Search Results (21)

We tried to synthesize the possibilities of predicting the response to clozapine treatment, which can significantly improve the efficacy of the active substance and reduce adverse reactions, and how the active substance acts at the D1 dopaminergic receptors D2, D3, D4, and D5, muscarinic M1, M2, M3, and M5, and the histamine and alpha 1 adrenergic receptor, as well as how it contributes to increased cerebral blood flow, the effect on ribosomal protein S6 function, or the effect on kynurenine 3-monooxygenase function. Clozapine is one of the most effective antipsychotics, and there is potential to improve performance by combining it with different compounds to limit adverse effects or by augmenting it with other antipsychotics (amisulpride, paliperidone), other active substances with different properties (minocycline, N-acetylcysteine, memantine), or alternative therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation). There are also significant steps in optimizing clozapine efficacy by predicting treatment response, which could be determined by testing the following: plasma levels of clozapine N-oxide and N-desmethylclozapine, serum levels of neurotrophins and glutamate, genetic testing, the polygenic risk score, morphometry, or even the identification and accurate determination of persistent negative symptoms. Full article

Most drugs excreted in urine are not filtered by wastewater treatment plants and end up in aquatic systems. At concentrations measured in waters, toxic effects on species have been described. Second, most of the drug consumption is attributable to primary care prescriptions. We thus present here, an ecotoxicity classification of the most sold drugs in primary care in Switzerland. Three datasets were combined: (1) surveyed ecotoxic drugs by the Swiss National Surface Water Quality Monitoring Programme and its European equivalent, (2) the top 50 drugs by sale in primary care in Switzerland, and (3) active pharmaceutical ingredient (API) concentrations in Lake Geneva and the rivers of the canton of Vaud between 2017 and 2022. We classified APIs into five categories from the safest to the least safe: (1) APIs found in concentrations (C) <10× their environmental quality standard (EQS·10⁻¹), (2) EQS·10⁻¹ < C < EQS and not listed by the Swiss or the EU Watch List, (3) EQS·10⁻¹ < C < EQS and listed, (4) C > EQS and not listed, and (5) C > EQS and listed. We obtained full ecotoxicological data for 35 APIs. Fifteen APIs were designated as safe (category (1):paracetamol, tramadol, amisulpride, citalopram, mirtazapine, metformin, gabapentin, lamotrigine, primidone, candesartan, irbesartan, atenolol, hydrochlorothiazide, ofloxacin, sulfadiazine), eleven as intermediately safe, and nine were of concern (azithromycin, ciprofloxacin, clarithromycin, sulfamethoxazole, carbamazepine, diclofenac, ibuprofen, iomeprol, iopromide). Full data were available for only one-third of the drugs most sold in primary care. Where data do exist, we observed significant differences in environmental impact among the same class of drugs. Our classification could therefore help guide doctors to adopt more eco-friendly prescriptions. Full article

Background/Objectives: Approximately one in five individuals will experience major depressive disorder (MDD), and 30% exhibit resistance to standard antidepressant treatments, resulting in a diagnosis of treatment-resistant depression (TRD). Historically, opium was used effectively to treat depression; however, when other medications were introduced, its use was discontinued due to addiction and other hazards. Recently, kappa opioid receptor (KOR) antagonism has been proposed as a potential mechanism for treating TRD. The main research question is whether commonly used psychotropic medications possess KOR antagonist properties and whether this characteristic could contribute to their efficacy in TRD. Methods: We investigated the antinociceptive effects of many psychotropic medications and their interactions with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of these agents. Results: The antidepressants mianserin and mirtazapine (separately) induced dose-dependent antinociception, each yielding a biphasic dose–response curve. Similarly, the antidepressant venlafaxine produced a potent effect and reboxetine produced a weak effect. The antipsychotics risperidone and amisulpride exhibited a dose-dependent antinociceptive effect. The sedative–hypnotic zolpidem induced a weak bi-phasic dose-dependent antinociceptive effect. All seven psychotropic medications elicited antinociception, which was reversed by the non-selective opiate antagonist naloxone and, separately, by the kappa-selective antagonist Nor-BNI. Conclusions: Clinical studies are mandatory to establish the potential efficacy of augmentation of the treatment with antidepressants with these drugs in persons with treatment-resistant depression and the optimal dosage of medications prescribed. We suggest a possible beneficial effect of antidepressants with kappa antagonistic properties. Full article

(1) Background: The concentration of amisulpride, an atypical antipsychotic drug, is most often determined in the blood, with many inconveniences. An alternative may be to use saliva as a diagnostic material for this purpose. The development of a method to determine amisulpride in saliva using a small volume of biological material could significantly improve patient comfort during Therapeutic Drug Monitoring (TDM). (2) Methods: Therefore, the aim of this study was to develop a method to determine amisulpride in 200 μL of saliva using solid-phase extraction for isolation and liquid chromatography with a diode array detector (LC-DAD) for quantitative analysis. (3) Results: The method was validated by determining its linearity in the concentration range 5–500 ng/mL (R² > 0.99), and the intra- and inter-day precision expressed as coefficient of variation (CV%) did not exceed 9%. (4) Conclusions: The developed method was used to determine the salivary concentration of amisulpride in patients treated with the studied compound, confirming its usefulness in TDM. Full article

Temporal discounting is a phenomenon where a reward loses its value as a function of time (e.g., a reward is more valuable immediately than when it delays in time). This is a type of intertemporal decision-making that has an association with impulsivity and self-control. Many pathologies exhibit higher discounting rates, meaning they discount more the values of rewards, such as addictive behaviors, bipolar disorder, attention-deficit/hyperactivity disorders, social anxiety disorders, and major depressive disorder, among others; thus, many studies look for the mechanism and neuromodulators of these decisions. This systematic review aims to investigate the association between pharmacological administration and changes in temporal discounting. A search was conducted in PubMed, Scopus, Web of Science, Science Direct and Cochrane. We used the PICO strategy: healthy humans (P-Participants) that received a pharmacological administration (I-Intervention) and the absence of a pharmacological administration or placebo (C-Comparison) to analyze the relationship between the pharmacological administration and the temporal discounting (O-outcome). Nineteen studies fulfilled the inclusion criteria. The most important findings were the involvement of dopamine modulation in a U-shape for choosing the delayed outcome (metoclopradime, haloperidol, and amisulpride). Furthermore, administration of tolcapone and high doses of d-amphetamine produced a preference for the delayed option. There was a time-dependent hydrocortisone effect in the preference for the immediate reward. Thus, it can be concluded that dopamine is a crucial modulator for temporal discounting, especially the D2 receptor, and cortisol also has an important time-dependent role in this type of decision. One of the limitations of this systematic review is the heterogeneity of the drugs used to assess the effect of temporal discounting. Full article

An interesting issue observed in some drugs is the “double peak phenomenon” (DPP). In DPP, the concentration-time (C-t) profile does not follow the usual shape but climbs to a peak and then begins to degrade before rising again to a second peak. Such a phenomenon is observed in the case of amisulpride, which is a second-generation antipsychotic. The aim of this study was to develop a model for the description of double peaks in amisulpride after oral administration. Amisulpride plasma C-t data were obtained from a 2 × 2 crossover bioequivalence study in 24 healthy adult subjects. A nonlinear mixed-effects modeling approach was applied in order to perform the analysis. Participants’ characteristics, such as demographics (e.g., body weight, gender, etc.), have also been investigated. A model for describing the double peak phenomenon was successfully developed. Simulations were run using this model to investigate the impact of significant covariates and recommend appropriate dosage regimens. For comparison purposes and to investigate the suitability of our developed model for describing the double peak phenomenon, modeling of previously published population pharmacokinetic models was also applied to the C-t data of this study. Full article

The objective of this work was to evaluate the efficiency of a solar photocatalytic process using g-C₃N₄ as photocatalyst on the degradation of pharmaceutical compounds detected in hospital wastewater treatment plant secondary effluents. A compound parabolic collector pilot plant, established in the secondary effluent stream of the Ioannina city hospital wastewater treatment plant, was used for the photocatalytic experiments. The analysis of the samples before and after the photocatalytic treatment was accomplished using solid phase extraction (SPE), followed by UHPLC-LTQ/Orbitrap HRMS. Initial effluent characterization revealed the presence of ten pharmaceutical compounds. Among these, amisulpride, O-desmethyl venlafaxine, venlafaxine and carbamazepine were detected in all experiments. Initial concentrations ranged from 73 ng L⁻¹ for citalopram to 2924.53 ng L⁻¹ for O-desmethyl venlafaxine. The evolution of BOD₅ and COD values were determined before and after the photocatalytic treatment. All detected pharmaceuticals were removed in percentages higher than 54% at an optimum catalyst loading ranging between 200 and 300 mg L⁻¹. The potential of the catalyst to be reused without any treatment for two consecutive cycles was studied, showing a significant efficiency decrease. Full article

In the present study, the photocatalytic degradation of amisulpride using g-C₃N₄ catalyst under UV-A irradiation was investigated. The photocatalytic process was evaluated in terms of its effectiveness to remove amisulpride from ultrapure and real municipal wastewater. High removal percentages were achieved in both aqueous matrices. However, a slower degradation rate was observed using wastewater as matrix that could be attributed to its complex chemical composition. The transformation products (TPs) were identified with liquid chromatography–mass spectrometry (LC–MS) in both ultrapure and real municipal wastewater. Based on the identified TPs, the photocatalytic degradation pathways of amisulpride are proposed which include mainly oxidation, dealkylation, and cleavage of the methoxy group. Moreover, the contribution of reactive species to the degradation mechanism was studied using well-documented scavengers, and the significant role of h⁺ and O₂^•− in the reaction mechanism was proved. The evolution of ecotoxicity was also estimated using microalgae Chlorococcum sp. and Dunaliella tertiolecta. Low toxicity was observed during the overall process without the formation of toxic TPs when ultrapure water was used as matrix. In the case of real municipal wastewater, an increased toxicity was observed at the beginning of the process which is attributed to the composition of the matrix. The application of heterogeneous photocatalysis reduced the toxicity, and almost complete detoxification was achieved at the end of the process. Our results are in accordance with literature data that reported that heterogeneous photocatalysis is effective for the removal of amisulpride from aqueous matrices. Full article

Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host’s eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018–2022) and identified twenty two eligible cases, restricted only to human patients’ experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (Lactobacillus and Bifidobacterium), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms. Full article

In this work, the degradation performance for the photocatalytic oxidation of eight micro-pollutants (amisulpride, benzotriazole, candesartan, carbamazepine, diclofenac, gabapentin, methlybenzotriazole, and metoprolol) within real secondary effluent was investigated using three different reactor designs. For all reactor types, the influence of irradiation power on its reaction rate and energetic efficiency was investigated. Flat cell and batch reactor showed almost similar substance specific degradation behavior. Within the immersion rotary body reactor, benzotriazole and methyl-benzotriazole showed a significantly lower degradation affinity. The flat cell reactor achieved the highest mean degradation rate, with half time values ranging from 5 to 64 min with a mean of 18 min, due to its high catalysts surface to hydraulic volume ratio. The EE/O values were calculated for all micro-pollutants as well as the mean degradation rate constant of each experimental step. The lowest substance specific energy per order (EE/O) values of 5 kWh/m³ were measured for benzotriazole within the batch reactor. The batch reactor also reached the lowest mean values (11.8–15.9 kWh/m³) followed by the flat cell reactor (21.0–37.0 kWh/m³) and immersion rotary body reactor (23.9–41.0 kWh/m³). Catalyst arrangement and irradiation power were identified as major influences on the energetic performance of the reactors. Low radiation intensities as well as the use of submerged catalyst arrangement allowed a reduction in energy demand by a factor of 3–4. A treatment according to existing treatment goals of wastewater treatment plants (80% total degradation) was achieved using the batch reactor with a calculated energy demand of 7000 Wh/m³. Full article

There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets. Full article

Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders. Full article

Obsessive slowness is described as a complex and disabling clinical syndrome that causes extreme slowness in performing tasks, with potential personal and functional impairment. It is a rare condition with a challenging differential diagnosis with obsessive-compulsive disorders, mental retardation and catatonia, and its existence as an independent syndrome is still debated by authors and not included by classification systems. Therefore, its treatment management is not well-defined and it still represents a clinical challenge for clinicians. Currently, the main proposal is a mix of antidepressant, antipsychotic, psychoeducation, psychotherapy and biological non-pharmacological interventions. Hereby, we describe a case of an 18-year-old male patient who presented debilitating slowness and severe impairment. Managing his treatment was particularly challenging for clinicians and was ultimately improved with escitalopram 30 mg/day combined with memantine 10 mg/day and amisulpride 400 mg/day. Full article

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO₂ laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals’ ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain. Full article

Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia. Full article