatic potential (MEP) mapping, analytical Fukui function evaluation, ADMET profiling and molecular docking in an effort to comprehensively evaluate eight important antipsychotic drugs. DFT studies highlighted important electronic features. Global reactivity descriptors indicated a higher oxidative stability in aripiprazole, opposite to the marked reactivity sensitivity of haloperidol. FMO analysis and Fukui condensation maps suggested that nucleophilic localisation was mainly on the nitrogen lone-pairs, while electrophilic areas were on the phenyl ring motifs. Structural divergence was observed in Olanzapine and Haloperidol. Comprehensive ADMET and multi-endpoint toxicity profiling for understanding physiological disposition revealed that gastrointestinal absorption is a common limitation, but all tested drugs possess excellent blood-brain barrier (BBB) permeability needed for central nervous system target engagement, along with generation-dependent acute toxicity profiles. Toxicity screening showed that aripiprazole had the highest LD50 (800 mg/kg) and minimum risks at the endpoints. Finally, target-directed molecular docking against human glycine transporter 1 (PDB ID: 8WFK) quantified binding architectures in the range of -7.3 to -10.0 kcal/mol. Risperidone showed the highest affinity (-10.0 kcal/mol) due to strong electrostatic interactions with the primary anchoring residue Asp474 and hydrophobic stabilisation through Tyr142, Trp322 and Pro383. The redocking validated the results with RMSD 1.24Å. The MEP maps confirmed that the binding affinity to GlyT1 is the large negative potential localisation around the hydrogen-bond accepting heteroatoms, as well as the large electrochemically neutral hydrophobic regions. These insights provide a crucial integrated framework for optimising the next generation antipsychotic drug design.

Background: Butyrophenone neuroleptics are used in veterinary practice-haloperidol in the capture and translocation of wild ungulates, azaperone in swine-and antipsychotics prescribed to owners are a recognised cause of accidental toxicosis in dogs and cats. Organ-level toxicity data for this drug class are nonetheless almost absent in any species. Intravenous lipid emulsion (ILE) is an established antidote in small-animal emergency medicine for lipophilic intoxications, but the veterinary evidence base consists of case reports with clinical endpoints, and no controlled study has examined what ILE does to the tissues themselves. This study used an acute rodent overdose model to provide that organ-level assessment. Methods: Forty male Wistar albino rats were randomised to four groups of ten: control (saline 2 mL/kg oral gavage), HP (17.5 mg/kg oral gavage), HP + ILE (17.5 mg/kg HP plus 20% ILE 7.5 mL/kg intravenously at 0.5 h and 8 h, an empirical regimen) and ILE alone. Endpoints were assessed at 24 h. Seventeen histopathological parameters across seven organs were scored semi-quantitatively by a blinded pathologist (n = 10 per group), with independent re-scoring of a stratified random 30% subsample by a second blinded pathologist. Serum total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and routine biochemistry were measured in animals with adequate serum (n = 34 and n = 35). Comparisons used Kruskal-Wallis and Mann-Whitney U tests with Benjamini-Hochberg false discovery rate (FDR) control. Results: Haloperidol produced significant injury in the liver, kidney, brain and testis (all p < 0.001 vs. control) and mild histological cardiac changes (degeneration p = 0.014; congestion p = 0.034); lung and eye were unaffected. Serum urea was markedly elevated in HP (67.4 ± 13.2 vs. 46.5 ± 8.8 mg/dL; p = 0.001, d = 1.82) and HP + ILE (61.5 ± 8.7 mg/dL; p = 0.003), with unchanged creatinine, and correlated strongly with renal histopathology (renal inflammation vs. urea ρ = 0.74, p < 0.001). ILE significantly attenuated histopathological injury in 8 of the 12 haloperidol-associated parameters after FDR correction (renal congestion q = 0.032, r = 0.70; testicular Johnsen score q = 0.032, r = 0.66); the testicular score improved significantly relative to HP (q = 0.032) but remained statistically indistinguishable from control (p = 0.072), which does not establish equivalence. ILE did not reduce serum urea (HP + ILE vs. HP, p = 0.26) and did not modify the mild histological cardiac changes (p ≥ 0.40); no functional or electrophysiological cardiac endpoint was assessed. No group difference was detected in serum TOS or OSI (p = 0.43 and p = 0.51), whereas TAS was significantly reduced in the ILE-alone group (p = 0.011); the biological interpretation of this TAS finding remains uncertain, because interference of residual lipaemia with the spectrophotometric assay could not be excluded and would also propagate to the derived OSI. No tissue oxidative marker was measured. Transaminases were not elevated by haloperidol and showed no correlation with hepatic histopathology (|ρ| ≤ 0.17, all p > 0.34). ILE alone caused no histopathological abnormality at this dose and time point. Inter-observer agreement was high (95.6% exact agreement; median weighted κ = 0.893). Conclusions: In this acute overdose model, ILE is associated with a differential and structurally incomplete histopathological response: microscopic injury improves in four organs while renal function does not, and the mild histological cardiac changes are unaltered. Serum transaminases did not reflect concurrent organ-level injury at 24 h. Serum TOS and OSI showed no detectable group differences, while TAS was reduced in the ILE-alone group with an uncertain biological interpretation. Given the analytical uncertainty and the limited sample size, these indices provided no usable surrogate information about organ-level injury in this model. These findings define which organ systems respond and require confirmation in target veterinary species before informing clinical practice.

Hypogonadism in males is associated with reduced motivation, fatigue, and decreased goal-directed behavior, yet the neural mechanisms underlying these changes remain poorly understood. Dopamine signaling within the nucleus accumbens (NAc) plays a central role in regulating effort-based decision making, and here we tested the hypothesis that loss of testicular hormones alters mesoaccumbal dopamine function to increase sensitivity to effort-related costs. Male mice underwent orchiectomy (ORX) either before puberty onset or in adulthood and were tested in a progressive ratio 1 closed economy (PR1-CE) task. Dopamine-related function was probed using systemic haloperidol administration and high-performance liquid chromatography to measure dopamine and its metabolites, while whole-cell recordings assessed the intrinsic excitability of NAc spiny projection neurons (SPNs). ORX increased sensitivity to effort costs, reflected by a shift toward energy-efficient responding while maintaining food intake. These behavioral changes were accompanied by reduced responsiveness to haloperidol. Postpubertal ORX increased NAc dopamine content and reduced metabolite-to-dopamine ratios, whereas prepubertal ORX did not alter dopamine neurochemistry. Prepubertal ORX selectively reduced excitability of NAc core D1R[+] SPNs, whereas postpubertal ORX increased excitability across both D1R[+] and D1R[-] populations. Together, these findings demonstrate that ORX increases effort cost sensitivity and is associated with alterations in mesoaccumbal circuit function. Although similar behavioral phenotypes emerged following pre- and postpubertal ORX, distinct neurochemical and cellular adaptations suggest that timing may shape the neural response to ORX. These results provide insight into the circuit mechanisms that may underlie altered motivation following testicular hormone loss.