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Background: People in a putatively late prodromal state not only have an enhanced risk for psychosis but already suffer from mental and functional disturbances. Aims: To evaluate the acute effects of a combined supportive and antipsychotic treatment on prodromal symptoms. Method: Putatively prodromal individuals were randomly assigned to a needs-focused intervention without (n=59) or with amisulpride (n=65). Outcome measures at 12-weeks effects were prodromal symptoms, global functioning and extrapyramidal side- effects. Results Amisulpride plus the needs- focused intervention produced superior effects on attenuated and full-blown psychotic symptoms, basic, depressive and negative symptoms, and global functioning. Main side-effects were prolactin associated. Conclusions: Coadministration of amisulpride yielded a marked symptomatic benefit. Effects require confirmation by a placebo-controlled study. Declaration of interest: None. Funding detailed in Acknowledgements. Adapted from the source document.

The aim of this study was to characterize the pharmacokinetic (PK) properties and assess the safety profiles of different formulations of levosulpiride in healthy Chinese volunteers. Levosulpiride was administered to 42 healthy male and female (1:1) subjects in tablet (PO) and injectable (IM and IV) dosage forms. Blood samples were collected at regular intervals after single and multiple drug administration. The concentration of levosulpiride in plasma was determined by a validated liquid chromatography tandem mass spectrometry method. Noncompartmental analysis was performed to estimate PK parameters. One-way ANOVA was used to test for linearity and assess the effect of sex on the PK properties of the drug. Adverse effects were monitored using investigators’ questionnaires and subjects’ spontaneous reports, vital sign measurements, hematology, clinical chemistry, and electrocardiography. Levosulpiride exhibited linear pharmacokinetic properties over the dose range of 25 to 100 mg by PO route and 25 to 75 mg by IM route. The corresponding mean AUC0−t increased from 449 to 1443 ng/h/mL and from 2874 to 7559 ng/h/mL, respectively. After repeated PO and IM administration, steady state was reached on day 4 of multiple dosing with accumulation index of 1.8 and on day 2 of multiple dosing with accumulation index of 1.3, respectively. The bioavailability of levosulpiride via IM and PO routes was 96.8% and 23.4%, respectively. No significant differences were observed on PK properties between male and female subjects. More than half (23 of 42 [54.8%]) of healthy volunteers experienced one or more adverse events in total, including constipation, diarrhea, drowsiness, skin rash, and extrapyramidal reactions. The regimen of 50-mg levosulpiride tablets 3 times daily and 50-mg levosulpiride injection (IM) twice daily provided similar accumulation coefficient, and the former reached steady state much more slowly. The bioavailability of levosulpiride after oral administration was poor and the absorption rate was slower compared with IM administration, which imply delayed clinical efficacy for patients with dyspepsia or neuropsychiatric disorders. On multiple dosing, levosulpiride exhibited poor tolerability with high incidence of adverse reactions. There was no need to adjust administration regimen based on sex. ClinicalTrials.gov Identifier: NCT02481583.

Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18–40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1–4 mg per day; n=103), amisulpride (200–800 mg per day; n=104), olanzapine (5–20 mg per day; n=105), quetiapine (200–750 mg per day; n=104), or ziprasidone (40–160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0·37, [95% CI 0·24–0·57]), olanzapine (HR 0·28 [0·18–0·43]), quetiapine (HR 0·52 [0·35–0·76]), and ziprasidone (HR 0·51 [0·32–0·81]). However, symptom reductions were virtually the same in all the groups, at around 60%. This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement. AstraZeneca, Pfizer, Sanofi-Aventis.

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, whereas loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.

ObjectiveIn this study, we aimed to evaluate the safety and efficacy of a combination of 100 mg mebeverine and 25 mg sulpiride (Colona®) in patients with functional gastrointestinal disorders.MethodsThis multicenter, cohort study was conducted in Egypt, comprising 253 patients diagnosed with functional gastrointestinal disorders. The treatment duration was 2 weeks. The primary endpoint was the percentage of relative change in the tailored gastrointestinal symptoms rating scale.ResultsThe baseline tailored gastrointestinal symptoms rating scale mean (±SD) score was 11.42 ± 4.10. However, after 2 weeks (±1 week) of combination therapy, the score significantly decreased to 3.11 ± 2.48 (p < 0.01), demonstrating a mean (±SD) improvement of 71.84% ±20.56%. Among 253 patients, 227 patients (89.72%, 95% confidence interval: 85.96%-93.49%) demonstrated ≥50% improvement in the tailored gastrointestinal symptoms rating scale total score, whereas 26 (10.28%) did not report any improvement. In terms of safety, 2 (0.79%) patients reported diarrhea, 1 (0.4%) had mild dyspepsia, and 1 (0.4%) had galactorrhea.ConclusionOur results suggest that the combination of mebeverine and sulpiride may represent a safe and effective treatment option for patients with functional gastrointestinal disorders.

Sulpiride (SUL), is a selective antidopaminergic drug that had extensive biological activities. However, its sparingly aqueous solubility and limited gastrointestinal permeability lead to scanty oral bioavailability which hinders its clinical efficacy. SUL-loaded lipospheres (SUL-LPS) were designed to serve as an oral biocompatible nanovector for improving SUL permeability as well as conquering its low oral absorption and then in turn enhancing its antidepressant action. SUL-LPS were fabricated via two processing techniques namely, melt emulsification and solvent evaporation. The impact of different lipid cores, phospholipid shells together with various surfactant concentrations and types on the lipospheres properties were screened. Detailed physicochemical elucidations were performed followed by ex vivo permeation appraisal using the non-everted intestine model. The pharmacokinetic parameters of SUL-LPS, free SUL and marketed product were assessed following oral administration to healthy rats. Reserpine-induced depression rat model was used to assess the antidepressant action of SUL-LPS on which full behavioural and biochemical analysis was conducted. Safety attributes of nanoencapsulated SUL on the brain and other internal organs were evaluated. The optimum LPS revealed an excellent nanosize with a narrow PdI, negative zeta potential and acceptable entrapment efficiency of 68.62 nm, 0.242, -30.4 mV and 84.12%, respectively. SUL-LPS showed a sustained release pattern and 2.1-fold enhancement in the intestinal permeation parameters with low mucin interaction. Oral pharmacokinetic appraisal exhibited that LPS provided 3.4-fold improvement in SUL oral bioavailability together with long-circulating properties, relative to the free drug. Pharmacodynamic study confirmed the superior antidepressant action of SUL-LPS as evident by 1.6 and 1.25-fold elevation in the serotonin and dopamine expressions, respectively. Meanwhile, nanotoxicological appraisal proved the biocompatibility of SUL-LPS upon repetitive oral administration. Rationally designed lipospheres hold promising in vitro and in vivo characteristics for efficient delivery of SUL with high oral bioavailability, antidepressant activity together with a good safety profile.

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n =41), the unspecific opioid receptor antagonist naltrexone (50 mg, n =40) or placebo ( n =40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.

Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals’ baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.

The relationship between symptom improvement (SI) and acceleration of gastric emptying (GE) for different drugs used in the treatment of idiopathic and diabetic gastroparesis is uncertain. In this paper we examined the study-specific correlations between SI and GE, and we performed a meta-regression analysis of the association across multiple studies. The MEDLINE database (1,946 to present) was searched, and only controlled trials or trials with an established effective comparator that compared both SI and GE were included. Studies were identified for metoclopramide (n=6), domperidone (n=6), cisapride (n=14), erythromycin (n=3), botulinum toxin (n=2), and levosulpiride (n=3). Even though most drugs concomitantly improved symptoms and accelerated GE, no study reported a significant correlation between SI and GE. Moreover, a correlation analysis over all studies using meta-regression did not show a significant relationship between SI and GE. Our findings need to be qualified by inconsistencies in study methods, which is a limitation but also suggests that our findings are robust to methodological factors. In this review, no evidence of a relationship between SI and GE was identified for different drugs used for the treatment of gastroparesis. This finding questions the use of GE measurement to direct drug development for gastroparesis.