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Background: Evenamide, a glutamate modulator, is currently in phase 3 of development as add-on treatment to antipsychotics in patients with inadequate response or treatment-resistant schizophrenia. This study was designed to determine if patients with chronic schizophrenia inadequately responding to a second-generation antipsychotic would benefit from add-on treatment with evenamide at a dose of 30 mg bid., Methods: Study 008A was a prospective, 4-week, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of oral doses of evenamide of 30 mg bid in patients with chronic schizophrenia treated at stable therapeutic doses of a second-generation antipsychotic. Outpatients aged ≥18 years, both males and females, with a diagnosis of schizophrenia (DSM-V), who had been receiving antipsychotics for at least 2 years at stable doses, but still symptomatic (PANSS 70-85, CGI-S 4-6, predominant positive symptoms), were eligible for the study. Patients were randomised equally to evenamide 30 mg or placebo, given bid, after completing a 21-day screening period. The primary outcome (change from baseline in PANSS total score) was assessed weekly, with the primary endpoint at 4 weeks., Results: A total of 291 patients were enrolled, of which 11 (3·8%) discontinued prematurely, overall. Add-on treatment with evenamide was associated to a statistically significant (the absolute difference of the two treatment groups for the PANSS Total at Day 29, primary efficacy endpoint, was = 2·5 [p-value<0.05] that is associated with a Cohen's d effect size = 0·33) and clinically meaningful benefit compared to placebo across all efficacy measures, and was well tolerated., Conclusion: The demonstration of statistically significant and clinically meaningful benefit of evenamide, a glutamate modulator, as add-on treatment in patients with chronic schizophrenia inadequately responding to their second-generation antipsychotic may represent a new treatment paradigm for this population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ravi Anand reports a relationship with Newron Pharmaceuticals SpA that includes: consulting or advisory and equity or stocks. Alessio Turolla reports a relationship with Newron Pharmaceuticals SpA that includes: employment and equity or stocks. Giovanni Chinellato reports a relationship with Newron Pharmaceuticals SpA that includes: employment. Francesca Sansi reports a relationship with Newron Pharmaceuticals SpA that includes: employment. Arjun Roy reports a relationship with CliniRx Research Pvt Ltd that includes: employment. Richard Hartman reports a relationship with Newron Pharmaceuticals SpA that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The high incidence and mortality rates of postoperative delirium (POD) among elderly patients highlights the pressing need for tailored prophylactic strategies. Despite various pharmacologic prophylactic strategies have been reported effective, their overall benefit and safety remain unclear in the geriatric population. Our network meta-analysis (NMA) aimed to systematically evaluate and rank the effectiveness of various pharmacological interventions in preventing POD in elderly patients., Methods: We conducted an extensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar for randomized controlled trials (RCTs) published up to August 1, 2023. We included RCTs examining pharmacological prophylactic effects of POD in elderly patients. To extract data in alignment with predefined areas of interest, we employed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The primary outcome was the incidence of POD. For secondary outcomes, we evaluated tolerability through all-cause discontinuation or drop-out rates, as well as all-cause mortality., Results: Our analysis encompassed a total of 44 RCTs involving 11,178 patients. Out of these, 26 RCTs involved comparisons with placebo only. For delirium prevention, the treatment groups receiving atypical antipsychotics (odds ratio (OR) of 0.27 and 95% confidence interval (CI) of 0.12-0.58), haloperidol (OR of 0.42; 95% CI of 0.25-0.71), dexmedetomidine (OR of 0.51 and 95% CI of 0.37-0.71 and melatonergic agents (MMA) (OR of 0.57 and 95% CI of 0.33-0.98) had significantly lower rates of delirium compared to the placebo group. Notably, the atypical antipsychotics ranked as the most effective treatment. For tolerability, no statistically differences in rates of dropout discontinuation and all-cause mortality among groups allocated to the placebo or individual pharmacological treatments., Conclusions: Based on indirect evidence, our network meta-analysis identified atypical antipsychotics, dexmedetomidine, MMA, and haloperidol as effective in preventing POD in the elderly, with atypical antipsychotics ranking highest. However, it is essential to note that these findings should be confirmed through further RCTs., Competing Interests: Declaration of Competing interest We have no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Schizophrenia is one of the psychiatric illnesses with a higher mortality rate. Xanomeline, an oral muscarinic receptor agonist, combined with Trospium, a pan-muscarinic receptor antagonist, represents a promising new treatment for schizophrenia that has been tested in clinical trials. Herein, we aimed to perform a meta-analysis assessing Xanomeline-Trospium Chloride's (XTC) safety and efficacy for treating schizophrenia., Materials and Methods: MEDLINE, EMBASE, and Cochrane databases were searched for randomized clinical trials testing XTC safety and efficacy in patients with schizophrenia on May 03, 2024. The research protocol was registered with the International Prospective Register of Systematic Reviews (CRD42024547487). Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed using I 2 statistics. R, version 4.3.2, was used for statistical analysis., Results: 3 RCTs and 674 patients were included, of whom 332 (49%) received XTC. The change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score was significantly higher in the XTC arm (MD -13.17; 95% CI -20.16 to -6.18; P = 0.0002; I 2  = 100%). Treatment with XTC resulted in improvements across all subscales of the PANSS. Additionally, XTC was associated with the occurrence of cholinergic adverse events, including nausea (18,52% vs. 3,79%; RR 4.37; 95% CI 2.43 to 7.84; P < 0.000001; I 2  = 19%) but was not associated with akathisia (MD -0.00; 95% CI -0.13 to 0.13; P = 0.9; I 2  = 0%) or body weight gain (MD -0.36; 95% CI -1.18 to 0.46; P = 0.38; I 2  = 51%)., Conclusion: XTC is effective in improving schizophrenia symptoms. However, it is associated with some bothersome AEs that may undermine its tolerability and lead to increased discontinuation rates, despite its efficacy., Competing Interests: Declaration of competing interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Evidence suggests a worse clinical course in women compared to men with bipolar disorder. However, little research has explored gender differences in the efficacy of anti-manic medication. We sought to determine whether there are gender differences in efficacy of drug treatment in acute manic episodes of bipolar I disorder, and the influence of dichotomized age as a proxy for menopausal status and baseline severity on gender differences. We performed an individual patient data meta-analysis of 10 short term placebo controlled registration trials for treatment of acute mania (N = 2199) performed between 1996 and 2007 using the (Young) Mania Rating Scale ((Y)MRS)) as outcome. We observed a difference in effect size in mean change and responder status between men and women (NNT = 6.3 vs. 5.3), with a small but significant effect of gender on treatment response (β = 0.031). The effect size was larger in women older than 47 compared to women aged 47 and under (NNT = 4.2 vs. 7.5), and to a lesser extent, larger in men over 47 years compared those aged 47 and under (NNT = 3.8 vs. 6). Results were mainly driven by differences in response in the placebo group and independent of baseline severity. These findings suggest that men and premenopausal women might have a clinically modest advantage over their women and postmenopausal counterparts in treatment with anti-manic medication. Our results were limited by our sample not including antimanic agents registered after 2007 and by the absence of direct biological information regarding sex and menopausal state. Future research should aim to replicate current findings utilizing biological confirmation on the menopausal status and test whether findings are generalizable to newer antimanic agents., Competing Interests: Declaration of competing interest The authors of this paper declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antipsychotic polypharmacy is commonly used in clinical settings, with a growing trend in using long-acting injections to mitigate many side effects of polypharmacy. A previous study demonstrated that long-acting aripiprazole once-monthly (AOM) injection increased treatment adherence, restored functionality, and improved symptoms. However, there is insufficient evidence to demonstrate the therapeutic effects of AOM in polypharmacy practice. This observational study aimed to investigate the real-world clinical benefits and effectiveness of AOM by assessing changes in drug dosage, the number of drugs, clinical functioning, psychotic symptoms, and the duration of drug efficacy. Study participants were recruited from eight study sites, with the baseline visit marking the initiation of drug treatment. Clinical and demographic data were collected from medical records at screening, baseline, and months 1, 3, 6, 9, and 12. Over 12 months, we analyzed changes in drug dosage, the number of drugs, and scores of the Positive and Negative Syndrome Scale-6 (PANSS-6), Global Assessment of Functioning (GAF), and Clinical Global Impression-Severity (CGIS). Data from 139 participants were analyzed. Total 12-month antipsychotic doses calculated in chlorpromazine equivalents (CPE) were reduced by 32.6%. A comparison of total monthly antipsychotic doses in CPE between the first and last months showed a 24.6% reduction in the dose. Additionally, the quantity of benzodiazepine tablets/capsules, total benzodiazepine doses calculated in lorazepam equivalents, and quantity of tablets/capsules of mood stabilizers, anticholinergics, and beta blockers were significantly reduced. GAF scores increased by 14.1% over 12 months, and PANSS-6 total scores reduced by 17.3% over 12 months, with significant differences observed from month 1 and baseline, respectively. The scores steadily improved until month 9 compared to those of the previous months, continuing to improve through month 12. The CGI-S score reduced by 14.3% over 12 months, showing a significant decrease from month 1 and a steady improvement until month 6, maintaining this improvement until month 12. In conclusion, this study demonstrated the early effectiveness of AOM in treating Korean patients with schizophrenia on polypharmacy. AOM improved function and clinical symptoms in patients with schizophrenia from treatment onset and caused a decrease in the quantity and dosage of drugs taken by the patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neurochemical dysregulations resulting from N-methyl-D-aspartate hypofunction (NMDA), are exacerbated by neuroimmune and oxidative stress and are known risk factors for neuropsychiatric disorders like schizophrenia-like diseases. Here, we investigate the protective and curative effects, and mechanisms of silymarin, a polyphenolic flavonoid with neuroprotective functions in preventive-reversal model of ketamine, an NMDA antagonist in mice., Methods: Mice were grouped into 6 cohorts (n = 9). In the pre-treatment, groups 1 and 2 received saline (10 mL/kg/p.o.), groups 3 and 4 (silymarin, 50 and 100 mg/kg/p.o.), and group 5 (risperidone, 0.5 mg/kg/p.o.) consecutively for 14 days, then combined with ketamine (20 mg/kg/i.p.) injection in groups 2-5 from days 8-14. However, mice in reversal study received intraperitoneal injection of ketamine for 14 days before silymarin (50 and 100 mg/kg, p.o) and risperidone (0.5 mg/kg, p.o.) treatment between days 8-14. The consequences on schizophrenia-like behavior, neurochemistry, inflammation, and oxidative/nitrergic stress markers were evaluated in critical brain regions of the disease., Results: Silymarin prevented and reversed ketamine-induced increase in dopamine, 5-hydroxyltryptamine, acetylcholinesterase, malondialdehyde and nitrite levels in the striatum, prefrontal-cortex and hippocampus. These were accompanied by improvement in hyperlocomotion, stereotypy, memory, and social impairments, notably devoid of cataleptogenic potential. Complementarily, silymarin reduced myeloperoxidase, tumor-necrosis factor-α, and interleukin-6 concentrations relative to the ketamine group. Moreover, ketamine-induced decreased brain-derived neurotrophic factor, glutathione, catalase, superoxide-dismutase levels were normalized by silymarin in the brain regions relative to ketamine., Conclusions: Overall, these findings suggest that silymarin's antipsychotic effect might be primarily associated, among other mechanisms, with the normalization of neurochemical and neurotrophic changes in the mice brains., Competing Interests: Declaration of competing interest Authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Prescribing of psychotropic drugs (PDs) and applying restrictive measures are both frequently used in managing challenging behaviour of people with intellectual disabilities (ID), which is not always according to guidelines or good clinical practice., Aims: This study aimed to investigate the potential triangular relationship between challenging behaviour, the application of restrictive measures and PD prescription., Methods and Procedures: In this cross-sectional study, data on challenging behaviour, PD prescription and restrictive measures were collected. We defined and compared four mutually exclusive groups of participants., Outcomes and Results: Challenging behaviour in the group in whom one or more PD were prescribed as a restrictive measures (PDRM) was more severe than in the other three groups. More severe challenging behaviour, a higher number of antipsychotics, antidepressants and anxiolytics/hypnotics prescriptions, a lower dosage, and more application of domotics as restrictive measure was shown in the PDRM compared to the group in whom PDs were prescribed according to guidelines (PDNRM)., Conclusions and Implications: We did not find indications for a triangular relationship of challenging behaviour, the application of restrictive measures and PD prescriptions. Future longitudinal research is needed to better understand this complex relationship and should investigate the indication and the effect of treatment. WHAT THIS PAPER ADDS?: This study is a first exploration of the potential triangular relationship between symptoms of challenging behaviour, psychotropic drug (PD) prescription, and the application of restrictive measures. Prescribing PDs and applying restrictive measures are two interventions which are commonly used to manage challenging behaviour in people with intellectual disabilities. Both have been subject of research separately in recent years. However, it is conceivable that the PD prescription in treatments for challenging behaviour could be a substitute for another form of a restrictive measure, for example a physical or mechanical restraint. For this purpose, we defined and compared four mutually exclusive groups of participants. We found no indication for this triangular relationship. On the other hand, we found the highest severity of challenging behaviour in the group who used PDs as restrictive measure next to other restrictive measures. Our results may suggest that both prescribing PDs and applying non-pharmacological restrictive measures are used simultaneously in managing challenging behaviour, are not sufficiently implemented or effective., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Schizophrenia is a complex neuropsychiatric disorder with positive, negative, and cognitive symptoms. In rats, sub-chronic administration of ketamine is used for the induction of schizophrenia model. Increased locomotor activity is one of the most important features of psychotic-like symptoms in rodents. On the other hand, risperidone is a potent antipsychotic medication that is approved for the treatment of schizophrenia and bipolar disorder. In the present research, we aimed to investigate the effect of sub-chronic treatment of ketamine on cognitive and behavioral functions, and brain-derived neurotrophic factor (BDNF) expression level in the prefrontal cortex. Also, we assessed the efficacy of risperidone on cognitive and behavioral impairments induced by ketamine. Possible sex differences were also measured. Ketamine was intraperitoneally injected at the dose of 30 mg/kg for five consecutive days. Risperidone was also intraperitoneally injected at the dose of 2 mg/kg. Novel object recognition memory, pain threshold, locomotor activity, rearing behavior, and BDNF level were evaluated. The results showed that ketamine injection for five consecutive days impaired the acquisition of long-term recognition memory and decreased BDNF level in the prefrontal cortex in both sexes. Also, it decreased pain threshold in females, increased rearing behavior in males, and induced hyperlocomotion with greater effect in females. On the other hand, risperidone restored or attenuated the effect of ketamine on all the behavioral effects and BDNF level. In conclusion, we suggested that there were sex differences in the effects of ketamine on pain perception, locomotion, and rearing behavior in a rat model of schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To investigate the clinical application value of pharmacogenetic testing in individualized drug therapy for adult male patients with schizophrenia. A total of 186 adult patients with schizophrenia were enrolled and randomised into the pharmacogenetic (PGx) intervention group and the standard care group. In the PGx intervention group, PGx testing was performed, and the medication regimen was adjusted according to the results of the pharmacogenomic analysis. In contrast, in the standard care group, patients were treated according to the physician's medication experience. Differences in the primary indicator of schizophrenia, the Positive and Negative Symptom Scale (PANSS), and the secondary efficacy measures, the Clinical Global Impressions-Severity of Illness scale (CGI-SI) and Clinical Global Impressions-Global Improvement (CGI-GI) scale, were compared between the intervention and standard care groups. At baseline, the PGx intervention group consisted of 109 individuals, while the standard care group had 77 participants. After 12 weeks of treatment, 49 individuals withdrew from the PGx group (a dropout rate of 45.0%), and 34 withdrew from the standard care group (a dropout rate of 44.2%), with no significant difference in dropout rates between the two groups. The PANSS score reduction rate in the PGx intervention group significantly exceeded that of the standard care group during weeks 3, 6, and 12 of follow-up (P < 0.05). At the 12th week, the PGx intervention group achieved a treatment response rate of 81.7%, significantly surpassing the 48.8% of the standard care group (odds ratio of 4.67, 95% confidence interval of 1.96-11.41; P = 0.001). Furthermore, the PGx intervention was significantly more effective than standard care regardless of whether the patient had a first episode or a relapse (P < 0.05). Furthermore, the Global Assessment of Functioning (GAF) scores and the Personal and Social Performance Scale (PSP) score changes in the PGx intervention group were both significantly different from those in the standard care group (P < 0.05). It is noteworthy that the PGx intervention similarly improves the prognostic outcomes for patients with and without a family history of mental disorders. In conclusion, the application of a PGx intervention treatment model based on PGx testing can significantly improve medication efficacy and shorten the time to achieve the effects of medication in schizophrenia., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H 1 , M 1 , M 3 , and 5-HT 2C receptors, the incidence of hyperglycemic progression was higher in the medium- and high-daily dose groups than in the low-daily dose group in the antipsychotic group with strong blockade of these receptors. Our study indicated that the type of antipsychotic had a greater affect on the incidence of hyperglycemic progression than the daily dose of antipsychotics or their number. Among these, zotepine was most likely to increase the incidence of hyperglycemic progression, suggesting the need for caution when these antipsychotics are prescribed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Clinical and preclinical studies have shown dysfunctions in genetic expression and neurotransmission of γ-Aminobutyric acid (GABA), GABA A receptor subunits, and GABA-synthesizing enzymes GAD 67 and GAD 65 in schizophrenia. It is well documented that there is significant weight gain after chronic neuroleptic treatment in humans. While there are limited studies on the effects of diet on GABA signaling directly, a change in diet has been used clinically as an adjunct to treatment for schizophrenic relief. In this study, rats chronically consumed either a chow diet (CD) or a 60% high-fat diet (HFD) and drank from bottles that contained one of the following solutions: water, haloperidol (1.5 mg/kg), or olanzapine (10 mg/kg) for four weeks. Rats were then euthanized and their brains were processed for GABA A in-vitro receptor autoradiography using [ 3 H] flunitrazepam. A chronic HFD treatment yielded significantly increased [ 3 H] flunitrazepam binding in the rat cerebellum independent of neuroleptic treatment. The desynchronization between the prefrontal cortex and the cerebellum is associated with major cognitive and motor dysfunctions commonly found in schizophrenic symptomatology, such as slowed reaction time, motor dyscoordination, and prefrontal activations related to speech fluency and cognitive alertness. These data support the notion that there is a dietary effect on GABA signaling within the cerebellum, as well as the importance of considering nutritional intervention methods as an adjunct treatment for patients chronically treated with neuroleptics. Finally, we indicate that future studies involving the analysis of individual patient's genetic profiles will further assist towards a precision medicine approach to the treatment of schizophrenia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aim: Although impaired extinction of fear memory (EFM) is a hallmark symptom of posttraumatic stress disorder (PTSD), the mechanisms underlying the impairment are unknown. Activation of the infralimbic cortex (IL) in the medial prefrontal cortex (mPFC) has been reported to predict successful fear extinction, whereas functionally disrupting this region impairs extinction. We examined whether chemogenetic activation of the IL could alleviate impaired EFM in a single prolonged stress (SPS) rat model of PTSD., Methods: Chemogenetic activation of IL and prelimbic (PL) excitatory neurons was undertaken to evaluate EFM using a contextual fear conditioning paradigm. Neuronal activity in the IL was recorded using a 32-multichannel silicon electrode. To examine histological changes in the mPFC, apoptosis was measured by TUNEL staining., Results: Chemogenetic activation of excitatory neurons in the IL, but not the PL, enhanced EFM in sham rats and resulted in alleviation of EFM impairment in SPS rats. The alleviation of impaired EFM in SPS rats was observed during the extinction test session. Neuronal activity in the IL of SPS rats was lower than that of sham rats after clozapine-n-oxide administration. Increased apoptosis was found in the IL of SPS rats., Conclusions: These findings suggest that a decreased excitatory response in the IL due, at least in part, to an increase in apoptosis in SPS rats leads to impaired EFM, and that neuronal activation during extinction training could be useful for the treatment of impaired EFM in PTSD patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D 2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D 2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D 1 , D 3 , 5-HT 1A , 5-HT 2A and 5-HT 7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M 1 and H 1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The pharmacological treatment of patients with an eating disorder (ED) often includes medications to treat their ED, comorbid mental health problems, malnutrition and the physical health problems resulting from it. The currently approved pharmacological treatment options for EDs are limited to fluoxetine for bulimia nervosa (BN) and - in some countries - lisdexamfetamine for binge eating disorder (BED). Thus, there are no approved pharmacological options for anorexia nervosa (AN), even though study results for olanzapine and dronabinol are promising. Topiramate might be an additional future option for the treatment of BN and BED. Selective serotonin reuptake inhibitors (SSRI), mirtazapine and bupropion could be considered for the treatment of comorbid unipolar depression. However, AN and BN are contraindications for bupropion. For ED patients with a manic episode, we recommend olanzapine in AN and risperidone in BN and BED; whereas for bipolar depression, olanzapine (plus fluoxetine) seems appropriate in AN and lamotrigine in BN and BED. Acute anxiety or suicidality may warrant benzodiazepine treatment with lorazepam. Proton-pump inhibitors, gastroprokinetic drugs, laxatives and hormones can alleviate certain physical health problems caused by EDs. Therapeutic drug monitoring, pharmacogenomic testing, a more restrictive use of "pro re nata" (PRN) medication, an interdisciplinary treatment approach, shared decision making (SDM) and the formulation of common treatment goals by the patients, their family or carers and clinicians could improve treatment success and safety. Novel genetic, immunological, microbiome and brain imaging research as well as new pharmacological developments like the use of psychedelics, stimulants, novel monoaminergic drugs, hormone analogues and drugs which enhance the effects of psychotherapy may extend our therapeutic options in the near future., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine., Methods: Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance., Results: In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance., Abstract: While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Schizophrenia is a devastating mental illness and its effective treatment is among the most challenging issues in psychiatry. The symptoms of schizophrenia are heterogeneous ranging from positive symptoms (e.g., delusions, hallucinations) to negative symptoms (e.g., anhedonia, social withdrawal) to cognitive dysfunction. Antipsychotics are effective at ameliorating positive symptoms in some patients; however, they are not reliably effective at improving the negative symptoms or cognitive impairments. The inability to address the cognitive impairments is a particular concern since they have the greatest long-term impact on functional outcomes. While decades of research have been devoted to the development of pro-cognitive agents for schizophrenia, to date, no drug has been approved for clinical use. Converging behavioral, neurobiological, and genetic evidence led to the identification of the α7-nicotinic acetylcholine receptor (α7-nAChR) as a therapeutic target several years ago and there is now extensive preclinical evidence that α7-nAChR ligands have pro-cognitive effects and other properties that should be beneficial to schizophrenia patients. However, like the other pro-cognitive strategies, no α7-nAChR ligand has been approved for clinical use in schizophrenia thus far. In this review, several topics are discussed that may impact the success of α7-nAChR ligands as pro-cognitive agents for schizophrenia including the translational value of the animal models used, clinical trial design limitations, confounding effects of polypharmacy, dose-effect relationships, and chronic versus intermittent dosing considerations. Determining the most optimal pharmacologic strategy at α7-nAChRs: agonist, positive allosteric modulator, or potentially even receptor antagonist is also discussed. article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'., Competing Interests: Declaration of competing interest The authors do not declare any conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: OLZ/SAM is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, and is in development for the treatment of schizophrenia and bipolar I disorder. OLZ/SAM is under development with the intent to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This thorough QT study assessed the effects of therapeutic and supratherapeutic doses of OLZ/SAM on cardiac repolarization in patients with schizophrenia., Methods: In this randomized, double-blind, placebo- and positive (moxifloxacin)-controlled, parallel-group study, 100 patients aged 18 to 60 years with stable schizophrenia were randomized 3:2 to the active arm and control arm. Subjects in the active arm received a therapeutic dose of 10/10 mg (10 mg olanzapine/10 mg samidorphan) on days 2-4, 20/20 mg on days 5-8, and a supratherapeutic dose of 30/30 mg (1.5 times and 3 times the maximum recommended daily dose of olanzapine and samidorphan, respectively) on days 9-13, and moxifloxacin-matched placebo on days 1 and 14. Subjects in the control arm received a single oral dose of moxifloxacin 400 mg and moxifloxacin-matched placebo on days 1 and 14 in a nested crossover fashion, along with OLZ/SAM-matched placebo on days 2-13. Serial electrocardiograms (ECGs) and simultaneous plasma drug concentrations were determined pre- and post-dose. The effects of OLZ/SAM on heart rate and ECG parameters (QT interval with Fridericia's correction [QTcF], PR and QRS interval, and T-wave morphology) were evaluated, and the primary endpoint was change from baseline in QTcF (ΔQTcF). The relationship between drug concentration and ΔQTcF (C-QTc) was evaluated using a linear mixed-effects model. Safety monitoring included adverse events reporting and clinical laboratory assessments., Results: Based on primary analysis using C-QTc modeling, no clinically concerning QTc effect (ie, placebo-corrected ΔQTcF [ΔΔQTcF] ≥10 msec) was observed across the OLZ/SAM dose range tested (10/10 to 30/30 mg), up to olanzapine and samidorphan concentrations of approximately 110 and 160 ng/mL, respectively. The slope (90% confidence interval [CI]) of the C-QTc relationship was shallow and not significant for either olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). The predicted ΔΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration (C max ) of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL) on day 13, respectively. The study's assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated at all doses; adverse events occurring in >5% of subjects treated with OLZ/SAM were somnolence, weight increased, nausea, and dizziness., Conclusions: This thorough QT study in patients with stable schizophrenia demonstrated that OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, does not have a clinically relevant effect on ECG parameters, including QT/QTc prolongation., Competing Interests: Declaration of Competing Interest Lei Sun, Sergey Yagoda, Narinder Nangia, Bhaskar Rege, and Lisa von Moltke are or were employees of Alkermes, Inc. Hongqi Xue and Randy Brown are employees of ERT. David McDonnell is an employee of Alkermes Pharma Ireland Limited. Borje Darpo is a consultant for ERT and Alkermes, Inc., and is eligible for stock options and holds stock in ERT., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

By combining knowledge of pharmacogenetics, therapeutic drug monitoring (TDM) and drug-drug interactions (DDIs) the author developed a model for personalizing antipsychotic dosing, which is applied to risperidone, 9-hydroxyrisperidone or paliperidone, and clozapine. Drugs are approved using an average dose for an ideal average patient, but pharmacologists have described outliers: genetic poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Environmental and personal variables can also make patients behave as PMs or UMs. Drug clearance is represented by the concentration-to-dose (C/D) ratio under steady-state and trough conditions. A very low C/D ratio indicates a UM, while a very high C/D ratio indicates a PM. Total risperidone C/D ratio for the oral formulation is around 7 ng/ml per mg/day and can be influenced by CYP2D6 polymorphism, DDIs with inducers and inhibitors, and renal function. Oral paliperidone has low availability; its C/D ratio is around 4.1 ng/ml per mg/d and can be influenced by inducers and renal impairment. Once-a-month long-acting paliperidone provides a C/D ratio around 7.7 ng/ml per mg/day at steady state, which is expected to be in the 8th month (before the 9th injection). TDM is particularly important for long-acting paliperidone formulations that may accumulate once steady state is reached (after years for the 3- and 6-month formulations). In the US, clozapine C/D ratios typically range from 0.6 (male smokers) to 1.2 (female non-smokers) ng/ml per mg/day. East Asians' clozapine C/D ratios appear to be twice as high. Inhibitors (including fluvoxamine and oral contraceptives) and inflammation can also increase clozapine C/D ratios. This article is part of the issue entitled 'Special Issue on Antipsychotics'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism., Methods: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m 2 ). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 μM - 20 μM) and aripiprazole (0.002 μM - 100 μM). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis., Results: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term pre-incubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondrial functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG., Conclusion: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically., Methods: Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ., Results: There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction., Conclusion: Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study evaluated the efficacy and safety/tolerability of quetiapine extended-release 300 mg/day (QUEXR300), quetiapine immediate-release 600 mg/day (QUEIR600), and quetiapine immediate-release 300 mg/day (QUEIR300) formulations for treating bipolar depression. A random-effect network meta-analysis of 8-week, double-blind, randomized placebo-controlled trials was used to determine the most optimal agent for intervention. Remission rate was set as the primary outcome. Secondary outcomes were response rate, improvement in the Montgomery-Åsberg Depression Rating Scale score, discontinuation rate, and the incidence of individual adverse events. Seven eligible studies including 3267 participants were included in the meta-analysis. The QUEIR600, QUEIR300, and QUEXR300 groups were superior to the placebo group in every efficacy outcome; however, there were no significant differences in the efficacy outcomes among the treatment groups. All treatment groups exhibited higher incidences of extrapyramidal symptoms, dry mouth, somnolence, constipation, and increase in body weight than the placebo group. The QUEIR600 and QUEIR300 groups had higher incidences of dizziness than the placebo group. The QUEIR600 group had a higher discontinuation rate due to adverse events than the placebo group, and the QUEIR300 group had higher blood HbA1c levels than the placebo group. The QUEIR600 and QUEXR300 groups had higher incidences of ≥7% weight gain than the placebo group. The QUEXR300 group had a higher incidence of fatigue than the QURIR300 and placebo groups. In conclusion, there were no significant differences in the efficacies of QUEIR600, QUEIR300, and QUEXR300 in treating bipolar depression; moreover, tolerance to QUEIR600 might be worse than the other treatments., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Antipsychotics have been shown to stimulate different forebrain areas, whereas some of them are sensitive to stress. In the present study, effect of a single administration of olanzapine (OLA), amisulpride (AMI), aripiprazole (ARI), and quetiapine (QUE) on the activity of cells in the striatal dorsolateral (stDL) area, the periventricular zone (peVZ), the septal ventrolateral (seVL) nucleus, and the accumbens nucleus shell (shACC) and core (coACC) was investigated in male rats preconditioned with a mild stress complex (CMS) for 20 days. The objective of the study was to extend the anatomical-functional knowledge on the mechanism of selected antipsychotics with the goals: 1) to analyze the ability of the selected antipsychotics to induce c-Fos protein expression in the above mentioned forebrain structures and to map the pattern of their topography and 2) to find out whether longer-lasting mild stress preconditioning may modify the impact of the selected antipsychotics on the activity of cells in the forebrain areas in adult rats. Ten groups of rats were used. CMS complex contained five stressors: cage crowding, air-puff noising, wet bedding, predator stress, and forced swimming. AMI (20 mg/kg), OLA (5 mg/kg), QUE (15 mg/kg), and ARI (10 mg/kg/b.w.) were administered intraperitoneally and 90 min later the animals transcardially perfused by fixative. c-Fos was visualized by ABC complex. In unstressed animals, OLA and ARI elevated c-Fos expression in all areas studied, AMI and QUE in all areas except stDL, seVL and coACC, shACC FL-2 (shACC posterior level), respectively. CMS potentiated the effect of AMI in coACC, and QUE in shACC FL-2 and suppressed the effect of AMI in peVZ, and ARI in peVZ and seVL. The present data provide new insights into activity of cells in response to CMS challenge, which might be helpful in understanding the diverse clinical effects of atypical antipsychotics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We performed a network meta-analysis to build clear hierarchies of efficacy and tolerability of antipsychotics to augment serotonin reuptake inhibitors (SRIs) for treatment-resistant obsessive-compulsive disorder (OCD) in adults. PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched on September 8, 2018. Randomized controlled trials investigating antipsychotics as augmentation agents were included. Network meta-analyses were performed using frequentist methods. Efficacy was measured by the Yale-Brown Obsessive-Compulsive Scale. Tolerability was measured by side-effect discontinuations. Mean differences (MDs) and odds ratios (ORs) were reported with 95% confidence intervals (CIs). Twenty articles with 790 patients were included. Our analyses showed that there was no significant difference in efficacy between antipsychotic agents. The order of efficacy rankings was inconsistent between primary analysis and sensitivity analyses. We found that there was considerable heterogeneity between studies. Comorbid tics was identified as a significant moderator. All antipsychotics except paliperidone were significantly superior to placebo in the subgroup without comorbid tics, while no antipsychotics was significantly superior to placebo in the comorbid tics subgroup. With respect to tolerability, quetiapine (OR, 3.45; 95% CI, 1.04-11.11) and paliperidone (20.00; 1.01->100) were significantly less tolerable than placebo. Based on this network meta-analysis, antipsychotic agents as augmentations to SRIs might be more effective in treatment-resistant OCD patients without comorbid tics. Definitive determination of which drug is optimal cannot be drawn currently because of the limited numbers of studies and heterogeneity across studies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dosing regimens for depot antipsychotics range from two-to twelve-weekly administration. There are limited meta-analytic data regarding the effect of different injection frequencies of the same depot antipsychotic at the equivalent dose on psychiatric outcomes and adverse effects. This study investigated differences in psychiatric outcomes and adverse effects between different frequencies of depot antipsychotics through a systematic review and meta-analysis. We performed a systematic search of MEDLINE, EMBASE, Cochrane database, PsycINFO and two Chinese databases for RCTs that compared the frequency of depot antipsychotic administration. The primary outcome was psychiatric symptomatology, with secondary outcomes of quality of life, admission rates, adverse drug reactions, cost-effectiveness and compliance. Twelve studies were included in the meta-analysis. Most studies compared two- and four-weekly injections (n = 10). Different injection frequencies did not lead to differences in clinical outcomes or adverse events. However, two-weekly injections led to significantly greater improvements on the CGI-S scale than four-weekly administration. A sensitivity analysis by removing low quality studies showed lower incidence of somnolence and injection site pain for 2-weekly compared with 4-weekly injections. There were limited data on admission rates and no RCT data on cost-effectiveness or compliance. While there is limited evidence on secondary measures to support 2-weekly over 4-weekly injections, patient choice and convenience should remain the priority when considering certain antipsychotics. Cost-effectiveness and adherence should also be considered, although further studies are required to further evaluate these parameters., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Treatment-resistant schizophrenia (TRS) is common and debilitating. A subgroup of patients even has clozapine-resistant schizophrenia (CRS). We aimed to evaluate the efficacy and safety of electroconvulsive therapy (ECT) augmentation of clozapine for CRS. Systematic literature search of randomized controlled trials (RCTs) reporting on ECT augmentation of clozapine in CRS. Co-primary outcomes included symptomatic improvement at post-ECT assessment and study endpoint. Eighteen RCTs (n = 1769) with 20 active treatment arms were identified and meta-analyzed. Adjunctive ECT was superior to clozapine regarding symptomatic improvement at post-ECT assessment (Standardized Mean Difference (SMD) = -0.88, 95% Confidence Interval (CI): -1.33 to -0.44; I 2  = 86%, P = 0.0001) and endpoint assessment (SMD: -1.44, 95%CI: -2.05 to -0.84; I 2  = 95%, P < 0.00001), separating as early as week 1-2 (SMD = -0.54, 95%CI: -0.88 to -0.20; I 2  = 77%, P = 0.002). Adjunctive ECT was also superior regarding study-defined response at post-ECT assessment (53.6% vs. 25.4%, Risk Ratio (RR) = 1.94, 95%CI: 1.59-2.36; I 2  = 0%, P < 0.00001, number-needed-to-treat (NNT) = 3, 95%CI: 3-5) and endpoint assessment (67.7% vs. 41.4%, RR = 1.66, 95%CI: 1.38-1.99; I 2  = 47%, P < 0.00001, NNT = 4, 95%CI: 3-8), and remission at post-ECT assessment (13.3% vs. 3.7%, RR = 3.28, 95%CI: 1.80-5.99; I 2  = 0%, P = 0.0001, NNT = 13, 95%CI: 6-100) and endpoint assessment (23.6% vs. 13.3%, RR = 1.80, 95%CI: 1.39 to 2.35; I 2  = 5%, P < 0.0001, NNT = 14, 95%CI: 6-50). Patient-reported memory impairment (24.2% vs. 0%; RR = 16.10 (95%CI: 4.53-57.26); I 2  = 0%, P < 0.0001, number-needed-to-harm (NNH) = 4, 95%CI: 2-14) and headache (14.5% vs 1.6%; RR = 4.03 (95%CI: 1.54-10.56); I 2  = 0%, P = 0.005, NNH = 8, 95%CI: 4-50) occurred more frequently with adjunctive ECT. No significant group differences were found regarding discontinuation and other adverse effects. Despite increased frequency of self-reported memory impairment and headache, ECT augmentation of clozapine is a highly effective and relatively safe treatment for CRS., Registration Number: CRD42018089959., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Current pathophysiological models of schizophrenia suggest that stress contributes to the etiology and trajectory of the disorder. We investigated if allostatic load (AL), an integrative index of neuroendocrine, immune and metabolic dysregulation in response to chronic stress, is elevated in patients with schizophrenia (SCZ) and first-episode psychosis (FEP) and related to psychotic symptoms and social and occupational functioning. Additionally, we assessed the temporal dynamics of AL in response to treatment with second-generation antipsychotics. AL, psychotic symptoms and psychosocial functioning were assessed in a longitudinal design in patients with SCZ (n = 28), FEP (n = 28), and healthy controls (n = 53) at baseline and 6 and 12 weeks after commencement of antipsychotic therapy. AL at baseline was higher in patients with SCZ and FEP relative to controls, but not different between patients with SCZ and FEP. Adjusting for age and smoking, we found that positive symptoms were positively correlated with AL and psychosocial functioning was negatively correlated with AL at trend level. Linear mixed model analysis demonstrated that AL decreased after treatment was commenced in patients with SCZ and FEP between the baseline assessment and the 6 and 12-week follow-up. AL was not predictive of treatment response or symptomatic remission. Our data provide evidence for cumulative physiological dysregulation in patients with SCZ and FEP that is linked to the experience of current positive psychotic symptoms. AL could be a useful tool to monitor biological signatures related to chronic stress and unhealthy behaviors in schizophrenia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naïve patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment. Comparisons were also made particularly along PREG-PROG-ALLO pathway in the same FEAN-SZ patients across multiple time points following initiation of treatment for 12 months (m). Firstly, at baseline, levels of PREG were significantly higher and those of ALLO were lower in FEAN-SZ than in HC, whereas PROG, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not different. Consequently, the molar ratios of ALLO/PREG and ALLO/PROG in FEAN-SZ were significantly reduced. Secondly, in response to APD at 1 month, ALLO levels in FEAN-SZ were markedly elevated, whereas PREG and PROG levels decreased. Thirdly, among FEAN-SZ, lower levels of PROG (reflecting higher conversion to ALLO) at baseline may predict better therapeutic outcome after 1 month of APD treatment. These findings point to the perturbations of the PREG-PROG-ALLO pathway early in psychosis, and further study of this pathway may inform alternative and innovative therapeutic targets for SZ., (Published by Elsevier Ltd.)

Objectives: Immunological/inflammatory processes have been proposed to play an important role in the pathophysiology of mood disorders, including bipolar disorder (BD). The present study aimed to examine the influence of immune activation, measured on the basis of inflammatory markers, on the course of illness, proxied by the number of affective episodes, in patients with BD., Methods: We investigated the relationship between high-sensitive CRP (hsCRP) and Interleukin 6 (IL-6), two inflammatory markers and characteristics of course of illness (e.g. number of affective episodes, depressive and manic symptoms) amongst a group of 190 individuals with BD., Results: Among females with BD, there was a positive correlation between levels of hsCRP and the number of manic and depressive episodes. Moreover, levels of hsCRP and IL-6 were positively correlated with current manic symptoms, as measured by Young-Mania-Rating-Scale. There were no significant correlations between levels of the foregoing inflammatory markers, and manic and depressive symptoms in male individuals with BD. Furthermore, compared to their untreated counterparts, female patients treated with lithium demonstrated higher levels of hsCRP and male patients treated with atypical antipsychotics lower levels of hsCRP, respectively., Conclusions: Our results are suggesting that the association between inflammatory state and affective response in patients with BD may be gender-dependent. A future research would be to evaluate whether or not these gender differences can be observed in other inflammatory pathways associated with BD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The use of early pharmacological intervention in treating young patients with schizophrenia is a debating issue for psychiatrists. However, on the basis of developmental theory, early antipsychotic intervention can be beneficial in terms of protecting neurons from further deterioration. This study investigated whether the initiation of second-generation antipsychotic (SGA) treatment at a younger age can effectively reverse schizophrenia-relevant behavioral and neurochemical features, namely acoustic prepulse inhibition (PPI) and accumbal dopamine (DA) efflux, respectively. Risperidone (RIS, 1mg/kg/day) or olanzapine (OLA, 2.5mg/kg/day) was administered for 6weeks in rats subjected to isolation rearing (IR) in adolescence or young adulthood. Behavioral testing was performed at 3 and 5 (for locomotor activity) and 2 and 4 (for PPI) weeks after the initiation of the pharmacological regimen. An additional PPI test was performed 6weeks after the initiation of the pharmacological regimen to assess the acute add-on effect of RIS or OLA. Dopamine (DA) efflux of the nucleus accumbens was evaluated through in vivo microdialysis at the end of the study, for measuring both the baseline levels after the chronic regimen and the responsiveness to acute add-on RIS or OLA treatment. Our results demonstrated that the effects of SGAs on PPI and accumbal DA efflux were dissociated. Specifically, RIS intervention was more beneficial for adolescent than young adult IR rats in restoring their PPI deficit, whereas OLA was age-independently effective in stimulating the accumbal DA efflux. Both PPI and accumbal DA could be employed to reflect IR-induced abnormalities, in which accumbal DA appeared to be more suitable in depicting the long-term effect of IR, whereas PPI might be a more accurate biological index for revealing the advantages of early RIS intervention., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: This study was conducted to evaluate the efficacy and metabolic effects of paliperidone palmitate (PP) injections against oral olanzapine in first-episode schizophrenia (FES) patients., Methods: Eligible patients were randomized to receive PP or olanzapine. Efficacy assessments and weight-related parameters were assessed at baseline, weeks 1, 5, 9, and endpoint or at early withdrawal. Lipid, glucose, insulin and prolactin were evaluated at baseline and endpoint or at early withdrawal., Results: The Positive And Negative Syndrome Scale (PANSS) scores declined significantly after treatment in both groups. Significant increases in weight-related parameters from baseline to endpoint were shown in both groups. Although there was no significant difference in PANSS scores and weight-related parameters between the two groups through the whole 13-week study. The increased level of triglyceride and HOMA-IR at endpoint from baseline in the olanzapine group was higher than the PP group. There was a stronger elevation of prolactin level in the PP group., Conclusions: In summary, PP and olanzapine showed similar improvement in the treatment of FES patients. This study also reinforced the necessity for regular monitoring of metabolic parameters in schizophrenia patients prescribed atypical antipsychotics. Clinical trial registration numbers: ChiCTR-IOR-14005304. Date of registration: 2014-10-11., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study compares the efficacy and tolerability of olanzapine versus risperidone among patients with schizophrenia who are established in outpatient psychiatric care and entering supported employment. A multicenter, randomized, double-blind trial was conducted among 107 outpatients with schizophrenia, who were cross-titrated to flexible dose risperidone or olanzapine over 2 weeks. Clinical endpoints included time to hospitalization and persistence on assigned medication. Weight, laboratory tests, psychopathology, neurologic side effects, social adjustment and role functioning were assessed at 3-6 month intervals. Data were analyzed first by randomized treatment, and then reassessed controlling for prior medication treatment. The proportion of patients on assigned medication at 18 months was 30.9% for risperidone and 37.3% for olanzapine. Mean doses were 6.4 ± 3.2 mg daily for risperidone, and 17.0 ± 5.0 mg daily for olanzapine. The groups did not differ significantly in time to medication discontinuation, first hospitalization or first employment. There were few differences in psychopathology, laboratory, or neurological assessments between groups at 18 months. Patients randomized to olanzapine gained modestly more weight. Controlling for pre-randomization medication suggested improvement in some aspects of psychopathology from switching medications; however, switching from olanzapine to risperidone was associated with more hospitalizations. Risperidone and olanzapine have similar efficacy and tolerability in patients with schizophrenia who are participating in supported employment. Randomization to olanzapine was associated with more weight gain, but randomization from olanzapine to risperidone appeared to be associated with a greater likelihood of hospitalization. Careful monitoring of metabolic effects and participation in supported employment may have contributed to minimal weight gain and metabolic effects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Antipsychotic treatment, particularly olanzapine and clozapine, induces severe obesity. The Histamine H1 receptor is considered to be an important contributor to olanzapine-induced obesity, however how olanzapine modulates the histaminergic system is not sufficiently understood. This study examined the effect of olanzapine on key molecules of the histaminergic system, including histidine decarboxylase (HDC), H1 receptor (H1R) and H3 receptor (H3R), in the brain at different stages of olanzapine-induced obesity. During short-term treatment (8-day), olanzapine increased hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH), without changing H3R binding density. HDC mRNA and Arc H1R binding were positively correlated with increased food intake, feeding efficiency and weight gain. When the treatment was extended to 16 and 36 days, H1R binding was increased not only in the hypothalamic Arc and VMH but also in the brainstem dorsal vagal complex (DVC). The H1R bindings in the Arc, VMH and DVC were positively correlated with weight gain induced by olanzapine treatment. However, the expression of HDC and H3R mRNA was not increased. These results suggest that olanzapine time-dependently modulates histamine neurotransmission, which suggested the different neuronal mechanisms underlying different stages of weight gain development. Treatment targeting the H1R may be effective for both short- and long-term olanzapine-induced weight gain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3β and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3β and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

There have been few studies of pregnenolone therapy in schizophrenia and those that exist have been subject to several critical limitations, thus yielding inconsistent results. We attempted to assess the therapeutic effect of pregnenolone in a patient sample as homogeneous as possible. In this randomized double-blind clinical trial, 82 female inpatients with chronic schizophrenia, who had discontinued their antipsychotic medications for at least one week in case of any oral antipsychotic medication or a month for any depot antipsychotic medication, received risperidone plus either pregnenolone (50 mg/day) or placebo for 8 weeks. Inclusion criteria were acute illness with a baseline Positive and Negative Syndrome Scale (PANSS) negative subscale score of ≥20. Exclusion criteria were the presence of severe depression or other concomitant psychiatric disorders. Primary outcome was defined as the difference in the PANSS total score change from baseline to week 8 in the pregnenolone group compared to the placebo group. No significant difference was found in the PANSS total score changes between the two arms (mean difference (CI 95%) = -9.41 (-20.24 to 1.41); p = 0.087). Significant differences were initially found for PANSS negative change scores (mean difference (CI 95%) = -2.61 (-5.03 to -0.19); p = 0.035) and general psychopathology change scores (mean difference (CI 95%) = -5.93 (-11.37 to -0.48); p = 0.033). However, these findings did not survive Bonferroni correction for multiple testing. While this trial may suggest a potential effect of pregnenolone on schizophrenia symptoms, further studies are warranted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of CB1Rs after antipsychotic treatment. These findings prompted us to study the effects of chronic oral intake of a first and a second generation antipsychotic, haloperidol and olanzapine, on the levels and distribution of CB1Rs in the rat brain. Rats consumed either regular chow or high-fat food and drank water, haloperidol drinking solution (1.5mg/kg), or olanzapine drinking solution (10mg/kg) for four weeks. Motor and cognitive functions were tested at the end of treatment week 3 and upon drug discontinuation. Two days after drug discontinuation, rats were euthanized and brains were processed for in vitro receptor autoradiography. In chow-fed animals, haloperidol and olanzapine increased CB1R levels in the basal ganglia and the hippocampus, in a similar, but not identical pattern. In addition, olanzapine had unique effects in CB1R upregulation in higher order cognitive areas, in the secondary somatosensory cortex, in the visual and auditory cortices and the geniculate nuclei, as well as in the hypothalamus. High fat food consumption prevented antipsychotic-induced increase in CB1R levels in all regions examined, with one exception, the globus pallidus, in which they were higher in haloperidol-treated rats. The results point towards the hypothesis that increased CB1R levels could be a confounding effect of antipsychotic medication in schizophrenia that is circumveneted by high fat feeding., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine. Rats received either continuous (CONT-HAL; achieved via subcutaneous osmotic minipump) or intermittent (INT-HAL; achieved via daily subcutaneous injection) haloperidol treatment for 16-17 days. Three to 5 days later, we injected neurotensin into the NAc and measured amphetamine-induced locomotion. Only CONT-HAL rats showed potentiated amphetamine-induced locomotion, indicating dopamine supersensitivity. Compared to intra-NAc saline, intra-NAc neurotensin suppressed amphetamine-induced locomotion in CONT-HAL rats, but not in INT-HAL or control rats. In a new cohort of CONT-HAL and INT-HAL rats, we measured striatal levels of proneurotensin mRNA and NTS1 receptors. The two treatments led to overlapping but also distinct neurochemical profiles. Neither treatment altered NTS1 receptor levels in the NAc, but both increased proneurotensin mRNA levels in the NAc core. In the caudate-putamen, only INT-HAL increased NTS1 receptor levels, while only CONT-HAL increased proneurotensin mRNA expression. Thus, antipsychotic-induced dopamine supersensitivity enhances the ability of neurotensin in the NAc to regulate dopamine-mediated behaviours, and this likely does not involve changes in local levels of NTS1 receptors or proneurotensin mRNA. We conclude that increasing neurotensin activity could be considered to attenuate antipsychotic-induced dopamine supersensitivity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Anxiety disorders are among the most frequent psychiatric disorders. Current treatment guidelines recommend antidepressants, the calcium modulator gabapentin, and benzodiazepines as pharmacological treatments. However, delayed onset of action precludes the use of antidepressants as an acute treatment, while benzodiazepines can be recommended only as an emergency treatment due to their inherent risk of dependence. Therefore, an alternative pharmacological agent with acute efficacy is needed. Preliminary evidence points towards possible anxiolytic properties of the atypical antipsychotic quetiapine. The goals of this study were to test the acute anxiolytic properties of quetiapine in patients suffering from arachnophobia in a challenge paradigm, and to assess the effects of quetiapine on the central nervous fear network., Methods: In a randomized, double-blind, placebo-controlled proof-of-concept study, n=58 arachnophobic patients underwent an fMRI scan while looking at phobia-related and neutral stimuli. Subjective anxiety was evaluated retrospectively in questionnaires., Results: The functional imaging data revealed that patients showed stronger amygdala activation to phobia-related than to neutral stimuli. However, no effect of quetiapine on fear network activity was detected. Further, on questionnaire measures, quetiapine significantly reduced somatic anxiety symptoms, but had no effect on general psychological anxiety., Conclusion: Viewing phobic pictures resulted in a robust amygdala activation in arachnophobic patients. Quetiapine seems to have no influence on activation in anxiety-related brain areas but appears to reduce acute somatic anxiety symptoms in patients with specific phobia. The central nervous correlates of the anxiolytic effects of quetiapine remain to be clarified in future studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Carbonyl stress in patients with schizophrenia has been reported to be reflected by an increase in peripheral pentosidine levels. This cohort study tested whether the accumulation of pentosidine was related to the disease severity or the treatment (routine administration of high antipsychotic doses)., Methods: We followed up our original investigation using a new group of 137 patients with acute schizophrenia and 45 healthy subjects, and then pooled the two cohorts to conduct the following analysis on a total of 274 patients. The associations of serum pentosidine and pyridoxal levels with duration of education, estimated duration of medication, the severity of symptoms, and daily doses of antipsychotics, antiparkinsonian drugs, and anxiolytics were evaluated by multiple linear regression analysis., Results: The combined cohort of 274 patients exhibited abnormally high serum levels of pentosidine, were associated with a higher daily dose of antipsychotic drugs and a longer estimated duration of medication without statistical significance of diagnosis. This was also observed in the patients treated with antipsychotic polypharmacy, but the serum pentosidine levels of patients treated with first- or second-generation antipsychotic monotherapy showed no relationship with these two variables., Conclusion: High levels of serum pentosidine were associated with high daily doses of antipsychotic drugs and a longer estimated duration of medication in patients treated with antipsychotic polypharmacy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: The postsynaptic density (PSD) represents a site of dopamine-glutamate integration. Despite multiple evidence of PSD involvement in antipsychotic-induced synaptic changes, there are no direct head-to-head comparisons of the effects at the PSD of antipsychotics with different receptor profile and at different doses after chronic administration., Methods: Molecular imaging of gene expression was used to investigate whether chronic treatment with first and second generation antipsychotics (haloperidol, asenapine and olanzapine) may induce changes in the expression levels of PSD transcripts involved in schizophrenia pathophysiology, i.e. Homers, Shank1, PSD-95 and Arc., Results: Genes' expression patterns were differentially modulated after chronic administration of typical and atypical antipsychotics as well as by the same compound administered at different doses. Antipsychotic treatment reduced gene expression in cortical regions, while Homer1a was still induced in striatum by haloperidol even after prolonged treatment. Moreover, chronic treatments appeared to cause a "de-recruitment" of brain regions demonstrated to be activated in acute treatments, with a prominent effect in the cortex rather than in striatum., Conclusions: These results let hypothesize that prolonged antipsychotic treatment may trigger a set of plastic changes involving scaffolding and effector molecules causing a possible re-arrangement of PSD transcripts in brain regions relevant to schizophrenia pathophysiology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Antipsychotic medication is an essential component for treating schizophrenia, which is a serious mental disorder that affects approximately 1% of the global population. Olanzapine (Olz), one of the most frequently prescribed atypical antipsychotics, is generally considered a first-line drug for treating schizophrenia. In contrast to psychotic symptoms, the effects of Olz on cognitive symptoms of schizophrenia are still unclear. In addition, the mechanisms by which Olz affects the neural circuits associated with cognitive function are unknown. Here we show that Olz interrupts depotentiation (reversal of long-term potentiation) without disturbing de novo LTP (long-term potentiation) and LTD (long-term depression). At hippocampal SC-CA1 synapses, inhibition of NMDARs (N-methyl-d-aspartate receptors), mGluRs (metabotropic glutamate receptors), or mAChRs (muscarinic acetylcholine receptors) disrupted depotentiation. In addition, co-activation of NMDARs, mGluRs, and mAChRs reversed stably expressed LTP. Olz inhibits the activation of mAChRs, which amplifies glutamate signaling through enhanced NMDAR opening and Gq (Gq class of G protein)-mediated signal transduction. Behaviorally, Olz impairs spatial reversal learning of mice in the Morris water maze test. Our results uncover a novel mechanism underpinning the cognitive modulation of Olz and show that the anticholinergic property of Olz affects glutamate signaling and synaptic plasticity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Ziprasidone (ZIP) is often used with olanzapine (OLZ) in 'switch' and combination therapy but empirical evidence to support these strategies is limited., Objective: This study was therefore designed to compare the efficacy and tolerability of switching from OLZ to ZIP, the combination of both medications, and OLZ and ZIP monotherapy, in patients with schizophrenia spectrum disorders (SSD)., Methods: In this 12 week open-label, assessor-blinded randomized trial, 148 patients with SSD who had not used antipsychotics for at least 3 months were assigned to ZIP (n = 49) or OLZ monotherapy (n = 31); OLZ for 4 weeks then a switch to ZIP (OLZ/ZIP, n = 35); or combination therapy (OLZ + ZIP, n = 33). The severity of psychosis and abnormal involuntary movements was evaluated at baseline, 1, 2, 4, 8, and 12 weeks using standard instruments. Baseline-to-endpoint changes in weight gain and metabolic measures were compared., Results: The efficacy of both OLZ/ZIP and OLZ + ZIP was comparable OLZ monotherapy and better than ZIP monotherapy in reducing overall psychotic and negative symptoms at most 8 and 12 week measurement points. Changes in weight gain, glucose, and lipid measures did not differ between OLZ/ZIP and OLZ + ZIP, but were markedly higher following OLZ monotherapy. The OLZ + ZIP group had the lowest overall incidence of adverse events and extrapyramidal symptoms of all the treatment regimens., Conclusions: We conclude that combining ZIP and OLZ at the outset of treatment is superior to switching from OLZ to ZIP in terms of improving psychotic symptoms and limiting movement side effects without increasing the risk of metabolic syndrome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist. The activity of PAM-2 was compared to that elicited by DMXBA, an α7 nAChR partial agonist. For this purpose, the attentional set-shifting task (ASST) and the novel object recognition task (NORT) were used. The efficacies of PAM-2 and DMXBA against ketamine-induced social withdrawal were assessed using the social interaction test (SIT). The results demonstrated that PAM-2 and DMXBA ameliorated ketamine-induced cognitive impairments on the ASST and NORT as well as produced pro-social activities in the SIT. Moreover, the co-administration of inactive doses of PAM-2 and antipsychotic drugs, clozapine or risperidone, reversed ketamine-induced deficits. The present findings provide further support for the concept that α7-PAMs could be used either alone or in combination with antipsychotics for schizophrenia therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Many neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism involve interneuron transcriptional dysregulation. The transcriptional coactivator PGC-1α regulates gene expression in GABAergic interneurons, which are important for regulating hippocampal network activity. Genetic deletion of PGC-1α causes a decrease in parvalbumin expression, similar to what is observed in schizophrenia postmortem tissue. Our lab has previously shown that PGC-1α -/- mice have enhanced GABAergic inhibition onto CA1 pyramidal cells, which increases the inhibition/excitation (I/E) ratio, alters hippocampal circuit function, and impairs hippocampal dependent behavior. The typical antipsychotic haloperidol, a dopamine receptor antagonist with selectivity for D2-like receptors, has previously been shown to increase excitation in the CA1 region of hippocampus. We therefore tested whether haloperidol could normalize the I/E balance in CA1 of PGC-1α -/- mice, potentially improving circuit function and behavior. Surprisingly, we discovered instead that interneuron transcriptional dysregulation caused by loss of PGC-1α alters the effects of haloperidol on hippocampal synaptic transmission and circuit function. Acute administration of haloperidol causes disinhibition in CA1 and decreases the I/E ratio onto CA1 pyramidal cells in slices from PGC-1α +/+ mice, but not PGC-1α -/- mice. The spread of activity in CA1, assessed by voltage sensitive dye imaging, is increased by haloperidol in slices from PGC-1α +/+ mice; however haloperidol decreases the spread of activity in slices from PGC-1α -/- mice. Haloperidol increased the power of hippocampal gamma oscillation in slices from PGC-1α +/+ mice but reduced the power of gamma oscillations in slices from PGC-1α -/- mice. Nest construction, an innate hippocampal-dependent behavior, is inhibited by haloperidol in PGC-1α +/+ mice, but not in PGC-1α -/- mice, which already have impaired nest building. The effects of haloperidol are mimicked and occluded by a D2 receptor antagonist in slices from PGC-1α +/+ mice, and the effects of blocking D2 receptors are lost in slices from PGC-1α -/- mice, although there is no change in D2 receptor transcript levels. Together, our results show that hippocampal inhibitory synaptic transmission, CA1 circuit function, and hippocampal dependent behavior are modulated by the antipsychotic haloperidol, and that these effects of haloperidol are lost in PGC-1α -/- mice. These results have implications for the treatment of individuals with conditions involving PGC-1α deficiency., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Postpartum psychosis (PP) is a severe psychiatric disorder affecting a small proportion of new mothers shortly after childbirth. The molecular pathophysiology underlying the disorder is currently poorly understood, and there are no amenable animal models for the condition; maternal deficiency for the enzyme steroid sulfatase has been proposed as a potential risk mechanism. Here we show that inhibition of steroid sulfatase with 667-COUMATE (10mg/kg p.o.) in new mouse mothers results in behavioural abnormalities that can be partially alleviated by the administration of the clinically-efficacious antipsychotic ziprasidone (0.3-1.0mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21-23cM on chromosome 15; of the 17 genes within this chromosomal interval, only one (Nov/Ccn3) was significantly differentially expressed in the brains of vehicle and 667-COUMATE-treated mice. Two additional members of the Ccn family (Ccn2/Ctgf and Ccn4/Wisp1) were also significantly differentially expressed between the two groups, as were three further genes co-expressed with Nov/Ccn3 in brain (Arhgdig) or previously implicated in disorder risk by clinical studies (Adcy8 and Ccl2). The expression of Nov/Ccn3, but not of the other differentially-expressed genes, could be normalised by ziprasidone administration (1.0mg/kg). NOV/CCN3 lies directly under a linkage peak for PP risk at 8q24, and the associated protein possesses numerous characteristics that make it an excellent candidate mediator of PP risk. Our data suggest the 667-COUMATE-treated mouse as a model for PP with some degree of face, construct, and predictive validity, and implicate a novel, and biologically-plausible, molecular risk pathway for PP., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations., Methods: The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57., Results: The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-α at any time-point of the study., Conclusion: This study provides data suggesting early alteration in adipose tissue endocrine function as a factor involved in mechanisms underlying metabolic adverse effects of antipsychotics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Alcohol use disorder in patients with schizophrenia dramatically worsens their clinical course, and few treatment options are available. Clozapine appears to reduce alcohol use in these patients, but its toxicity limits its use. To create a safer clozapine-like drug, we tested whether the antipsychotic iloperidone, a drug that combines a weak dopamine D2 receptor blockade and a potent norepinephrine alpha-2 receptor blockade would reduce alcohol drinking, and whether its effect on alcohol drinking could be increased if combined with an agent to facilitate norepinephrine activity. Syrian golden hamsters (useful animal model for screening drugs that reduce alcohol drinking in patients with schizophrenia) were given free access to water and alcohol (15% v/v) until stable drinking was established. Animals (n = 6-7/group), matched according to alcohol intake, were treated daily with each drug (iloperidone; clozapine; haloperidol; desipramine [norepinephrine reuptake inhibitor]; with idazoxan [norepinephrine alpha-2 receptor antagonist]) or with a two-drug (iloperidone + desipramine; iloperidone + idazoxan) combination for 14 days. Moderate doses of iloperidone (1-5 mg/kg) significantly reduced alcohol drinking (p < 0.05) in the hamster, whereas higher doses (10-20 mg/kg) did not. In addition, 5 mg/kg of iloperidone reduced alcohol drinking to the same extent as clozapine (8 mg/kg), whereas haloperidol (0.2 mg/kg) did not. Moreover, iloperidone's effects were enhanced via the addition of desipramine (3 mg/kg), but not idazoxan (1.5/3 mg/kg). In this animal model, iloperidone decreases alcohol drinking as effectively as clozapine, and desipramine appears to amplify this effect. The data suggest that iloperidone, alone or in combination with desipramine, should be tested in patients with schizophrenia and alcohol use disorder., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to autoantibodies affecting the neuromuscular junction. Co-occurrence of myasthenia gravis and schizophrenia is very rare and raises a challenge in management of both diseases. Antipsychotic drugs exhibit anticholinergic side effects and have the potentials of worsening myasthenia. Long-acting risperidone is an injectable atypical antipsychotic drug that has not been previously reported to worsen myasthenia gravis in literature. We report the first case report of worsening of myasthenia after receiving long-acting risperidone injection for schizophrenia in a 29-year-old female with both diseases. She started to have worsening 2 weeks following the first injection and her symptoms persisted despite receiving plasma exchange. This could be explained by the pharmacokinetics of the drug. We recommend that long-acting risperidone should be used with caution in patients with myasthenia gravis, and clinicians must be aware of the potential risks of this therapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Emerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients' treatment expectations and prior treatment experiences. Animal research confirmed that "enriched environments" support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug×environment interactions to improve trial sensitivity and treatment outcome., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)