N-acetylcysteine enhances the antipsychotic effect of aripiprazole in the neurodevelopmental rat model of schizophrenia.

Impaired glutathione (GSH) synthesis and dopaminergic transmission are important factors in the pathophysiology of schizophrenia. Our research aimed to assess the effects of l-buthionine-(S,R)-sulfoximine (BSO), a GSH synthesis inhibitor, and GBR 12909, a dopamine reuptake inhibitor, administered alone or in combination, to Sprague–Dawley rats during early postnatal development (p5–p16), on the levels of GSH, sulfur amino acids, global DNA methylation, and schizophrenia-like behavior. GSH, methionine (Met), homocysteine (Hcy), and cysteine (Cys) contents were determined in the liver, kidney, and in the prefrontal cortex (PFC) and hippocampus (HIP) of 16-day-old rats. DNA methylation in the PFC and HIP and schizophrenia-like behavior were assessed in adulthood (p90–p93). BSO caused the tissue-dependent decreases in GSH content and alterations in Met, Hcy, and Cys levels in the peripheral tissues and in the PFC and HIP. The changes in these parameters were accompanied by alterations in the global DNA methylation in the studied brain structures. Parallel to changes in the global DNA methylation, deficits in the social behaviors and cognitive functions were observed in adulthood. Only BSO + GBR 12909-treated rats exhibited behavioral alterations resembling positive symptoms in schizophrenia patients. Our results suggest the usefulness of this neurodevelopmental model for research on the pathomechanism of schizophrenia.

Preclinical and clinical studies have shown that the antipsychotic drug aripiprazole and the antioxidant N-acetylcysteine have unique biological properties. The aim of the study was to investigate, in a rat model of schizophrenia, the effects of chronic administration of these drugs on schizophrenia-like behaviors and anaerobic cysteine metabolism in the hippocampus (HIP). The schizophrenia-type changes were induced in Sprague-Dawley rats by repeated administration of the glutathione synthesis inhibitor l-butionine-(S,R)-sulfoximine in combination with the dopamine reuptake inhibitor GBR 12909 in the early postnatal period. Adult model rats were chronically treated with aripiprazole (0.3 mg·kg-1 , i.p.) or N-acetylcysteine (30 mg·kg-1 , orally), and their effects on schizophrenia-like behaviors were assessed using the social interaction test and novel object recognition test. In the HIP, the level of anaerobic cysteine metabolites, H2 S, and bound sulfane sulfur were determined by a fluorescence method, while the expression of H2 S-synthetizing enzymes: cystathionine β-synthase (CBS) and mercaptopyruvate sulfurtransferase (MST) by western blot. Long-term treatment with aripiprazole or N-acetylcysteine reversed social and cognitive deficits and reduced the exploratory behaviors. In the HIP of 16-day-old model pups, H2 S levels and MST protein expression were significantly decreased. In adult model rats, H2 S levels remained unchanged, bound sulfane sulfur significantly increased, and the expression of CBS and MST slightly decreased. The studied drugs significantly reduced the level of bound sulfane sulfur and the expression of tested enzymes. The reduction in bound sulfane sulfur level coincided with the attenuation of exploratory behavior, suggesting that modulation of anaerobic cysteine metabolism in the HIP may have therapeutic potential in schizophrenia.

The present study was designed to identify conditions that would increase the sensitivity of resistant cancer cells to anti-mitotic drugs. Previously, we showed that KBV20C cancer cells highly resistant to Halaven® (HAL) were sensitized by co-treatment with fluphenazine (FLU). In this study, we found that low doses of aripiprazole (ARI), another antipsychotic drug, sensitized HAL-resistant KBV20C cancer cells. We then investigated the mechanisms and roles of ARI in the sensitization of HAL-treated KBV20C cancer cells. First-generation P-glycoprotein (P-gp) inhibitor verapamil required a dose that was nearly four-fold higher than that of ARI for P-gp inhibition, which suggested that ARI had a high specificity for P-gp binding to prevent efflux of anti-mitotic drugs. ARI was also found to sensitize HAL-treated KBV20C cells at a low dose, approximately 4-fold lower than that of verapamil. Co-treatment of ARI with another anti-mitotic drug, vincristine, also increased the sensitization of KBV20C cells. ARI caused a reduction in cell viability, increased G2 arrest, and up-regulated expression of the DNA damage protein, pH2AX, when co-treated with HAL. Moreover, G2 phase arrest and apoptosis in HAL-ARI co-treated cells resulted from the up-regulation of retinoblastoma protein, reduced extracellular signal-regulated kinase pathway activity, and down-regulation of cell division cyclin protein. Cancer cells that are highly resistant to HAL can be sensitized with the antipsychotic drug, ARI, which exerts specific P-gp inhibitory effects at a low dose.

This study aims to compare the positive and negative symptoms of schizophrenia in patients who had psychotic symptoms more than one month after discontinuation of methamphetamine abuse. These factors were analyzed by the positive and negative syndrome scale (PANSS) questionnaire. Sixty participants were selected from patients referred to Iran Psychiatric Hospital with psychotic symptoms (delusions or hallucinations, disorganized behavior, and speech). The control group was 30 patients with schizophrenia based on a semi-structured interview according to DSMIV-TR (SCID). Thirty patients with a prolonged methamphetamine-induced psychotic disorder were also placed in the case group. For both groups of patients, questionnaires of PANSS, Brief Psychiatric Rating Scale (BPRS), and Global Assessment Of Functioning (GAF) were filled out after obtaining the companions' consent. The scale scores were compared between groups. We used the Mann-Whitney and the Chi-square test to evaluate the mean values of PANSS, BPRS, and GAF scores between the two groups. here was an insignificant difference in positive and general pathology scores between the two groups, but the total score of negative symptoms in the schizophrenia group was significantly higher than in the group of prolonged methamphetamine psychotic disorders (P=0.034). Average scores of uncooperativeness (0.008), difficulty in abstract thinking (0.004), motor retardation (0.002), unusual thought content (0.001), and hostility (0.011) in the schizophrenia group were significantly higher than those in the prolonged methamphetamine psychosis. The results showed that most of the disturbances in patients with schizophrenia might be more influenced by the expression of cognitive disabilities than those with methamphetamine psychosis. The difference in negative symptom scores suggests that schizophrenia and prolonged methamphetamine psychotic disorder can be two different disorders. General and positive symptoms scores don't have significant differences.Negative symptoms are much more in schizophrenia.Uncooperativeness, unusual thought content and, motor retardation have more scores in schizophrenia. In clinical practice, Schizophrenia and prolonged methamphetamine-induced psychotic disorder have some similar mental presentations. Additionally, in scientific literature, there is scarce evidence about these similarities. In this regard, this research was designed to investigate the aforementioned obscurity. Determination of similarities and differences between them helps us to address these disorders in terms of treatment and follow-up and awareness of their prognosis of them. This research is a case-control study in which we examine positive and negative psychotic symptoms in schizophrenia and prolonged methamphetamine-induced psychotic disorder. Researchers investigated psychotic symptoms with positive and negative syndrome scale (PANSS), brief psychiatric rating scale (BPRS), and global assessment of functioning (GAF) questionnaires. Moreover, results demonstrate general and positive symptoms scores don't have many differences but negative symptoms are much more in patients with schizophrenia than in patients with a prolonged methamphetamine-induced psychotic disorder. Also, other features like uncooperativeness, unusual thought content, motor retardation, difficulty in abstract thinking, and hostility have higher scores in schizophrenia than the others. In conclusion, this research showed that these disorders are two distinct disorders with some similarities in positive symptoms but not in all features. So, some studies can be designed about why there are similarities between them?

ObjectiveA growing body of research suggests the presence of alexithymia (a form of social cognitive impairment) in patients with schizophrenia (SCZ), which may be related to their psychopathological symptoms. Patients with SCZ exhibit high rates of obesity. Interestingly, studies of the general population have found that alexithymia acts a pivotal role in the development and maintenance of obesity. However, little is known regarding the relationship between obesity, alexithymia, and clinical symptoms in SCZ patients. The study was aim to explore the relationship between obesity, alexithymia, and clinical symptoms in SCZ patients.MethodsDemographic and clinical data were collected from 507 patients with chronic SCZ. Their symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS), and alexithymia was assessed with the Toronto Alexithymia Scale (TAS).ResultsCompare with nonobese SCZ patients, obese SCZ patients scored higher on PANSS positive symptoms, TAS total score, difficulty identifying feelings, and difficulty describing feelings (all p<0.05). Correlation analysis revealed a significant association between difficulty identifying feelings and positive symptoms in SCZ patients. Further correlation analysis showed that this association was only present in obese SCZ patients (p<0.05).ConclusionObesity may moderate the association between alexithymia and positive symptoms in chronic SCZ patients.

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.

Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25−0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug–drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.

Mirtazapine augmentation enhances cognitive and reduces negative symptoms in schizophrenia patients treated with risperidone: A randomized controlled trial

SummaryBackgroundThe antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I.FindingsBetween April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference −0·19, 95% CI −1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group).InterpretationMinocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy.FundingNational Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Background:Abnormal metabolism of dopamine and glutamate in schizophrenia induces oxidative stress that is exacerbated by brain glutathione (GSH) deficiency. N-acetyl cysteine (NAC) increases brain GSH levels and is being used as an adjunctive agent in patients with schizophrenia. This open-label exploratory study in a naturalistic setting was conceived to examine the efficacy of NAC augmentation in treating negative syndrome in schizophrenia.Aims:To examine the efficacy of add-on NAC (1200 mg) in treating negative symptoms measured using Scale for the Assessment of Negative Symptoms (SANS) and clinical global impression (CGI) at baseline and 24 weeks.Subjects and Methods:In a 24-week feasibility study with open-label design, thirty patients with the International Classification of Diseases-Tenth Edition diagnosis of schizophrenia were recruited. Eligible patients were required to have been treated with stable dose of clozapine or amisulpride for negative symptoms for a minimum period of 8 weeks were selected for the study. The subjects were assigned to receive NAC (1.2 g/day) as an add-on treatment. Severity of negative symptoms was measured using SANS and CGI-severity at baseline and improvement with NAC measured using CGI-improvement at 24 weeks. Serum interleukin-6 was assessed before NAC initiation at baseline.Results:NAC augmentation showed a significantly greater improvement in negative symptoms on total SANS and CGI scores at 24 weeks.Conclusions:NAC may be effective as an adjunct for the treatment of negative symptoms in schizophrenia.

Negative symptoms represent pervasive symptoms in schizophrenia (SZ) and major depressive disorder (MDD). Empirical findings suggest that disrupted striatal function contributes significantly to negative symptoms. However, the changes in striatal functional connectivity in relation to these negative symptoms, in the transdiagnostic context, remain unclear. The present study aimed to capture the shared neural mechanisms underlying negative symptoms in SZ and MDD. Resting-state functional magnetic resonance imaging data were obtained from 60 patients with SZ and MDD (33 with SZ and 27 with MDD) exhibiting predominant negative symptoms, and 52 healthy controls (HC). Negative symptoms and hedonic capacity were assessed using the Scale for Assessment of Negative Symptoms (SANS) and the Temporal Experience of Pleasure Scale (TEPS), respectively. Signal extraction for time series from 12 subregions of the striatum was carried out to examine the group differences in resting-state functional connectivity (rsFC) between striatal subregions and the whole brain. We observed significantly decreased rsFC between the right dorsal rostral putamen (DRP) and the right pallidum, the bilateral rostral putamen and the contralateral putamen, as well as between the dorsal caudal putamen and the right middle frontal gyrus in both patients with SZ and MDD. The right DRP-right pallidum rsFC was positively correlated with the level of negative symptoms in SZ. However, patients with SZ showed increased rsFC between the dorsal striatum and the left precentral gyrus, the right middle temporal gyrus, and the right lingual gyrus compared with those with MDD. Our findings expand on the understanding that reduced putaminal rsFC contributes to negative symptoms in both SZ and MDD. Abnormal functional connectivity of the putamen may represent a partially common neural substrate for negative symptoms in SZ and MDD, supporting that the comparable clinical manifestations between the two disorders are underpinned by partly shared mechanisms, as proposed by the transdiagnostic Research Domain Criteria.

Although genome wide association studies have highlighted MicroRNA 137 (MIR137) as a novel susceptibility gene for schizophrenia, the mechanisms by which MIR137 risk variants mediate the neurobiology of schizophrenia are not clear. Based on extant data linking MIR 137 gene with structural brain anomalies and functional brain activations in schizophrenia, we hypothesized that MIR137 risk variants rs1625579 and rs1198588 would be associated with reduced fractional anisotropy in frontostriatal brain regions, impaired neurocognitive functioning and worse psychotic symptoms in schizophrenia patients compared with healthy controls. A total of 147 Chinese participants (84 patients with DSM-IV diagnosis of schizophrenia (SCZ) and 63 healthy controls (HC)) were genotyped using blood samples and underwent diffusion tensor imaging. Neurocognitive domains and psychotic symptoms were assessed using The Brief Assessment of Cognition Battery for Schizophrenia and Positive and Negative Syndrome Scale respectively. We found significant diagnosis-genotype interactions in the right orbitofrontal regions (rs1625579: F = 5.44, P = 0.021; rs1198599: F = 7.55, P = 0.005), left striatum (rs1625579: F = 8.09, P=0.007; rs1198599: F=9.56, P = 0.002), and negative symptoms (rs1625579: t = 2.45, P = 0.016; rs1198588: t = 2.29, P = 0.024). Specifically, SCZ carrying the risk TT genotype had worse negative symptoms and decreased FA in the fronto-striatal regions compared to G and A allele carriers for rs1625579 and rs1198588 respectively, and worse attention and processing speed compared with G-allele for rs1625579. Our findings suggested that the MI137 risk variants were associated with decreased fronto-striatal brain white matter integrity which may underlie poorer attention, processing speed, and greater negative symptoms in schizophrenia.

IntroductionThe ICD-10 acute and transient psychotic disorders (ATPD, F23) without symptoms of schizophrenia are considered predominantly reactive psychotic disorders or affective pathology. However, negative symptoms of schizophrenia may be revealed in some of these cases after the psychotic reduction.ObjectivesTo investigate the association between the developmental characteristics of psychosis and the negative symptoms detection after the psychotic reduction of ATPD without symptoms of schizophrenia.Methods68 adult inpatients with ATPD without symptoms of schizophrenia (F23.0) were examined. Negative symptoms were assessed with the PANSS negative symptom subscale (PANSS-NSS). The sample was divided into two groups: with PANSS-NSS score&gt;14 (n=12) and with PANSS-NSS score≤14 (n=56), respectively. Clinical-psychopathological, psychometric and statistical methods were applied.ResultsThe results of the study are presented in Table 1.Table 1. The ATPD developmental featuresFeaturesThe 1st group (n=12)The 2nd group (n=56)Pearson’s contingency coefficient (C)Males7 (58,3%)37 (66,1%)0.062Females5 (41,7%)19 (33,9%)0.062Mean age of psychotic onset, years (М±m)24,9±10,530,8±10,2-Family history of schizophrenia*4 (33,3%)1 (1,8%)0.418Poor premorbid social adaptation*5 (41,7%)00.520Prodromal functional decline*9 (75,0%)4 (7,1%)0.550Prodromal non-psychotic symptoms9 (75,0%)30 (53,6%)0.163Associated acute stress4 (33,3%)27 (48,2%)0.113*p&lt;0,001ConclusionsThe probability of negative symptoms detection in ATPD without symptoms of schizophrenia is relatively strongly associated with the family history of schizophrenia, poor premorbid social adaptation and functional decline prior to the psychotic onset.DisclosureNo significant relationships.

Hypoactivity of the lateral habenula contributes to negative symptoms and cognitive dysfunction of schizophrenia in rats

Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.