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Rationale: Neuroinflammation may inhibit oligodendrocyte and astrocyte differentiation, which causes demyelination and synaptic degeneration. The myelin component nervonic acid (NA) may improve demyelinating and neurodegenerative diseases., Objectives: This study firstly explored relationships between glial cell dysfunction and demyelination or synaptic degeneration in schizophrenia patients, and secondly determined nervonic acid therapeutic effects in a preclinical schizophrenia model of mice., Methods: Plasma samples were collected from 18 male healthy controls and 18 male schizophrenic patients (diagnosed by DSM-V) at aged 18-55. Mouse brain samples were collected from a maternal immune activation (MIA) model of schizophrenia via injecting 5 mg/kg polyinosinic-polycytidylic acid. Male mouse offspring (age 2.5 months, n = 12) were treated by clozapine (15 mg/kg/day) or fed 0.5% NA for 6 weeks. Cytokine and dopamine (DA) concentrations, and glial phenotypes and myelin markers were measured in both human plasma and mouse brain samples., Results: In patient plasma, increased proinflammatory cytokines were associated with reactive microglia (Iba-1) up-regulation, while decreased anti-inflammatory cytokines were related to microglia (CD206) downregulation. Decreased astrocyte marker (p11) concentrations were accompanied by reduced concentrations of oligodendrocyte and synaptic markers. However, NA and DA contents were increased. Compared with control mice, SZ-like behaviors appeared in MIA male mice. Changes in microglia and astrocytes markers, and cytokine concentrations in the frontal cortex were consistent with those observed in patients' plasma. Hippocampal oligodendrocyte and synaptic marker expression were also decreased. DA content and DA/metabolite (DAPOC) were increased in MIA mouse brains. Most of these changes were normalized by both clozapine and NA. Even though some NA effects were more pronounced than clozapine, only clozapine restored cytokine function., Conclusion: The data suggest a possible therapeutic route for schizophrenia patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention., Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms., Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT 2A , 5-HT 2C , and 5-HT 7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition., Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5 mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2 mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130 h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63 ng/mL, 4.53 ± 3.61 h, 57.65 ± 23.77 L/h and 53.58 ± 52.28 h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19 ng/mL, 9.38 ± 9.33 h and 62.67 ± 82.57 h, respectively; of clozapine-N-oxide were 1.15 ± 0.36 ng/mL, 4.53 ± 2.19 h and 19.15 ± 23.11 h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Patients with schizophrenia with second-generation antipsychotics (SGAs) treatment have shown an increased risk of bone fragility and susceptibility to fracture; however, it is still unclear whether this risk is derived from the effect of antipsychotics on balance of bone metabolism., Objectives: We investigated the changes of two bone turnover biomarkers (BTMs) concentrations in people with schizophrenia receiving SGAs: procollagen type I aminoterminal propeptide (PINP) and C-terminal telopeptide of type I collagen (CTX-1) as BTMs of osteogenesis and bone resorption, respectively, to explore how antipsychotics contribute to bone fragility., Methods: We recruited 59 Chinese male patients with schizophrenia (32 drug-naïve first-episode (DNFE) patients and 27 chronic patients) to undergo 8 weeks SGAs treatment. Fasting peripheral blood samples of pre- and posttreatment were collected, plasma levels of PINP and CTX-1 were measured., Results: The interaction effects of group and time on PINP and CTX-1 concentrations were found (P = .016 and P = .008). There was a significant decrease for both BTMs concentrations of the posttreatment compared to the pretreatment (P<.001 and P = .003). Chronic patients had significantly higher changes of BTMs concentrations compared to DNFE patients (P = .048 and P = .024). There was a positive correlation of the two BTMs of pretreatment with disease course in DNFE group (r = .37, P = .039;r = .38, P = .035) and a negative correlation of PINP of pretreatment with age in the chronic group (r=-.40, P = .039)., Conclusion: Long-term SGAs medication inhibited osteogenesis in a dose- and time-dependent manner and damaged the balance of bone formation and bone resorption., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue., Objectives: We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA., Methods: This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed., Results: Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia., Conclusions: Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed., (© 2024. The Author(s).)

Rationale: Changes in the density and diversity of gut microbiota in chronic use of methamphetamine have been mentioned as contributors to psychotic and anxiety symptoms, sleep problems, and loss of appetite., Objective: In this placebo-controlled clinical trial, we investigated the effect of the probiotic Lactobacillus Acidophilus in improving psychiatric symptoms among hospitalized patients with chronic methamphetamine use along with psychotic symptoms., Methods: 60 inpatients with a history of more than 3 years of methamphetamine use, were randomly assigned to one of two groups receiving either a probiotic capsule or placebo along with risperidone for 8 weeks based on a simple randomization method. In weeks 0, 4, and 8, patients were evaluated using the Brief Psychiatric Rating Scale (BPRS), Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), Simple Appetite Nutritional Questionnaire (SANQ), and Body Mass Index (BMI)., Results: Compared to the control group, patients receiving probiotics had better sleep quality, greater appetite, and higher body mass index (there were significant interaction effects of group and time at Week 8 in these variables (t = -3.32, B = -1.83, p = .001, d = 0.89), (t = 10.50, B = 2.65, p <.001, d = 1.25) and (t = 3.40, B = 0.76, p <.001, d = 0.30), respectively. In terms of the improvement of psychotic and anxiety symptoms, there was no statistically significant difference between the two groups., Conclusions: The use of probiotics was associated with improved sleep quality, increased appetite, and increased body mass index in patients with chronic methamphetamine use. Conducting more definitive clinical trials with larger sample sizes and longer-term follow-up of cases is recommended., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Withdrawal syndrome (WDS) has been described after discontinuation of antipsychotics. WDS could be the consequence of an over-activation of the dopaminergic pathway. Antipsychotics with a higher affinity for dopamine D2 receptors could be associated with a higher risk of WDS. This study aims to address this statement and evaluate the risk difference for withdrawal syndrome between antipsychotics based on pharmacovigilance data., Methods: We collected individual reports registered in Vigibase® between 01/01/2000 and 31/12/2022 of patients treated with antipsychotics and who had presented WDS. A disproportionality analysis was performed to evaluate the risk of reporting WDS with each antipsychotic compared to all other antipsychotics. We performed a correlation analysis to assess the correlation between the risk of reporting WDS for each antipsychotic in relation with their pKi for D2 and 5HT2A receptors., Results: The most frequent psychiatric withdrawal symptoms after antipsychotic discontinuation were insomnia, anxiety and depression. Tremor, headache and dizziness were among the most frequently reported neurologic withdrawal symptoms. Tiotixene had the highest risk of reporting WDS (ROR 7.08; 95%CI 3.49 - 14.35) followed by pimozide (ROR 4.35; 95%CI 1.93 - 9.77), quetiapine (ROR 4.24; 95%CI 3.87 - 4.64), thioridazine (ROR 4.17; 95%CI 2.50-6.98) and ziprasidone (ROR 2.98; 95%CI 2.41-3.67). We found a poor correlation between D2/5HT2A binding affinity and the risk of reporting withdrawal syndrome (R 2  = 0,094)., Conclusion: Our results suggest that there might be a risk difference for WDS between antipsychotics. Tiotixene, pimozide and quetiapine were associated with a higher risk of reporting a WDS whereas this risk was lower with chlorpromazine, clozapine and fluphenazine. We could not address the issue of withdrawal psychosis, withdrawal dyskinesia, rebound psychosis or supersensitivity psychosis due to the lack of specific WHO medDRA coded terms to identify potential cases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Drug-induced liver injury (DILI) is a serious health burden. It has diverse clinical presentations that can escalate to acute liver failure. The worldwide increase in the use of psychotropic drugs, their long-term use on a daily basis, common comorbidities of psychiatric and metabolic disorders, and polypharmacy in psychiatric patients increase the incidence of psychotropics-induced DILI. During the last 2 decades, hepatotoxicity of various antidepressants (ADs) and antipsychotics (APs) received much attention. Comprehensive review and discussion of accumulated literature data concerning this issue are performed in this study, as hepatotoxic effects of most commonly prescribed ADs and APs are classified, described, and discussed. The review focuses on ADs and APs characterized by the risk of causing liver damage and highlights the ones found to cause life-threatening or severe DILI cases. In parallel, an overview of hepatic oxidative stress, inflammation, and steatosis underlying DILI is provided, followed by extensive review and discussion of the pathophysiology of AD- and AP-induced DILI revealed in case reports, and animal and in vitro studies. The consequences of some ADs and APs ability to affect drug-metabolizing enzymes and therefore provoke drug-drug interactions are also addressed. Continuous collecting of data on drugs, mechanisms, and risk factors for DILI, as well as critical data reviewing, is crucial for easier DILI diagnosis and more efficient risk assessment of AD- and AP-induced DILI. Higher awareness of ADs and APs hepatotoxicity is the prerequisite for their safe use and optimal dosing.

Rationale: Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive., Objective: Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia., Methods: We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4., Results: Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus., Conclusions: Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.

Rationale: Stress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed. Cannabidiol (CBD) has antipsychotic and anxiolytic effects., Objectives: We investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients., Methods: Thirty-two CHR patients and 26 healthy controls (HC) took part in the Trier Social Stress Test (TSST) and their serum cortisol, anxiety and stress associated with public speaking were estimated. Half of the CHR participants were on 600 mg/day of CBD (CHR-CBD) and half were on placebo (CHR-P) for 1 week., Results: One-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p's < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change., Conclusions: Our findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.

Rationale: The licensed dose range for the long-acting injectable antipsychotic flupentixol decanoate (Depixol®) in the treatment of schizophrenia is very broad. This provides little useful direction to prescribers and may ultimately result in patients receiving unnecessarily high doses., Objectives: We aimed to estimate the effect of dose of flupentixol decanoate on relapse rates in schizophrenia and on tolerability by expanding on an earlier review and including non-RCT and German-language studies, as well as using pharmacokinetic and pharmacodynamic data to offer guidance on dosing., Methods: A literature review using EMBASE, Medline, PsycINFO and PubMed was conducted. Treatment success rates at 6 months were extracted or extrapolated from the studies and plotted against dose to estimate a dose-response curve., Results: Data from 16 studies (n = 514) allowed estimation of a dose-response curve which rises steeply between the chosen placebo anchor (25% success rate) and 10 mg every 2 weeks before reaching a maximum between 20 and 40 mg every 2 weeks (80-95% success rates). Extrapyramidal side effects (EPSEs) were frequently seen (12-71% of participants) in that dose range. Two -weekly injections seem to provide the highest trough plasma concentration per dose administered and the lowest peak-to-trough concentration ratio. Plasma concentration varied up to 5-fold among individuals receiving the same dose., Conclusions: The optimal dose of flupentixol decanoate is likely to be between 20 mg and 40 mg every 2 weeks although higher doses may be required in some individuals owing to variation in drug handling. Doses of flupentixol should be individually established in the range of 10 to 40 mg every 2 weeks according to response and tolerability.

Rationale: N-3 polyunsaturated fatty acids (n-3 PUFA) influence multiple biochemical mechanisms postulated in the pathogenesis of schizophrenia that may influence BDNF synthesis., Objectives: A randomized placebo-controlled study was designed to compare the efficacy of a 26-week intervention composed of either 2.2 g/day of n-3 PUFA or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between n-3 PUFA clinical effect and changes in peripheral BDNF levels., Methods: Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the following study arms: 36 to the EPA + DHA group and 35 to the placebo group. Plasma BDNF levels were assessed three times, at baseline and at weeks 8 and 26 of the intervention. BDNF levels were determined in plasma samples using Quantikine Human BDNF ELISA kit. Plasma BDNF level changes were further correlated with changes in the severity of symptoms in different clinical domains., Results: A significantly greater increase in plasma BDNF levels was observed in the intervention compared to the placebo group (Cohen's d = 1.54). Changes of BDNF levels inversely correlated with change in depressive symptoms assessed using the Calgary Depression Rating Scale in Schizophrenia (Pearson's r = - 0.195; p = 0.018)., Conclusions: The efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to an increase in BDNF levels, which may be triggered by the activation of intracellular signaling pathways including transcription factors such as cAMP-reactive element binding protein.

Rationale: Δ-9-Tetrahydrocannabinol (Δ-9-THC) produces psychotomimetic effects in humans. However, the role of dopamine signaling in producing such effects is unclear. We hypothesized that dopaminergic antagonism would reduce the psychotomimetic effect of Δ-9-THC., Objective: The objective of this study was to evaluate whether pre-treatment with haloperidol would alter the psychotomimetic and perceptual-altering effects of Δ-9-THC, measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinician-Administered Dissociative Symptom Scale (CADSS) in humans., Methods: In a two-test-day double-blind study, 28 healthy individuals were administered with active (0.057 mg/kg) or placebo oral haloperidol, followed 90 and 215 min later by intravenous administration of active (0.0286 mg/kg) Δ-9-THC and placebo, respectively. This secondary analysis was conducted because of the observation in other studies and in our data that a significant proportion of individuals may not have an adequate response to THC (floor effect), thus limiting the ability to test an interaction. Therefore, this analysis was performed including only responders to THC (n = 10), defined as individuals who had an increase of at least one point on the PANSS positive scale, consistent with prior human laboratory studies., Results: In the 10 responders, Δ-9-THC-induced increases in PANSS positive scores were significantly lower in the haloperidol condition (1.1 + 0.35) compared with the placebo condition (2.9 + 0.92)., Conclusion: This responder analysis showed that haloperidol did reduce the psychotomimetic effect of Δ-9-THC, supporting the hypothesis that dopaminergic signaling may participate in the psychosis-like effects of cannabinoids.

Rationale: Antipsychotics exert therapeutic effects by modulating various cellular signalling pathways and several types of receptors, including PKA- and GSK3β-mediated signalling pathways, and NMDA receptors. The ventral midbrain, mainly containing the ventral tegmental area (VTA) and substantia nigra (SN), are the nuclei with dopamine origins in the brain, which are also involved in the actions of antipsychotics. Whether antipsychotics can modulate these cellular pathways in the ventral midbrain is unknown., Objective: This study aims to investigate the effects of antipsychotics, including aripiprazole (a dopamine D 2 receptor (D 2 R) partial agonist), bifeprunox (a D 2 R partial agonist), and haloperidol (a D 2 R antagonist) on the PKA- and GSK3β-mediated pathways and NMDA receptors in the ventral midbrain., Methods: Male rats were orally administered aripiprazole (0.75 mg/kg, t.i.d. (ter in die)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for either 1 week or 10 weeks. The levels of PKA, p-PKA, Akt, p-Akt, GSK3β, p-GSK3β, Dvl-3, β-catenin, and NMDA receptor subunits in the ventral midbrain were assessed by Western Blots., Results: The results showed that chronic antipsychotic treatment with aripiprazole selectively increased PKA activity in the VTA. Additionally, all three drugs elevated the activity of the Akt-GSK3β signalling pathway in a time-dependent manner, while only aripiprazole stimulated the Dvl-3-GSK3β-β-catenin signalling pathway in the SN. Furthermore, chronic administration with both aripiprazole and haloperidol decreased the expression of NMDA receptors., Conclusion: This study suggests that activating PKA- and GSK3β-mediated pathways and downregulating NMDA receptor expression in the ventral midbrain might contribute to the clinical effects of antipsychotics.

Objective: This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia., Method: Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12., Results: Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (- 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; - 26 ± 76 vs - 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100)., Conclusion: In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. CLINICALTRIALS., Gov Identifier: NCT00981526.

Genome-wide association study results have linked ADCK1 genetic variation with paliperidone efficacy in a European cohort. However, the generalizability of this locus to non-European populations is unknown. Han Chinese schizophrenia patients (n = 159) were treated with paliperidone palmitate and symptom severity was assessed over 3 months. Examination of 13 ADCK1 genetic variants revealed two single nucleotide polymorphisms (rs12590199, rs11159291) and one haplotype (rs2364747-rs12590199) associated with paliperidone palmitate response. Future work into ADCK1's function and its potential interaction with paliperidone is warranted.

Rationale: Quetiapine fumarate is an atypical antipsychotic indicated for various mental disorders, but it has not been studied in Japanese patients with bipolar depression., Objectives: To evaluate the efficacy and safety of quetiapine XR (extended release) in Japanese patients with bipolar depression., Methods: In this multi-center, randomized, double-blind, placebo-controlled, fixed-dose study of 431 Japanese adults with bipolar I or II disorder, efficacy was determined by analyzing the mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary end points included MADRS response and remission rates, Hamilton Depression Scale 17-Item (HAM-D 17 ), and Clinical Global Impressions-Bipolar (CGI-BP) scale scores. Safety was determined by monitoring adverse events and clinical assessments., Results: This study revealed a statistically significantly greater decrease in MADRS total score after 8 weeks of quetiapine XR 300 mg/day monotherapy compared with placebo (- 12.6 vs. - 10.1; p = 0.034). There were also improvements in MADRS response (44.1 vs. 35.6%) and remission (38.0 vs. 26.6%) rates as well as in HAM-D 17 and CGI-BP scale scores compared with placebo. In the subgroup analysis of patients with bipolar I or II disorder, the adjusted mean changes in MADRS total score compared to placebo were - 2.3 and - 2.1, respectively. Adverse events occurred in 149 patients (83.2%) receiving quetiapine XR 300 mg/day and in 81 patients (45.8%) receiving placebo. The most common adverse events were somnolence and thirst, which is consistent with the previously reported safety profile., Conclusions: Once-daily monotherapy with quetiapine XR is an effective and well-tolerated treatment for bipolar depression in Japanese patients.

Rationale: This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment., Objective: We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia., Methods: The primary outcome was an improvement in total symptoms. Other outcomes were psychopathology subscales (positive, negative, general, and depressive symptoms), discontinuation due to all-cause and adverse events, and individual adverse events. The meta-analysis evaluated the effect size based on a random-effects model., Results: Although we included ten RCTs with 925 patients in total (seven folic acid RCTs (n = 789), two methylfolate RCTs (n = 96), and one folinic acid RCT (n = 40)) in the systematic review, only seven RCTs were included in the meta-analysis. Pooled FA + AP treatments were not superior to placebo + AP in the improvement of total (N = 7, n = 340; standardized mean difference (SMD) = - 0.20, 95% confidence interval (CI) = - 0.41, 0.02, p = 0.08, I 2  = 0%), positive, general, or depressive symptoms. Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04, I 2  = 0%). Although pooled FA + AP treatments were associated with a lower incidence of serious adverse events than placebo treatments (N = 4, n = 241; risk ratio = 0.32, 95% CI = 0.12-0.82, p = 0.02, I 2  = 0%; number needed to harm = not significant), there were no significant differences in other safety outcomes between both treatments., Conclusions: Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients. Moreover, this treatment was well tolerated. However, because our results might exhibit a small-study effect, future studies with a larger sample should be conducted to obtain more robust results.

Rationale: Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS)., Objective: This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial., Methods: This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6 weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly., Results: There was no main effect of time or drug on MCCB Composite score, but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p < 0. 0001) but there was no significant drug × time interaction (p = 0.18). Side effects were similar between CBD and placebo, with the one exception being sedation, which was more prevalent in the CBD group., Conclusions: At the dose studied, CBD augmentation was not associated with an improvement in MCCB or PANSS scores in stable antipsychotic-treated outpatients with schizophrenia. Overall, CBD was well tolerated with no worsening of mood, suicidality, or movement side effects., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00588731.

Breastfeeding women are excluded from clinical trials of psychoactive drugs because of ethical concerns. Animal testing, which often is predictive of adverse effects in humans, represents the only avenue available for assessing drug safety for human offspring exposed to drugs during lactation. I determined whether behavioral outcomes for children exposed during breastfeeding to antidepressants, anxiolytics, antipsychotics, anti-seizure medications, analgesics, sedatives, and marijuana can be predicted by rodent studies of offspring exposed to drugs during lactation. Animal data were available for only 10 of 80 CNS-active drugs canvassed. Behavioral deficits in adolescence or adulthood in rats and mice after various drug exposures during lactation included reductions in sexual behavior, increased anxiety, hyperactivity, and impaired learning and memory. Whether similar adverse effects will emerge in adulthood in children exposed to drugs during breastfeeding is unknown. Rodent research has the potential to forecast impairments in breastfed children long before information emerges from post-marketing reports and should be prioritized during preclinical drug evaluation by the FDA for new drugs and for drugs currently prescribed off-label for lactating women.

Objective: The aim of this study was to compare the effect of quetiapine extended release (ER) versus aripiprazole on corrected QT interval (QTc) and QT dispersion (QTd) in youths with first-episode psychosis., Methods: Youths 12-17 years were randomized to quetiapine ER (daily dose range = 50 to 800 mg) or aripiprazole (daily dose range = 2.5 to 30 mg) in a 12-week double-blinded trial and examined at weeks 0, 4, and 12. Primary outcome was QTc change using Hodges formula (QTcH); secondary outcomes included QTcH > 450 ms, QTcH > 500 ms, QTcH change > 60 ms, QTd, and heart rate (HR)., Results: Among 113 randomized youths, follow-up ECG was available for 93 patients (82.3%) (age = 15.8 ± 1.3 years, males = 34.4%, schizophrenia = 67.7%). Quetiapine ER treatment (n = 47) was associated with a significant increase in QTcH of + 6.8 ± 20.2 ms (p = 0.025), while the change from baseline in patients receiving aripiprazole (n = 46) was non-significant (- 3.4 ± 18.9 ms, p = 0.225). One patient in the quetiapine ER group had a QTcH change of + 62.3 ms. Age, sex, smoking, body mass index, and concomitant medication were not significantly associated with QTcH change, but higher baseline potassium was correlated to higher QTcH change in the quetiapine ER group. The HR increased significantly with quetiapine ER (+ 11.0 ± 14.2 bpm, p < 0.001) but not with aripiprazole (- 0.8 ± 12.0 bpm, p = 0.643). QTd did not significantly change with quetiapine ER or aripiprazole., Conclusion: QTcH and HR increased significantly with quetiapine ER, although changes were small and likely not clinically significant in otherwise healthy patients. QTcH and HR were unchanged with aripiprazole. No significant change in QTd was seen. ClinicalTrials.gov: NCT01119014, EudraCT: 2009-016715-38.

Background: The long-term administration of antipsychotics is known to induce dopamine supersensitivity psychosis (DSP). Although the mechanism of DSP involves mainly a compensatory upregulation of dopamine D2 receptors, the precise mechanisms underlying DSP are unknown. It is known that glutamatergic signaling plays a key role in psychosis. We thus conducted this study to investigate whether glutamatergic signaling plays a role in the development of DSP., Methods: Haloperidol (0.75 mg/kg/day for 14 days) or vehicle was administered to rats via osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSP rats and non-DSP rats based on locomotion data. Tissue levels of glutamate, glutamine, glycine, L-serine, D-serine, and GABA and the protein expressions of N-methyl-D-aspartate receptors (NMDAR), glutamic acid decarboxylase (GAD), and serine hydroxymethyltransferase (SHMT) in the rat brain regions were examined., Results: In the DSP rats, the ratio of GABA to glutamate was significantly increased. In addition, the ratio of L-serine to glycine was increased. The striatal expressions of GAD and SHMT2 in the DSP rats were significantly increased. In contrast, the striatal expression of NMDAR2B in the non-DSP rats was significantly decreased., Conclusions: The present study suggests that glutamatergic signaling is relatively decreased to GABA in DSP rats. Our results also showed that excessive doses of haloperidol can induce striatal NMDAR hypofunction in non-DSP rats, which could prevent the formation of tardive dyskinesia but cause treatment resistance. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, further research exploring our present findings is necessary.

Rationale: We studied the influence of zinc, haloperidol or olanzapine on neurobehaviour (open-field, radial arm maze and elevated plus maze) and brain antioxidant status in vehicle- or ketamine-treated mice, with the aim of ascertaining the potentials of zinc in counteracting ketamine's effects., Objectives: Experiment 1 assessed the effects of zinc in healthy animals and the relative degrees of modulation of ketamine's effects by zinc, haloperidol or olanzapine, respectively. Experiment 2 assessed the modulation of ketamine's effects following co-administration of zinc with haloperidol or olanzapine., Methods: Male mice weighing 18-20 g each were used. Animals were pretreated with ketamine (except vehicle, zinc, haloperidol and olanzapine controls) for 10 days before commencement of 14-day treatment (day 11-24) with vehicle, zinc, haloperidol or olanzapine (alone or in combination). Ketamine injection also continued alongside zinc and/or standard drugs in the ketamine-treated groups. Zinc, haloperidol and olanzapine were administered by gavage. Treatments were given daily and behaviours assessed on days 11 and 24. On day 24, animals were sacrificed and whole brain homogenates used for estimation of glutathione, nitric oxide and malondialdehyde (MDA) levels., Results: Ketamine increased open-field behaviours, nitric oxide and MDA levels, while it decreased working memory, social interaction and glutathione. Administration of zinc alone or in combination with haloperidol or olanzapine was associated with variable degrees of reversal of these effects., Conclusion: Zinc may have the potential of a possible therapeutic agent and/or adjunct in the reversal of schizophrenia-like changes in behaviour and brain oxidative status.

Objective: This study aims to compare treatment response in bipolar I or II depression and generalized anxiety disorder (GAD) with and without recent alcohol and/or cannabis use disorder (ALC/CAN) to quetiapine-XR (extended release) or placebo., Methods: A randomized, double-blind, 8-week study of quetiapine-XR versus placebo in patients with bipolar I or II depression and GAD with or without a recent ALC/CAN was used to compare changes in Hamilton Depression Rating Scale-17, Hamilton Anxiety Rating Scale, the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16), Clinical Global Impression for Bipolar Disorder-Severity (CGI-BP-S), and Timeline Follow Back within and between groups., Results: In the quetiapine-XR group, patients with a recent ALC/CAN (n = 22) had significant decreases in QIDS-SR-16 (-9.6 ± 1.6 vs. -3.7 ± 1.7) and CGI-BP-S (-1.6 ± 0.4 vs. -0.8 ± 0.03) than those without a recent ALC/CAN (n = 24). In the placebo group, both patients with a recent ALC/CAN (n = 23) and those without (n = 21) had similar reductions in these measures. The reduction of QIDS-SR-16 scores in patients with a recent ALC/CAN was also significantly different from that of their counterparts in the placebo group. Patients who received quetiapine-XR had larger decreases in the number of drinking days/week (p = 0.17) and number of cannabis joints/week (p = 0.09) compared to those who received placebo., Conclusion: Quetiapine-XR was superior to placebo in reducing QIDS-SR-16 total score in patients with a recent ALC/CAN. Patients taking quetiapine-XR used less alcohol and cannabis than patients on placebo, suggesting that quetiapine-XR may be of use in patients with bipolar disorder accompanied by GAD and other comorbidities.

The nucleus accumbens (NAcc) has been implicated in schizophrenia (SZ) pathology, based on antipsychotic action therein. However, recent imaging studies suggest that the NAcc may not be a locus of dopamine dysregulation in SZ. This study examined postmortem human tissue to determine if abnormalities are present in dopamine synthesis in the NAcc in SZ. We compared the immunohistochemical localization of tyrosine hydroxylase (TH), the rate-limiting synthesizing enzyme of dopamine, in postmortem tissue from SZ subjects and demographically matched controls. To study the effects of chronic antipsychotic drug (APD) treatment on TH immunolabeling in the NAcc, rats were treated for 6 months with haloperidol or olanzapine. In the NAcc, TH immunolabeling was similar in control and SZ subjects, in both the core and shell. Rats had similar TH optical density levels across treatment groups in both the core and shell. Similar levels of TH suggest DA synthesis may be normal. These findings provide further insight into the role of the NAcc in SZ.

Rationale: Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial., Objective: The objective of this study was to examine the relationship between antipsychotic-related dopamine D 2/3 receptor occupancy and negative symptoms in patients with schizophrenia., Methods: Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [ 11 C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose., Results: No significant relationship was found between antipsychotic-related dopamine D 2/3 receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship., Conclusions: Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined.

A widely discussed shortcoming of long-term care in nursing homes for the elderly is the inappropriate or suboptimal drug utilization, particularly of psychotropic drugs. Using administrative data from the largest sickness fund in Germany, this study was designed to estimate the effect of institutionalization on the drug intake of the frail elderly. Difference-in-differences propensity score matching techniques were used to compare drug prescriptions for the frail elderly who entered a nursing home with those who remained in the outpatient care system; findings suggest that nursing home residents receive more doses of antipsychotics, antidepressants, and analgesics. The potential overprescription correlates with estimated drug costs of about €87 million per year.

In recent years, several studies have investigated genetic polymorphisms of antipsychotic drug-metabolizing enzymes and receptors. However, most studies focused on drug response and very few have investigated the genetic influence on antipsychotic dosage. The aim of the present study is to test the association between antipsychotic dosages at genome-wide level. The current dosage of antipsychotic medications was collected from 79 schizophrenia patients. The dosage was standardized using three different methods: chlorpromazine equivalent (CPZe), defined daily dose (DDD), and percentage of maximum dose (PM %). The patients were then genotyped using the Illumina HumanOmni2.5-8 BeadChip Kit. All markers were screened for significance using linear regression, and the p values were visualized using a Manhattan plot. The genome-wide analysis showed that the top Single-Nucleotide Polymorphisms (SNPs) associated with dosage variation were rs981975 on chromosome 14 for CPZe, rs4470690 on chromosome 4 for PM %, and rs79323383 on chromosome 8 for DDD. However, no genome-wide significantly associated SNPs were identified. In this pilot sample, we found promising trends for pharmacodynamic targets associated with antipsychotic dosage. Therefore, studies combining large prescription databases may identify genetic predictors to adjust the dose of antipsychotic medication.

Rationale: The only systematic in vivo studies comparing antipsychotic (AP) effects on nucleus accumbens (NAc) shell and core dopamine (DA) transmission are voltammetric studies performed in pargyline-pretreated, halothane-anaesthetized rats. Studies in freely moving rats not pretreated with pargyline are not available. This study was intended to fill this gap by the use of in vivo microdialysis in freely moving rats., Methods: Male Sprague-Dawley rats were implanted with microdialysis probes in the NAc shell and core and medial prefrontal cortex (PFCX). The next day, rats were administered intravenously with two or three doses of APs, and dialysate DA was monitored in 10-min samples. Some rats were pretreated with pargyline (75 mg/kg i.p.) and after 1 h were given clozapine or risperidone., Results: Clozapine, risperidone, quetiapine, raclopride, sulpiride and amisulpride increased DA preferentially in the NAc shell. Such preferential effect on shell DA was not observed after haloperidol, chlorpromazine and olanzapine. In contrast to voltammetric studies, a preferential effect on NAc core DA was not observed after any dose of AP. Pargyline pretreatment did not reduce but actually amplified the preferential effect of clozapine and risperidone on NAc shell DA., Conclusions: Apart from raclopride and olanzapine, the APs with lower extrapyramidal effects could be distinguished from typical APs on the basis of their ability to preferentially stimulate DA transmission in the NAc shell. There was no relationship between stimulation of PFCX DA and atypical APs profile. The differences between this study and voltammetry studies were not attributable to pargyline pretreatment.

Rationale: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect., Objective: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats., Methods: 2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested., Results: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance., Conclusions: Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC.

Rationale: It is well established that the rewarding effects of alcohol are modulated by the mesolimbic dopaminergic system. Olanzapine, a D2 dopamine antagonist, has been shown to reduce alcohol craving and consumption., Objective: To clarify whether olanzapine has clinical utility in the treatment of alcohol dependence, a 12-week, double-blind, and randomized clinical trial was conducted., Methods: One hundred twenty-nine treatment-seeking alcohol-dependent adults were randomly assigned to 12 weeks of olanzapine (5 vs. 2.5 mg) or placebo. Outcomes examined were average drinks per drinking day (DDD), proportion of drinking days (PDD) to total days in treatment, alcohol craving, and impaired control over alcohol use. Mixed models were used to examine medication effects during the course of treatment on specified outcomes., Results: All of the analyses indicated a main effect for time, such that there were reductions in alcohol use and craving and an increase in control over alcohol use across treatment conditions. Dose-response analyses indicated that, in comparison to placebo, participants in the 5 mg group experienced reduced craving for alcohol and participants in the 2.5 mg group decreased in PDD and increased in their control over alcohol use. Better control over alcohol use remained significant 6 months post-treatment for the 2.5 mg group. Subjective experiences of the medication suggest that 2.5 and 5 mg were equally well tolerated., Conclusions: Results provide some support for the notion that dosage is an important consideration in relation to effectiveness; however, the cost-benefit balance does not support the clinical utility of olanzapine in treating alcohol dependence.

Rationale: Recent case reports describe recreational use of quetiapine and drug-seeking behaviour to obtain quetiapine, an atypical antipsychotic., Objective: We examined the hypothesis that quetiapine (10, 20 or 40 mg/kg) alone or co-administered with (+)-amphetamine (0.25, 0.5, 0.75 or 2.0 mg/kg) will affect reward and/or decrease anxiety in rats, as measured by conditioned place preference (CPP) and elevated plus maze (EPM) test, respectively., Results: Quetiapine (20 mg/kg) produced greater open arm time and entries in the EPM test compared to 10 and 40 mg/kg, and quetiapine (10 mg/kg) significantly increased open arm entries and time when co-administered with (+)-amphetamine (0.5 mg/kg) compared to (+)-amphetamine (0.5 mg/kg) alone, suggesting decreased anxiety. Quetiapine (10, 20 or 40 mg/kg) produced no CPP when administered alone; the lowest dose of quetiapine (10 mg/kg) reduced CPP produced by a low dose of (+)-amphetamine (0.25 mg/kg), but had no significant effect on CPP produced by a higher dose (0.5 mg/kg)., Discussion: The quetiapine-induced anxiolytic effect in the EPM might explain why humans are misusing quetiapine and combining it with (+)-amphetamine. It is possible that humans experience an anxiolytic effect of the combined drugs and relatively unaltered rewarding effects of (+)-amphetamine. The results shed some light on the question of why humans are abusing and misusing quetiapine, despite its dopamine (DA) D2 receptor antagonism; it will be the task of future studies to identify the pharmacological mechanism mediating this behaviour.

Rationale: Antipsychotic dosage is generally adjusted by physicians depending on the stability of the patient and the response to that particular drug. Our hypothesis is that patients with previous suicide attempt are prescribed higher doses of antipsychotics., Objective: We examined the dosage and patterns of antipsychotic use in regard to past suicidal behaviour., Methods: For this study, 304 subjects with schizophrenia spectrum disorders between the ages of 18 and 75 were recruited. A cross-sectional assessment was used for this study, in which data were collected from each patient through an interview and self-report questionnaires. The percentages of the Compendium of Pharmaceuticals and Specialties (CPS) maximum recommended daily dose were applied to standardize antipsychotic dosages across different treatments. We compared the standardized dosage of antipsychotics in schizophrenics with previous suicide attempts and those who have never attempted suicide., Results: Applying the ANCOVA, our preliminary results show no significant difference (P = 0.467) in antipsychotic dosage in the attempters and non-attempters. The prescribed clozapine dosage fails to show a significant relationship with suicidal history (P >0.05)., Conclusions: In summary, our analysis does not show antipsychotic dosage adjustment based on past suicide attempt, after controlling for the current suicidal ideation and hopelessness.

Objective: Despite higher smoking rates in schizophrenia, few studies have explored the clinical-demographic correlates of different amounts of smoking exposure. Little is known about the association between smoking severity and clinical phenotypes in Chinese patients with schizophrenia., Materials and Methods: We investigated differences between heavy (≥1 pack/day) and non-heavy (<1 pack/day) smoking in 550 male inpatients with schizophrenia using clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence. They also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS), as well as were assayed with laboratory tests and an electrocardiogram., Results: Heavy smoking prevalence was approximately 31 %. Compared to the non-heavy smokers, the heavy smokers were younger, more with paranoid subtype but less with disorganized subtype schizophrenia, smoked at an earlier age, fewer getting clozapine or all atypical antipsychotics together, and were taking larger doses of antipsychotic drugs. The heavy smokers scored significantly lower on the PANSS negative symptom subscore and total score, and also on the SAES and AIMS scores than the non-heavy smokers. In addition, heavy smokers displayed longer rate-corrected electrocardiographic QT intervals, but without any significant differences in other laboratory tests., Conclusion: Our results suggest several clinical or demographic differences between the heavy and non-heavy smoking patients with schizophrenia in a Chinese population. Heavy smoking remains a general health risk for schizophrenia.

Rationale: Both typical and atypical antipsychotic drugs are D2 receptor antagonists but yet appear to have markedly different effects upon the induction of dopamine sensitization., Objective: This study aims to compare the effects of subchronic regimens of low-dose olanzapine and haloperidol administered to rats previously sensitized to apomorphine., Methods: Initially, rats received apomorphine (2.0 mg/kg) or vehicle treatments for five consecutive days followed by a conditioning test and an apomorphine challenge test. Next, there was an antipsychotic exposure phase in which three vehicle groups and three apomorphine groups received 10 daily injections of either vehicle, haloperidol (0.03 mg/kg) or olanzapine (0.01 mg/kg). In the final phase, all groups were given a second conditioning test and apomorphine challenge test., Results: Apomorphine induced sensitization and conditioning effects. Following haloperidol exposure, apomorphine conditioned and sensitization effects were potentiated but, in contrast, olanzapine exposure eliminated apomorphine sensitization effects. In addition, the sensitization induced by apomorphine transformed the low-dose haloperidol treatment into a potent locomotor stimulant treatment. In the vehicle groups, haloperidol and olanzapine exposure effects were equivalent and not different from vehicle treatment., Conclusions: The profound differences observed between typical and atypical antipsychotic exposure in animals with an upregulated dopamine system are consistent with clinical evidence for lower risk of psychomotor disturbances with chronic treatment with atypical antipsychotic. Importantly, the finding that a very low dose of olanzapine reversed sensitization effects suggests that low-dose olanzapine may have clinical utility in a variety of disorders linked to sensitization of the dopamine system.

Rationale: Clozapine affects the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the brain, which plays an important role in its antipsychotic action. However, previous findings are inconsistent, and related molecular mechanisms require further clarification., Objectives: Time- and dose-dependent effects of clozapine on the ERK1/2 pathway and its regulatory mechanism were investigated in rat frontal cortex., Methods and Results: At 15, 30, 60, and 120 min after intraperitoneal injection of clozapine (5, 10, and 20 mg/kg), changes in ERK1/2, its upstream canonical kinases (Raf1 and mitogen-activated protein kinase kinase 1/2 [MEK1/2]), and its downstream molecule (p90 ribosomal S6 kinase [p90RSK]) were investigated in rat frontal cortex. At 15 min, p-Raf1, p-MEK1/2, p-ERK1/2, and p-p90RSK all increased dose-dependently. At 30 min, p-ERK1/2 and p-p90RSK showed no significant changes, while dose-dependent increases in p-Raf1 and p-MEK1/2 were found. At 60 and 120 min, although p-ERK1/2 and p-p90RSK decreased, increases in p-Raf1 and p-MEK1/2 were maintained. A clozapine-induced reduction in ERK1/2 phosphorylation was evident at both tyrosine and threonine residues, suggesting the involvement of dual specificity phosphatases (DUSPs; mitogen-activated protein kinase phosphatases [MKPs]). mRNA expression of seven Dusps that can dephosphorylate ERK1/2 were examined; Mkp-1 (Dusp1) mRNA increased following clozapine treatment. Moreover, MKP-1 protein and phosphatase activity increased, and binding of MKP-1 to ERK1/2 was also upregulated by clozapine administration., Conclusions: In rat frontal cortex, clozapine regulates ERK1/2 phosphorylation via MKP-1, which induces uncoupling between Raf1-MEK1/2 and ERK1/2-p90RSK activity. These findings suggest an important role of MKP-1 in the mechanism of action of clozapine.

Rationale: We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity., Method: Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed., Results: In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p < 0.05) and leptin (p < 0.05) levels, and elevation in cortisol (p < 0.05) and DHEA (p < 0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin., Conclusions: Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morbidity merits further large-scale, long-term investigation.

Objective: To compare matched paliperidone-ER- and olanzapine-treated schizophrenic patients on measures of glucose and lipid metabolism., Methods: Eighty hospitalized patients with schizophrenia (DSM-IV) were randomly assigned to treatment with paliperidone ER or olanzapine for a period of 12 weeks. At baseline and every 4 weeks, we assessed weight, subcutaneous fat, waist and hip circumferences, fasting glucose, insulin, glycohemoglobin A1, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and prolactin. We also assessed at every time point body mass index (BMI), homeostasis insulin resistance (HOMA-IR), and homeostasis β-cell function (HOMA-B)., Results: Thirty-three patients randomly assigned to paliperidone ER and 23 patients randomly assigned to olanzapine groups completed the entire 12-week treatment. Within-group analyses showed that fasting measures in both groups increased for weight, BMI, waist circumferences, hip circumference, subcutaneous fat, cholesterol, triglycerides, and prolactin. In contrast, fasting glucose, LDL, and HOMA-B increased during treatment only in the olanzapine group. We also detected significantly different serum prolactin levels at all time point between the paliperidone ER- and olanzapine-treated groups, as well as a statistical trend for HOMA-B to increase more in the olanzapine compared to paliperidone-ER group over the 12 weeks of the trial. We did not detect, however, differential drug effects over the 12 weeks of the trial on fasting measures of BMI, glucose, glycohemoglobin A1, insulin, HDL, LDL, cholesterol, triglyceride, or HOMA-IR., Conclusion: This study reinforces the necessity of regularly monitoring metabolic parameters in patients with schizophrenia taking atypical antipsychotics, including paliperidone ER.

Rationale: Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759-765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis., Objectives: This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis., Methods: We used ex vivo ¹³C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-¹³C]glucose and [1,2-¹³C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months., Results: Administration of haloperidol for 1 month produced no changes in ¹³C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased ¹³C labeling of glutamine by [1,2-¹³C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort., Conclusions: Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment.

Rational: A growing body of evidence illustrates that 5-HT3 receptor antagonist drugs may be of benefit in the treatment of negative symptoms in schizophrenia., Objective: The objective of this study was to assess the efficacy and tolerability of tropisetron add-on to risperidone on negative symptoms in patients with chronic stable schizophrenia., Methods: In a double-blind, placebo-controlled 8-week trial, 40 patients with chronic schizophrenia who were stabilized on risperidone were randomized into tropisetron or placebo add-on groups. Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) every 2 weeks. Furthermore, extrapyramidal and depressive symptoms as well as side effects were assessed. The primary outcome measure was the difference in change from baseline of negative subscale scores between the two groups at week 8., Results: Tropisetron resulted in greater improvement of the total PANSS scores [F(1.860,70.699) = 37.366, p < 0.001] as well as negative scores [F(2.439,92.675) = 16.623, p < 0.001] and general psychopathology [F(1.767,67.158) = 4.602, p = 0.017], but not positive subscale scores [F(1.348, 51.218) = 0.048, p = 0.893] compared to placebo. In a multiple regression analysis controlling for positive, extrapyramidal, and depressive symptoms, treatment group (standardized β = -0.640) significantly predicted changes in primary negative symptoms. The side effect profile did not differ significantly between the two groups., Conclusion: Tropisetron add-on to risperidone improves the primary negative symptoms of patients with chronic stable schizophrenia.

Rationale: A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced IKr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP)., Objectives: The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP., Method: We identify case reports using PubMed, Medline, EMBASE, and Cochrane., Results: Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, "elderly", 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n = 10), older age (n = 4), heart disease (n = 3), hypokalemia (n = 2), bradycardia (n = 1), liver disease (n = 1), QTc interval prolonging drugs other than risperidone (n = 8), and metabolic inhibitors (n = 2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP., Conclusion: Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.

Objective: This study aims to investigate the developmental effects of atypical antipsychotics on infants who were born to mothers taking an atypical antipsychotic throughout pregnancy., Method: The developmental progress of 76 infants who experienced fetal exposure to atypical antipsychotics was compared to that of 76 matched control infants who had no fetal exposure to any antipsychotics. Planned assessment included Apgar score, body weight, height, and the cognitive, language, motor, social-emotional, and adaptive behavior composite scores of the Bayley Scales of Infant and Toddler Development, third edition (BSID-III). Student's t test and Chi-square analysis were used as appropriate. Repeated measurements were evaluated by analysis of covariance., Results: At 2 months of age, the mean composite scores of cognitive, motor, social-emotional, and adaptive behavior of BSID-III were significantly lower in atypical antipsychotic-exposed infants than the controls. More atypical antipsychotic-exposed infants had delayed development in cognitive, motor, social-emotional, and adaptive behavior domains as defined by the composite score of <85 in these subscales of BSID-III. At 12 months of age, there were no significant differences between the two groups in all mean composite scores of BSID-III. More atypical antipsychotic-exposed infants had low birth weight than the controls (13.2 vs. 2.6 %, P = 0.031), although there were no significant difference in mean birth weight and height between the two groups., Conclusion: Fetal exposure to atypical antipsychotics may cause short-term delayed development in cognitive, motor, social-emotional, and adaptive behavior, but not in language, body weight, or height.

Rationale: Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia., Objective: This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model., Method: Forty-five male Lister hooded rats were housed in groups of 3-4 (n = 16) or singly (n = 29) for 4 weeks immediately after weaning on postnatal day (PND) 22-24. On PND 51, novel cage-induced locomotor activity (LMA) was assessed to subdivide rats into groups balanced for behavioural response. On PNDs 58, 59, 65 and 72, rats received either vehicle (1 ml/kg; i.p.) or risperidone (0.2 or 0.5 mg/kg; i.p.) 30 min prior to testing in LMA, novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle and conditioned emotional response (CER) learning paradigms, respectively., Results: Isolation rearing had no effect on PPI, but produced LMA hyperactivity and impaired NOD and CER compared to group-housed controls. Risperidone caused a dose-dependent reduction in LMA, irrespective of rearing condition, but selectively reversed the NOD deficit in isolation-reared rats. Risperidone did not reverse the isolation rearing-induced CER deficit., Conclusions: Similar to its clinical profile, risperidone only partially reverses the schizophrenic symptomology; since it reversed some, but not all, of the learning and memory deficits induced by post-weaning isolation, the isolation rearing model may be useful to predict antipsychotic activity of novel therapeutic agents.

Rationale: Numerous case reports have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia., Objectives: We reviewed reported cases which have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia and evaluated each regarding quality of the causal relationship., Methods: A systematic literature search was conducted on August 18, 2012, using the PubMed and the EMBASE. Twenty-two cases met the following inclusion criteria: (1) diagnosis of schizophrenia or schizoaffective disorder, (2) worsening of psychotic symptoms associated with aripiprazole, and (3) aripiprazole dose ≤ 30 mg/day. Information about the causal relationship between aripiprazole and increased psychotic symptoms was extracted. The quality of the causal relationship was evaluated according to the modified guidelines for evaluation of drug-associated events and classified as "questionable," "moderately suggestive," or "highly suggestive.", Results: Patients were chronic in at least 15 cases, and prior antipsychotic dose exceeded recommended guidelines in 19 cases. Psychotic symptoms worsened after simply adding aripiprazole to the current regimen in eight cases. Besides psychotic symptoms, increasing agitation (nine cases), aggression (11 cases), and/or activation (seven cases) were reported. Clinical resolution occurred after aripiprazole discontinuation in eight cases. Regarding causal relationship, 11 cases were classified as "highly suggestive," three as "moderately suggestive," and eight as "questionable"., Conclusions: Clinicians should be vigilant when adding aripiprazole to patients with chronic schizophrenia also receiving relatively high doses of other antipsychotics, and discontinuation of aripiprazole should be considered if psychotic symptoms and/or agitation/aggression/activation increase.

Rationale: Treatment studies for the management of pediatric bipolar disorder are limited., Objectives: This study evaluates the safety and efficacy of paliperidone monotherapy as an acute treatment of mania and related symptoms in youth with bipolar spectrum disorders., Methods: An 8-week, prospective, open-label paliperidone monotherapy trial to assess effectiveness and tolerability in treating pediatric bipolar spectrum and related disorders (depression, psychosis, attention-deficit/hyperactivity disorder [ADHD]). Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impression scale (CGI), Children's Depression Rating Scale-Revised (CDRS-R), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis., Results: Fifteen youth with bipolar spectrum disorders (YMRS at entry: 32.8 ± 6.1) were enrolled in the study and 11 (73 %) completed the 8-week trial. The total daily dose of paliperidone at study endpoint was 3 mg in 12 subjects and 6 mg in three subjects. Treatment with paliperidone was associated with statistically significant levels of improvement in mean YMRS scores (-18.7 ± 13.9, p < 0.001) at endpoint. Paliperidone treatment also resulted in significant improvement in the severity of ADHD and psychotic symptoms. Although treatment with paliperidone was generally well tolerated and was not associated with clinically significant change in cardiovascular or metabolic parameters, increases in body weight (4.1 ± 5.5 lb) were substantial., Conclusions: Open-label paliperidone treatment appears to be beneficial in the treatment of bipolar spectrum disorders and associated conditions in youth. Future placebo-controlled studies are warranted to confirm these findings.

Rationale: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia., Objectives: Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations., Results: LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used., Conclusions: Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent.

Rationale: Combination treatment with reboxetine, a selective norepinephrine reuptake inhibitor, and betahistine, a histamine H1 receptor agonist/H3 antagonist, was developed to produce complementary action in CNS pathways regulating appetite and body weight. In the present placebo-controlled study, we evaluated whether a reboxetine-betahistine combination attenuates olanzapine-induced weight gain in schizophrenia patients., Method: Forty-three inpatients with DSM-IV schizophrenic disorder participated in a randomized double-blind study. Reboxetine (4 mg/day) with betahistine (48 mg/day) (N = 29) or placebo (N = 14) was co-administered with olanzapine (10 mg/day) for 6 weeks. Mental status was assessed at baseline and endpoint with relevant rating scales. Intention-to-treat method was used for statistical analysis., Results: Seven patients in the study group and four in the placebo group discontinued the trial. At the end of the trial, patients in the olanzapine/reboxetine + betahistine group gained significantly less weight than those in the olanzapine/placebo group [2.02 ± 2.37 and 4.77 ± 3.16 kg, respectively; t = 2. 89, degrees of freedom (df) = 41, p = 0.006]. The weight-attenuating effect of this combination was twofold larger than the weight-attenuating effect previously demonstrated with reboxetine alone. Significantly fewer patients in the study group than in the comparison group increased their initial weight by >7 %, the cutoff for clinically significant weight gain [3/29 (10.3 %) and 6/14 (42.9 %), respectively; χ (2) = 6.03, df = 1, p = 0.014]. The reboxetine-betahistine combination was safe and well tolerated., Conclusions: Reboxetine-betahistine combination produces a clinically meaningful attenuation of olanzapine-induced weight gain. These results justify direct comparison between the reboxetine-betahistine combination and reboxetine alone.

Rationale: Obsessive-compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD., Objectives: In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior., Methods: The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated., Results: Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble-burying behavior in ddY mice. The selective GABA(A) receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA(B) receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA(A) receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg)., Conclusions: These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA(A) receptor-dependent mechanism.