Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment.

BACKGROUND: Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. METHODS: We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain). RESULTS: Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. CONCLUSIONS: Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.

Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making.

BACKGROUND: It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown. METHODS: Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol. RESULTS: Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making. CONCLUSIONS: Our data suggest that intra-AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats' preference for the response option known to be associated with higher risk-related costs.

Cognitive performance during the first year of treatment in first-episode schizophrenia: a case-control study.

BACKGROUND: Several questions remain unanswered regarding the magnitude and time course of cognitive improvement in response to antipsychotic treatment. The purpose of this study was to assess changes in cognitive performance in antipsychotic-naive or minimally medicated patients with first-episode schizophrenia during the first 12 months of treatment, in a case-control design. Patients were treated with flupenthixol decanoate depot injection, according to a standard algorithm. The primary outcome measure was change in MATRICS Cognitive Consensus Battery (MCCB) composite score over 12 months. METHOD: The sample comprised 92 patients and 100 healthy controls matched for age, sex, ethnicity and educational status. Cognitive function was assessed by means of the MCCB. RESULTS: A mixed-effects model identified a significant group × time effect (p ≤ 0.0001) for the MCCB composite score, with patients showing a greater degree of change than the controls. For the other MCCB domains there were significant group × time effects at adjusted significance level for attention and vigilance (p ≤ 0.0001), visual learning (p ≤ 0.0001), verbal learning (p = 0.005) and working memory (p ≤ 0.0001), but not for reasoning and problem solving (p = 0.04), speed of processing (p = 0.03) and social cognition (p = 0.06). There were moderate correlations between change in MCCB composite score and change in symptomatology as assessed by Positive and Negative Syndrome Scale factor analysis-derived domains. CONCLUSIONS: Substantial improvements in cognitive function were observed over and above a practice effect, and were significantly correlated with improvements in psychopathology and functionality.

Modelling individual differences in the form of Pavlovian conditioned approach responses: a dual learning systems approach with factored representations.

Reinforcement Learning has greatly influenced models of conditioning, providing powerful explanations of acquired behaviour and underlying physiological observations. However, in recent autoshaping experiments in rats, variation in the form of Pavlovian conditioned responses (CRs) and associated dopamine activity, have questioned the classical hypothesis that phasic dopamine activity corresponds to a reward prediction error-like signal arising from a classical Model-Free system, necessary for Pavlovian conditioning. Over the course of Pavlovian conditioning using food as the unconditioned stimulus (US), some rats (sign-trackers) come to approach and engage the conditioned stimulus (CS) itself - a lever - more and more avidly, whereas other rats (goal-trackers) learn to approach the location of food delivery upon CS presentation. Importantly, although both sign-trackers and goal-trackers learn the CS-US association equally well, only in sign-trackers does phasic dopamine activity show classical reward prediction error-like bursts. Furthermore, neither the acquisition nor the expression of a goal-tracking CR is dopamine-dependent. Here we present a computational model that can account for such individual variations. We show that a combination of a Model-Based system and a revised Model-Free system can account for the development of distinct CRs in rats. Moreover, we show that revising a classical Model-Free system to individually process stimuli by using factored representations can explain why classical dopaminergic patterns may be observed for some rats and not for others depending on the CR they develop. In addition, the model can account for other behavioural and pharmacological results obtained using the same, or similar, autoshaping procedures. Finally, the model makes it possible to draw a set of experimental predictions that may be verified in a modified experimental protocol. We suggest that further investigation of factored representations in computational neuroscience studies may be useful.

Sertraline plus deanxit to treat patients with depression and anxiety in chronic somatic diseases: a randomized controlled trial.

BACKGROUND: Patients in chronic somatic diseases are often accompanied with depression and anxiety, remission of which may be observed in the third or fourth week after applying common antidepressant medications. We investigate the efficacy and safety of sertraline plus deanxit on patients with depression and anxiety in chronic somatic diseases. METHODS: 75 Patients who met the criteria were randomly assigned to deanxit group or placebo group: sertraline (75 mg/day) plus deanxit (one piece/day) (N = 38), or sertraline (75 mg/day) plus placebo (one piece/day) (N = 37) for 2 weeks, both groups received sertraline (75 mg/day) in the following 2 weeks. Changes from baseline to day 4, day 8, day 15, and day 29 in Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) total scores were the efficacy measures. Adverse events were monitored and registered systematically during the trial. RESULTS: Response rates for HAM-D scores in deanxit group and placebo group were significantly different on day 8(55.26% ± 2.56% VS 24.32% ± 2.19%, p = 0.006) and day 15(78.95% ± 3.89% VS 40.54% ± 4.18%, p = 0.001), while no statistical differences were observed on day 4 and day 29. Respectively, response rates for HAM-A scores on day 4 (34.21% ± 2.21% VS 8.11% ± 1.37%, p = 0.006), day 8 (57.89% ± 3.56% VS 18.92% ± 2.68%, p = 0.001) and day 15 (78.95% ± 4.37% VS 43.24% ± 4.68%, p = 0.002), favoring the deanxit group. However, HAM-A scores were not remarkably different at the end point. The overall safety profile of both groups was favorable with no distinct differences. CONCLUSIONS: The efficacy was exhibited in the deanxit group, with evidence for similar safety. The rapid onset of sertraline plus short-term deanxit indicated that it might be an inspiring strategy to manage depression and anxiety within the first two weeks in chronic somatic diseases.

Pathological gambling induced by dopamine antagonists: a case report.

Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.

Efficacy and safety of esomeprazole with flupentixol/melitracen in treating gastroesophageal reflux disease patients with emotional disorders.

BACKGROUND AND AIM: This study was designed to demonstrate the safety and efficacy of esomeprazole combined with flupentixol/melitracen for the treatment of gastroesophageal reflux disease (GERD) patients with emotional disorders. METHODS Two hundred eighty-nine GERD patients with emotional disorders were divided randomly into two groups: group 1 received esomeprazole only (monotherapy) and group 2 received esomeprazole and flupentixol/melitracen (combination therapy). The patients' GERD questionnaire (GerdQ) and hospital anxiety and depression (HAD) scores were obtained before and after treatment. Changes in the scores, rates of symptom remission, and adverse effects were compared between the two groups. RESULTS: After 2 weeks of treatment, the average decrease in GerdQ score in the combination group (4.04 ± 2.34) was significantly greater than that in the monotherapy group (3.34 ± 2.74; P < 0.05). Significant differences between the two groups were also found for changes in HAD anxiety scores (5.45 ± 2.41 vs 3.34 ± 2.43, P < 0.05), depression scores (5.47 ± 2.47 vs 3.00 ± 3.28, P < 0.05), and anxiety-depression scores (5.20 ± 2.71 vs 3.60 ± 2.56, P < 0.05). The remission of symptoms (eructation, abdominal pain, anorexia, and other accompanying symptoms) in the combination group was significantly better than that in the monotherapy group, and no significant difference in the incidence of adverse events was observed between the two groups. CONCLUSIONS: The combination therapy has better efficacy than the monotherapy in improving the symptoms of gastroesophageal reflux in patients with emotional disorders. In addition, this combination treatment is safe, with a low incidence of adverse events.

Flupenthixol decanoate (depot) for schizophrenia or other similar psychotic disorders.

BACKGROUND: Long-acting depot injections of drugs such as flupenthixol decanoate are extensively used as a means of long-term maintenance treatment for schizophrenia. OBJECTIVES: To evaluate the effects of flupenthixol decanoate in comparison with placebo, oral antipsychotics and other depot neuroleptic preparations for people with schizophrenia and other severe mental illnesses, in terms of clinical, social and economic outcomes. SEARCH METHODS: We identified relevant trials by searching the Cochrane Schizophrenia Group Trials Register in March 2009 and then for this update version, a search was run in April 2013. The register is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA: All randomised controlled trials that focused on people with schizophrenia or other similar psychotic disorders where flupenthixol decanoate had been compared with placebo or other antipsychotic drugs were included. All clinically relevant outcomes were sought. DATA COLLECTION AND ANALYSIS: Review authors independently selected studies, assessed trial quality and extracted data. For dichotomous data we estimated risk ratios (RR) with 95% confidence intervals (CI) using a fixed-effect model. Analysis was by intention-to-treat. We summated normal continuous data using mean difference (MD), and 95% CIs using a fixed-effect model. We presented scale data only for those tools that had attained prespecified levels of quality. Using Grading of Recommendations Assessment, Development and Evaluation (GRADE) we created 'Summary of findings tables and assessed risk of bias for included studies. MAIN RESULTS: The review currently includes 15 randomised controlled trials with 626 participants. No trials compared flupenthixol decanoate with placebo.One small study compared flupenthixol decanoate with an oral antipsychotic (penfluridol). Only two outcomes were reported with this single study, and it demonstrated no clear differences between the two preparations as regards leaving the study early (n = 60, 1 RCT, RR 3.00, CI 0.33 to 27.23,very low quality evidence) and requiring anticholinergic medication (1 RCT, n = 60, RR 1.19, CI 0.77 to 1.83, very low quality evidence).Ten studies in total compared flupenthixol decanoate with other depot preparations, though not all studies reported on all outcomes of interest. There were no significant differences between depots for outcomes such as relapse at medium term (n = 221, 5 RCTs, RR 1.30, CI 0.87 to 1.93, low quality evidence), and no clinical improvement at short term (n = 36, 1 RCT, RR 0.67, CI 0.36 to 1.23, low quality evidence). There was no difference in numbers of participants leaving the study early at short/medium term (n = 161, 4 RCTs, RR 1.23, CI 0.76 to 1.99, low quality evidence) nor with numbers of people requiring anticholinergic medication at short/medium term (n = 102, 3 RCTs, RR 1.38, CI 0.75 to 2.25, low quality evidence).Three studies in total compared high doses (100 to 200 mg) of flupenthixol decanoate with the standard doses (˜40mg) per injection. Two trials found relapse at medium term (n = 18, 1 RCT, RR 1.00, CI 0.27 to 3.69, low quality evidence) to be similar between the groups. However people receiving a high dose had slightly more favourable medium term mental state results on the Brief Psychiatric Rating Scale (BPRS) (n = 18, 1 RCT, MD -10.44, CI -18.70 to -2.18, low quality evidence). There was also no significant difference in the use of anticholinergic medications to deal with side effects at short term (2 RCTs n = 47, RR 1.12, CI 0.83 to 1.52 very low quality evidence). One trial comparing a very low dose of flupenthixol decanoate (˜6 mg) with a low dose (˜9 mg) per injection reported no difference in relapse rates (n = 59, 1 RCT, RR 0.34, CI 0.10 to 1.15, low quality evidence). AUTHORS' CONCLUSIONS: In the current state of evidence, there is nothing to choose between flupenthixol decanoate and other depot antipsychotics. From the data reported in clinical trials, it would be understandable to offer standard dose rather than the high dose depot flupenthixol as there is no difference in relapse. However, data reported are of low or very low quality and this review highlights the need for large, well-designed and reported randomised clinical trials to address the effects of flupenthixol decanoate.

Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride.

The objective of the present study was to develop fast dissolving oral film of the antipsychotic drug, flupentixol dihydrochloride, to enhance its bioavailability, optimize its therapeutic effect when used to treat depression with anxiety, and increase the convenience and compliance by the mentally ill, developmentally disable, elderly, and pediatric patients. Six formulae were prepared with different concentrations of water-soluble polymers vis. hydroxypropyl methylcellulose (HPMC E5) and carboxymethyl cellulose (CMC) by solvent casting technique. The prepared films were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern, and drug content. Physical compatibility between the drug and excipients was guaranteed in the selected formulation (2% HPMC) by means of differential scanning calorimetry analysis and Fourier-transform infrared spectroscopy. This formulation revealed high stability after testing according to the International Conference on Harmonisation guidelines. In vivo studies based on single phase parallel design were carried out for the optimized formulation in healthy human volunteers. The concentration of flupentixol dihydrochloride in plasma samples was analyzed by a developed validated LC-MS/MS assay method and the pharmacokinetic parameters of the established formulation were compared with the commercially available oral tablets. Faster rate of absorption of flupentixol could be obtained from the oral film formulation and the relative bioavailability was found to be 151.06% compared to the marketed product.

Effectiveness and Safety of Flupentixol and Melitracen Tablets for the Treatment of Patients with Persistent Idiopathic Facial Pain: A Retrospective Observational Study.

BACKGROUND: Flupentixol and melitracen are being investigated for their potential effectiveness in managing persistent idiopathic facial pain (PIFP), based on their mechanisms of action as dopamine receptor antagonists and noradrenaline/serotonin reuptake inhibitors, respectively. The efficacy and safety of flupentixol and melitracen (FM) tablets in treating PIFP were retrospectively analyzed at our hospital. OBJECTIVES: The aim of this study is to determine the effectiveness and safety of FM tablets in treating PIFP. STUDY DESIGN: Retrospective unicentric cohort design. SETTING: An academic university hospital. METHODS: A retrospective analysis was conducted on a cohort comprising 128 patients with a definite diagnoses of PIFP who were treated with FM tablets (flupentixol 0.5 mg and melitracen 10 mg tablet, >= 4 tablets/d) from January 2022 through May 2023 at an academic university hospital. Baseline conditions were statistically described, and Numeric Rating Scale (NRS-11) scores of pain levels before and during treatment were collected. Pain relief rates were calculated. Differences in baseline characteristics between responsive and unresponsive patients were evaluated using statistical tests. Additionally, the side effects experienced during treatment were summarized. RESULTS: Among the included 128 patients, 105 (82.0%) patients achieved pain relief (pain NRS-11 score reduction rate >= 50%). The median treatment onset time was 3 (1-7) days. NRS-11 scores of responsive patients at week 2, week 4, week 8, and week 12 were significantly lower than the baseline NRS-11 scores (P < 0.001), regardless of their Hamilton Depression Rating Scale score. Pain duration was the only factor that related to responsiveness (Wilcoxon rank sum test, P < 0.001; logistic regression, P = 0.001). No serious side effects that could affect patients' lives were observed during the first week of treatments. LIMITATIONS: Due to its retrospective nature, this study is limited by its lack of a randomized control. The lack of data on nonresponders who did not achieve significant pain relief hinders assessing overall change and the placebo effects'. Patients previously treated with antidepressants were excluded, making it hard to determine if FM tablets were a better treatment for PIFP. Additionally, the small sample size in a single center may be influenced by chance variation in pain relief. CONCLUSIONS: FM tablets showed its potential in the management of PIFP with considerable efficacy and safety. Early administration of FM tablets after a PIFP diagnosis may result in a high possibility of pain relief.

Evidence of significant synergism between antibiotics and the antipsychotic, antimicrobial drug flupenthixol.

Previously, the antipsychotic, non-antibiotic compound flupenthixol dihydrochloride (Fp) was shown to exhibit distinct in vitro antibacterial activity against Gram-positive and Gram-negative bacteria and to significantly protect Swiss albino mice challenged with a known mouse virulent salmonella. The present study was designed to ascertain whether this drug could efficiently augment the action of an antibiotic or a non-antibiotic when tested in combination. A total of 12 bacterial strains belonging to various genera were selected for this study and were sensitive to the antibiotics penicillin (Pc), ampicillin, chloramphenicol, tetracycline, streptomycin, gentamicin, erythromycin, ciprofloxacin, and to the non-antibiotics methdilazine, triflupromazine, promethazine, and Fp. Pronounced and statistically significant synergism (p < 0.01) was observed when Fp was combined with Pc following the disc diffusion assay system. With the help of the checkerboard method, the fractional inhibitory concentration (FIC) index of this pair was found to be 0.375, confirming synergism. This pair of Fp+ Pc was then subjected to in vivo experiments in mice challenged with Salmonella enterica serovar Typhimurium NCTC 74. Statistical analysis of the mouse protection test suggested that this combination was highly synergistic (p < 0.001, Chi-squared analysis). Fp also revealed augmentation of its antimicrobial property when combined with streptomycin, gentamicin, ciprofloxacin, and the non-antibiotic methdilazine. The results of this study may provide alternatives for the therapy of problematic infections such as those associated with Salmonella spp.

Maintenance Treatment With Long-Acting Injectable Antipsychotics for People With Nonaffective Psychoses: A Network Meta-Analysis.

OBJECTIVE: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. METHODS: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RESULTS: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). CONCLUSIONS: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

Effects of disconnection of amygdala dopamine and nucleus accumbens N-methyl-d-aspartate receptors on ethanol-seeking behavior in mice.

There is a strong interest in harnessing the genetic manipulations that are possible in mice to investigate the functional neural mechanisms modulating the associative processes that control drug-seeking behavior. However, it is unknown whether intracranial techniques, such as the disconnection procedure commonly used in rats to examine serial connectivity between implicated areas, can be successfully applied to mice. We have previously demonstrated that the expression of ethanol-seeking behavior in mice is dependent upon amygdala (Amy) dopamine and nucleus accumbens (Acb) N-methyl-d-aspartate (NMDA) receptor activation (Gremel & Cunningham, 2009). Here, we used a neuropharmacological disconnection procedure to investigate whether dopamine activation of the Amy directly leading to increases in Acb glutamate release and binding of NMDA receptors modulates the expression of ethanol-seeking behavior. Immediately before testing the expression of an ethanol-induced conditioned place preference, mice were given an Amy infusion of flupenthixol and either an ipsilateral or contralateral Acb infusion of AP-5. Although both ipsilateral and contralateral manipulations reduced the expression of ethanol conditioned place preference, in a separate experiment we demonstrated that a unilateral Acb infusion of AP-5, but not Amy flupenthixol, is sufficient to disrupt preference. The finding of a significant blockade by unilateral AP-5 into the Acb precludes any conclusions about a unique role for the Amy/Acb neuroanatomical connection in this model of ethanol-seeking behavior. Further, the current results suggest potential limitations in transferring techniques from rats to mice in order to study serial interactions between neural areas underlying motivated behaviors. Nevertheless, these findings provide evidence showing that Acb NMDA receptors play an important role in the expression of ethanol-conditioned behavior.

Large nest building and high marble-burying: Two compulsive-like phenotypes expressed by deer mice (Peromyscus maniculatus bairdii) and their unique response to serotoninergic and dopamine modulating intervention.

This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders.

Long-term treatment with flupentixol results of a post-marketing surveillance study.

Schizophrenia is one of the most expensive illnesses. Antipsychotics are an essential component of the acute and preventative treatment of this illness, and long-term treatment is necessary to decrease the risk of psychotic relapse. The efficacy and tolerability of flupentixol was evaluated in a post-marketing surveillance study (PMS) in schizophrenic patients receiving long-term treatment in routine clinical practice. Psychiatrists in office practice treated patients for approximately 10 weeks, with a subsequent follow-up period of up to 18 months. We here report on the follow-up period in 128 patients. The benefit for schizophrenic patients increased with the treatment duration of flupentixol as documented by the Clinical Global Impression (CGI). Subjective quality of life improved during the first study period, and this remained stable in the follow-up period. No increase in body weight was observed during the study. The relapse rate was much lower than in other studies. Anticholinergic medication was necessary for 22.7% of the patients at any time. More than 70% of the psychiatrists involved evaluated the treatment as very good or good. The results of this study suggest that flupentixol is a potent and safe antipsychotic for the long-term treatment of schizophrenia in routine clinical practice.

Estimating the optimal dose of flupentixol decanoate in the maintenance treatment of schizophrenia-a systematic review of the literature.

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.

Bioequivalence Study Of A Fixed-Dose Combination Tablet Containing Melitracen 10 mg And Flupentixol 0.5 mg In Healthy Chinese Volunteers Under Fasted And Fed Conditions.

PURPOSE: A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation. METHODS: The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs). RESULTS: The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0-t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.

Dopaminergic modulation of reproductive behavior and activity in male zebra finches.

We previously demonstrated that hormone treatments which stimulate female-directed singing increased levels and turnover of dopamine (DA) in brain areas controlling the motor patterning of song. To help determine how DA affects singing, we quantified the effects of treating adult male finches with the D1/D2 receptor antagonist cis-flupenthixol. Adult males were given subcutaneous silastic implants of androgen, in case drug treatment interfered with androgen secretion. One week later, they were tested with females. Males were divided into three groups matched for levels of courtship singing. Males were then subcutaneously implanted with osmotic minipumps containing either saline, a low, or a high dose of cis-flupenthixol. Each male was tested with a different female 5 and 10 days after implantation to determine how this D1/D2 receptor antagonist affected behavior. Both drug doses affected female-directed singing 5 days after initiation of treatment. High-dose males sang to females significantly less often than males in the other two groups. Low-dose males showed fewer high-intensity courtship displays in which males dance towards females as they sing. These effects on courtship singing were not seen at day 10, though other behavioral effects were seen at this time. Male beak wipes, rocks, following females and female withdrawals from males were also affected by drug treatment. General activity in the home cage was decreased by day 11. These data demonstrate that singing and several other female-directed behaviors are sensitive to perturbations in DA receptor function.

Medial prefrontal cortex infusion of alpha-flupenthixol attenuates systemic d-amphetamine-induced disruption of conditional discrimination performance in rats.

RATIONALE: It has been argued that tasks that necessitate the use of context in the service of goal-directed behaviour are disrupted in both schizophrenic patients and in animal analogues by dopamine (DA) manipulation with the prefrontal cortex being implicated. OBJECTIVES: To determine the effects on conditional discrimination performance of direct infusion of the DA D(1)/D(2) receptor antagonist alpha-flupenthixol into the medial prefrontal cortex (mPFC) and of its reversal potential on d-amphetamine-induced task disruption. MATERIALS AND METHODS: Conditional discrimination performance in which rats learn to respond on an appropriate lever, conditional upon specific auditory stimuli, was acquired and later tested under the above drug treatment protocol in extinction. RESULTS: Conditional discrimination performance was unaffected by bilateral intra-mPFC alpha-flupenthixol at doses of 12, 24 or 36 microg/microl. A dose of D-amphetamine (1.5 mg/kg) shown previously to disrupt conditional discrimination performance was attenuated by direct PFC infusion of alpha-flupenthixol at doses of 24 and 36 but not 12 microg/microl per site. CONCLUSIONS: These results show that conditional discrimination performance is at least in part mediated by prefrontal DA as local PFC DA antagonism attenuates task performance disruption by the indirect DA agonist d-amphetamine further implicating the role of dysfunctional forebrain DA in cognitive deficits evident in schizophrenia.