Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

Electrophysiological underpinnings of dysfunctional inhibitory control in adults with attention-deficit/hyperactivity disorder: evidence for reduced NoGo anteriorization.

Our aim was to delineate the electrophysiological basis of dysfunctional inhibitory control of adult ADHD via investigating the anteriorization of the P3 component of the event-related brain response associated with the NoGo task condition (i.e., NoGo anteriorization, NGA). NGA is a neurophysiological measure of brain topography for cognitive response control, which indexes an overall shift of the brain's electrical activity in anterior direction towards the prefrontal areas. While the NoGo P3 received considerable attention in the adult ADHD literature, the brain topography of this component, which reflects the inhibitory process, remains largely unaddressed. EEG recordings were obtained during a Go/NoGo task from 51 subjects (n = 26 adult patients with ADHD, n = 25 healthy controls) using a high-density, 128-channel BioSemi ActiveTwo recording system. ADHD patients had significantly lower P3 NGA response compared to controls. The decrease in NGA was related to impulsivity scores as measured by the Conners' Adult ADHD Rating Scale: patients with higher impulsivity scores had significantly lower NGA. Treatment with stimulant medication, as compared to the lack of such treatment, was associated with a correction of the lower NGA response in ADHD patients. The current study revealed a lower NGA in adult ADHD, a finding which is consistent with the inhibitory control and frontal lobe dysfunctions described in the disorder. Our finding of the inverse relationship between NGA and impulsivity suggests that clinically more severe impulsivity is linked to a more pronounced frontal dysfunction in adult ADHD subjects.

Elevated Serum Purine Levels in Schizophrenia: A Reverse Translational Study to Identify Novel Inflammatory Biomarkers.

BACKGROUND: Immunological markers and related signaling molecules in the blood are altered in schizophrenia mouse models, in acutely relapsed patients with schizophrenia, and in persons at a clinically high risk for subsequently developing psychosis, highlighting their potential as prognostic and theranostic biomarkers. Therefore, we herein aimed to identify novel potential biomarkers in the serum that are associated with purinergic signaling. METHODS: To our knowledge, this is the first study to assess the correlations among the levels of human serum adenine nucleotides (ATP, ADP), adenosine, P2X7 receptor, and disease activity in patients hospitalized due to an acute relapse of schizophrenia (n = 53) and healthy controls (n = 47). In addition, to validate these findings using a reverse translational approach, we examined the same parameters in an acute phencyclidine-induced schizophrenia mouse model. RESULTS: We found consistently elevated levels of ATP, ADP, interleukin (IL)-6, and IL-10 in both schizophrenia groups compared with the controls. The levels of adenosine, IL-1ß, IL-12, and C-reactive protein were also increased in the human patient samples. Moreover, ATP and ADP were significantly positively correlated with the Positive and Negative Symptom Scale item "lack of judgment and insight"; IL-1ß, IL-12, and tumour necrosis factor alpha were significantly positively correlated with "tension" and "depression"; and "disorientation" and "poor attention" were correlated significantly with IL-6 and IL-8. CONCLUSIONS: Our study suggests the promising potential of blood purines and inflammatory markers as future prognostic tools.

[Comments].

No abstract available.

Atypical resting-state gamma band trajectory in adult attention deficit/hyperactivity disorder.

Decreased gamma activity has been reported both in children and adults with attention deficit/hyperactivity disorder (ADHD). However, while ADHD is a lifelong neurodevelopmental disorder, our insight into the associations of spontaneous gamma band activity with age is limited, especially in adults. Therefore, we conducted an explorative study to investigate trajectories of resting gamma activity in adult ADHD patients (N = 42) versus matched healthy controls (N = 59). We investigated the relationship of resting gamma activity (30-48 Hz) with age in four right hemispheric electrode clusters where diminished gamma power in ADHD had previously been demonstrated by our group. We found significant non-linear association between resting gamma power and age in the lower frequency gamma1 range (30-39 Hz) in ADHD as compared to controls in all investigated locations. Resting gamma1 increased with age and was significantly lower in ADHD than in control subjects from early adulthood. We found no significant association between gamma activity and age in the gamma2 range (39-48 Hz). Alterations of gamma band activity might reflect altered cortical network functioning in adult ADHD relative to controls. Our results reveal that abnormal gamma power is present at all ages, highlighting the lifelong nature of ADHD. Nonetheless, longitudinal studies are needed to confirm our results.

Using informative prior based on expert opinion in Bayesian estimation of the transition probability matrix in Markov modelling-an example from the cost-effectiveness analysis of the treatment of patients with predominantly negative symptoms of schizophrenia with cariprazine.

BACKGROUND: When patient health state transition evidence is missing from clinical literature, analysts are inclined to make simple assumptions to complete the transition matrices within a health economic model. Our aim was to provide a solution for estimating transition matrices by the Bayesian statistical method within a health economic model when empirical evidence is lacking. METHODS: We used a previously published cost-effectiveness analysis of the use of cariprazine compared to that of risperidone in patients with predominantly negative symptoms of schizophrenia. We generated the treatment-specific state transition probability matrices in three different ways: (1) based only on the observed clinical trial data; (2) based on Bayesian estimation where prior transition probabilities came from experts' opinions; and (3) based on Bayesian estimation with vague prior transition probabilities (i.e., assigning equal prior probabilities to the missing transitions from one state to the others). For the second approach, we elicited Dirichlet prior distributions by three clinical experts. We compared the transition probability matrices and the incremental quality-adjusted life years (QALYs) across the three approaches. RESULTS: The estimates of the prior transition probabilities from the experts were feasible to obtain and showed considerable consistency with the clinical trial data. As expected, the estimated health benefit of the treatments was different when only the clinical trial data were considered (QALY difference 0.0260), its combination with the experts' beliefs were used in the economic model (QALY difference 0.0253), and when vague prior distributions were used (QALY difference 0.0243). CONCLUSIONS: Imputing zeros to missing transition probabilities in Markov models might be untenable from the clinical perspective and may result in inappropriate estimates. Bayesian statistics provides an appropriate framework for imputing missing values without making overly simple assumptions. Informative priors based on expert opinions might be more appropriate than vague priors.

Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure.

The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients' CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients' CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible. The role of CYP3A4 expression in aripiprazole metabolism did not predominate even in the patients with nonfunctional CYP2D6 alleles. Furthermore, dehydroaripiprazole exposure was also CYP2D6 genotype-dependent. Dehydroaripiprazole concentrations were comparable with aripiprazole levels in patients with functional CYP2D6 alleles, and 35% or 22% of aripiprazole concentrations in patients with one or two non-functional CYP2D6 alleles, respectively. The concomitant intake of CYP2D6 inhibitors, risperidone, metoprolol, or propranolol was found to increase aripiprazole concentrations in patients with at least one wild-type CYP2D6*1 allele. Risperidone and 9-hydroxy-risperidone inhibited both dehydrogenation and hydroxylation of aripiprazole, whereas metoprolol and propranolol blocked merely the formation of the active dehydroaripiprazole metabolite, switching towards the inactivation pathways. Patients' CYP2D6 genotype and co-medication with CYP2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics. Taking into account CYP2D6 genotype and co-medication with CYP2D6 inhibitors may improve the outcomes of aripiprazole therapy.

Impaired early information processing in adult ADHD: a high-density ERP study.

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) often demonstrate sensory processing difficulties in the form of altered sensory modulation, which may contribute to their symptomatology. Our objective was to investigate the neurophysiological correlates of sensory processing deficits and the electrophysiological characteristics of early information processing in adult ADHD, measured by the P1 event-related potential (ERP). METHODS: We obtained ERPs during a Go/NoGo task from 26 adult patients with ADHD and 25 matched controls using a high-density 128-channel BioSemi ActiveTwo recording system. RESULTS: ADHD patients had a significantly reduced P1 component at occipital and inferotemporal scalp areas compared to controls. The reduction was associated with inattention and hyperactivity symptom severity, as measured by the Conners' Adult ADHD Rating Scale. ADHD patients with higher inattention scores had significantly smaller P1 amplitudes at posterior scalp sites, while higher hyperactivity scores were associated with higher P1 amplitudes. CONCLUSIONS: Deficits in early sensory processing, as measured by the P1 ERP component, are present in adult ADHD patients and are associated with symptom severity. These findings are suggestive of bottom-up cognitive deficits in ADHD driven by impairments in early visual processing, and provide evidence that sensory processing problems are present at the neurophysiological level in this population.

Binding Modes of a Phenylpyridinium Styryl Fluorescent Dye with Cucurbiturils.

In order to explore how cucurbituril hosts accommodate an N-phenyl-pyridinium derivative guest, the complexation of the solvatochromic dye, 4-(4-(dimethylamino)styryl)-1-phenylpyridinium iodide (PhSt) with ,',δ,δ'-tetramethyl-cucurbit[6]uril (Me4CB6) and cucurbit[7]uril (CB7) was investigated by absorption spectroscopic, fluorescence and NMR experiments. In aqueous solutions, PhSt forms 1:1 complexes with both cucurbiturils, the complex with CB7 has a higher stability constant (Ka = 6.0 × 106 M-1) than the complex with Me4CB6 (Ka = 1.1 × 106 M-1). As revealed by NMR experiments and confirmed by theoretical calculations, CB7 encapsulates the whole phenylpyridinium entity of the PhSt cation guest, whereas the cavity of Me4CB6 includes only the phenyl ring, the pyridinium ring is bound to the carbonyl rim of the host. The binding of PhSt to cucurbiturils is accompanied by a strong enhancement of the fluorescence quantum yield due to the blocking of the deactivation through a twisted intramolecular charge transfer (TICT) state. The TICT mechanism in PhSt was characterized by fluorescence experiments in polyethylene glycol (PEG) solvents of different viscosities. The PhSt-CB7 system was tested as a fluorescence indicator displacement (FID) assay, and it recognized trimethyl-lysine selectively over other lysine derivatives.

[Therapeutic drug monitoring of atypical antipsychotics and antidepressants: conclusions of the first year at Semmelweis University].

INTRODUCTION: Pharmacotherapy supported by therapeutic drug monitoring (TDM) has a tradition in psy - chiatry. Novel diagnostic infrastructure based on mass spectrometry has been developed at Semmelweis University, allowing the renewal of psychiatric treatments supported by TDM. In a cooperation of the Department of Laboratory Medicine, and the Department of Psychiatry and Psychotherapy 13 drugs were assayed in a routine setting. Several drugs were determined with their pharmacologically active metabolites. METHODS: In 2019, 678 TDM tests were performed on samples taken from 465 patients receiving treatment at the Depart - ment of Psychiatry and Psychotherapy. No patient-related data were used for the presented evaluation. Analytical method performance was evaluated by method validation, using internal controls and participating in an inter - national external quality assessment scheme. The assay results were compared to reference ranges recommended in the leading international consensus guideline. RESULTS: Tests of clozapine, olanzapine and miscellaneous drugs comprised 35.8%, 34.9% and 29.3% of all orders, res - pec tively. A high proportion of results was outside the limits of the therapeutic ranges. Similarly, several concentra tion ratios of metabolites and parent drugs were outside the reference ranges. CONCLUSIONS: The reference ranges related to drug and metabolite concentrations are useful indicators but do not pre - sent therapeutic goals or a basis for clinical decisions by themselves. The interpretation of TDM results should be based on the condition of the patient, the clinical goals and the therapeutic context (e.g. the coadministration of other drugs), handled as an element of more complex decision making, and should serve the individualization of therapy.

Alterations in resting-state gamma activity in patients with schizophrenia: a high-density EEG study.

Alterations of EEG gamma activity in schizophrenia have been reported during sensory and cognitive tasks, but it remains unclear whether changes are present in resting state. Our aim was to examine whether changes occur in resting state, and to delineate those brain regions where gamma activity is altered. Furthermore, we wanted to identify the associations between changes in gamma activity and psychopathological characteristics. We studied gamma activity (30-48 Hz) in 60 patients with schizophrenia and 76 healthy controls. EEGs were acquired in resting state with closed eyes using a high-density, 256-channel EEG-system. The two groups were compared in absolute power measures in the gamma frequency range. Compared to controls, in patients with schizophrenia the absolute power was significantly elevated (false discovery rate corrected p < 0.05). The alterations clustered into fronto-central and posterior brain regions, and were positively associated with the severity of psychopathology, measured by the PANSS. Changes in gamma activity can lead to disturbed coordination of large-scale brain networks. Thus, the increased gamma activity in certain brain regions that we found may result in disturbances in temporal coordination of task-free/resting-state networks in schizophrenia. Positive association of increased gamma power with psychopathology suggests that altered gamma activity provides a contribution to symptom presentation.

[How we see the development of clinical trials from the investigators' side?]

This is a discussion paper on research in clinical pharmacology in the field of psychiatry. In addition to other factors the decline in discovery and development of new drugs in the field of psychiatry and the developments and growing complexity in the field of clinical trial technology, including outsourcing and risk based monitoring, reduced the number of young clinical researchers interested in this important field. The challenges posed by the restructuring within the pharmacological industry - including digitalization - should induce changes in the structure and in the processes of clinical pharmacology research and in the training of clinical research staff members. The approval of esketamine nasal spray for treatment resistant depression by the FDA and the results of research with psychedelics call for more education and training in this specific field.

Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.

BACKGROUND: Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms. METHODS: In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36. FINDINGS: Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment. INTERPRETATION: Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia. FUNDING: Gedeon Richter Plc.

Experimental evidence of TICT state in 4-piperidinyl-1,8-naphthalimide - a kinetic and mechanistic study.

The excited state processes in N-propyl-4-piperidinyl-1,8-naphthalimide have been studied by measuring its fluorescence spectra and decay curves in solvents of different polarity and viscosity and also in a frozen solvent glass. The results unanimously proved the formation of a dark twisted intramolecular charge transfer (TICT) state from the emissive charge transfer (CT) species, the direct product of excitation. The rate coefficients of the TICT process and the deactivations of the CT and TICT species were determined, using a reversible two-state kinetic model. The temperature dependence of the kinetic data was consistent with a kinetic barrier consisting of three terms, the inherent barrier of the reaction, and the contributions of the solute-solvent interactions related to the solvent viscosity and polarity. The potential energy surfaces were calculated in the S0 and the S1 states along the coordinate of turning motion which was conclusive concerning the direction of the twisting and indicated a possible conformational change of the piperidinyl unit. The theoretical calculations confirmed that the TICT species is dark and has a stronger charge transfer character compared to the CT state.

Suicidal ideation in adult ADHD: Gender difference with a specific psychopathological profile.

OBJECTIVE: To investigate suicidal ideation (SI) in patients with adult ADHD (aADHD), and its association with gender and psychopathology. METHODS: Case-control study with 206 participants (patients = 103/healthy controls = 103; matched on gender, age, and education). SI was assessed by the Beck-I Depression-Inventory. The Conners' Adult ADHD Rating Scale (CAARS) was used to characterize the ADHD symptom-domains. RESULTS: Compared to controls, the likelihood of SI was significantly higher in females with ADHD (odds ratio[OR] = 25.0 (95%CI:2.98-200.0); the difference was not significant in males (OR = 2.09 (95%CI:0.75-5.81). In females, "Problems with Self-Concept" scores on the CAARS showed the closest association with SI (OR = 5.60,95%CI:2.34-13.41]), while in males it was "Impulsivity" scores (OR = 3.01,95%CI:1.50-6.06). CONCLUSION: Our findings extend previously described transdiagnostic associations of specific psychopathological risk factors to aADHD, including problems with self-concept and impulsivity, which are robustly associated with suicidality across diagnostic boundaries. In addition, they indicate that these associations exhibit pronounced gender-specificity in aADHD.

An uracil-linked hydroxyflavone probe for the recognition of ATP.

Background: Nucleotides are essential molecules in living systems due to their paramount importance in various physiological processes. In the past years, numerous attempts were made to selectively recognize and detect these analytes, especially ATP using small-molecule fluorescent chemosensors. Despite the various solutions, the selective detection of ATP is still challenging due to the structural similarity of various nucleotides. In this paper, we report the conjugation of a uracil nucleobase to the known 4'-dimethylamino-hydroxyflavone fluorophore. Results: The complexation of this scaffold with ATP is already known. The complex is held together by stacking and electrostatic interactions. To achieve multi-point recognition, we designed the uracil-appended version of this probe to include complementary base-pairing interactions. The theoretical calculations revealed the availability of multiple complex structures. The synthesis was performed using click chemistry and the nucleotide recognition properties of the probe were evaluated using fluorescence spectroscopy. Conclusions: The first, uracil-containing fluorescent ATP probe based on a hydroxyflavone fluorophore was synthesized and evaluated. A selective complexation with ATP was observed and a ratiometric response in the excitation spectrum.

Potential Role of Patients' CYP3A-Status in Clozapine Pharmacokinetics.

Background: The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy. Methods: Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients' CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients. Results: The patients' CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53±56.53 in low expressers vs 78.05±29.57 or 66.52±0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18±0.64 vs 4.98±1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers. Conclusion: Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy.

Neural Correlates of Error Monitoring in Adult Attention Deficit Hyperactivity Disorder After Failed Inhibition in an Emotional Go/No-Go Task.

The authors' aim was to investigate the modulation of event-related potentials (ERPs) by the affective content of stimuli in adult attention deficit hyperactivity disorder (ADHD) patients during error monitoring. By obtaining ERPs from 26 adult ADHD patients and 14 healthy controls in an emotional go/no-go task, the authors investigated two error-related ERP components, the error-related negativity (ERN) and error positivity (Pe). In ADHD patients, the ERN amplitude decreased for negative stimuli after failed response inhibition ("no-go response") and Pe amplitude decreased for neutral stimuli compared with the controls. These findings suggest that ADHD patients differ from controls both in the early and in the later stages of error processing.