Extrapyramidal side effects in first-episode schizophrenia treated with flupenthixol decanoate.

BACKGROUND: Concern for the development of extrapyramidal side effects (EPSEs) represents a barrier to the routine use of long-acting injectable (LAI) antipsychotic medication in patients with first-episode schizophrenia (FES). Flupenthixol decanoate is a first-generation antipsychotic, which is readily available in the public healthcare system in South Africa. AIM: The aim of this study was to describe the nature, occurrence and severity of EPSEs and their impact on patients with FES over 12 months of treatment with flupenthixol decanoate (fluanxol depot). SETTING: The study was based in Cape Town, South Africa, and patients with FES were recruited from inpatient services at Stikland and Tygerberg Hospitals and surrounding psychiatric clinics. This was a sub-study of a larger study, which examined several outcomes in patients with FES treated with the lowest effective dose of flupenthixol decanoate. METHODS: The Extrapyramidal Symptom Rating Scale (ESRS) was used to assess both subjective experience and objective measures of EPSEs in a cohort of patients with FES (N = 130). The relationship between demographic and clinical risk factors for individual subsets of EPSEs was also determined. RESULTS: In the context of an overall good 12-month tolerability, EPSEs peaked at month 3. Patients with akathisia were more likely to have greater symptoms of depression, and Parkinsonism was predicted by higher Positive and Negative Syndrome Scale scores (independent of medication dosage). Black and white patients showed higher total ESRS and higher subjective ESRS scores, compared with patients of mixed ancestry, and white patients scored higher on Parkinsonism ratings. CONCLUSION: Flupenthixol decanoate is well tolerated in patients with FES. Certain clinical features of schizophrenia may be related to EPSEs. Ethnicity is a socio-cultural construct, and hence the differential risk of EPSEs should be interpreted according to ethnicity. Variations in the environment, diet, substance use and genetics may all affect the pharmacokinetics and pharmacodynamics of psychotropic drugs and warrant further investigation.

Factors associated with dropout at 2 years post-initiation of treatment in the first episode of schizophrenia.

BACKGROUND: Prevention of new episodes during the first 2 years after a first episode of schizophrenia (FES) may delay treatment refractoriness and brain morphological changes over time. However, adherence to treatment is characteristically poor in these patients. AIM: The aim of this study was to examine clinical and sociodemographic factors associated with patient dropout in patients with FES. SETTING: This study was set at inpatient and outpatient services at a psychiatric hospital in the Western Cape, between 2007 and 2011. METHODS: Data were collected as part of a prospective longitudinal study, which followed up patients with FES treated with flupenthixol decanoate. We examined the relationship between treatment adherence and sociodemographic and clinical factors at baseline and at 24 months. Unadjusted and adjusted logistic regression models were used to determine adherence variables. RESULTS: A total of 62% of patients completed the 24 months of treatment. Participants with FES and a substance use disorder (dual diagnosis) were at greater risk of dropout (p = 0.01). On univariate analysis, dual diagnosis participants who dropped out were older (p = 0.04) had completed more years of schooling (p = 0.001), older age of onset (p = 0.02) and higher baseline positive symptoms (p = 0.05). On regression analysis, non-completer substance users achieved a higher level of education (odds ratio [OR]: 3.87, confidence interval [CI]: 1.34-11.11, p = 0.01). CONCLUSION: Substance use disorder was associated with non-adherence to follow up in a cohort of FES patients treated with flupenthixol decanoate. Interventions that take into account age, education and baseline positive symptoms may afford the opportunity to influence adherence and patient outcome.

[Analysis of the flupenthixol distribution in the internal organs of laboratory animals for the diagnosis of acute poisoning]. / Analiz raspredeleniya flupentiksola vo vnutrennikh organakh laboratornykh zhivotnykh dlya diagnostiki ostrykh otravlenii.

Flupentixol has been used for a long time in Russia in psychiatric practice; however, there are cases of its overdose and poisoning with it. In the literature, there are no systematic studies to identify flupenthixol in the diagnosis of acute poisoning. OBJECTIVE: The purpose of the work is to analyze the distribution of flupenthixol in the internal organs of laboratory animals in acute poisoning. The studies were carried out on Wistar rats of both sexes. Sample preparation and isolation of flupenthixol from model samples and internal organs of laboratory animals was carried out according to proposed methods. To detect flupenthixol in extracts the TLC was used. HPLC and liquid mass spectrometry were used for confirmatory analysis and quantitative determination of flupenthixol in the extracts. Amethod was developed for the detection of flupenthixol in extracts from the internal organs of laboratory animals using the TLC method. HPLC/MS/MS was used as a confirmatory method for detecting flupenthixol in extracts from internal organs of laboratory animals. In all mass spectra of extracts from internal organs, a pronounced molecular ion of flupenthixol was present. In the mass spectrum of kidney extraction at 30 minutes a molecular ion of the metabolite (m/z 629.13), corresponding to flupentixolglucuronide was detected. After acute poisoning of laboratory animals, the flupenthixol was found in the maximum amount in the liver, spleen and brain, in smaller amounts in the stomach, intestines with contents and kidneys.

[A preliminary study of resting-state fMRI in patients with diarrhea-type irritable bowel syndrome after pinaverium bromide combined treatment with flupentixol-melitracen].

Objective: To observe the difference of brain activity in patients with diarrhea-type irritable bowel syndrome (IBS-D) treated with pinaverium bromide (PB) combined with flupentixol-melitracen (FM), and to explore the mechanism of efficacy of combined with anxiolytic/antidepressant drugs in IBS-D patients at the central level, using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-eight patients with IBS-D, including 28 males, 20 females, mean age 22-48 (33±7) years, were selected from the Affiliated Hospital of Hangzhou Normal University from October 2015 to October 2018.All patients with IBS-D underwent rs-fMRI scans before and after receiving either PB (basic treatment group, n=16), PB combined with FM (combination therapy group, n=16), or no medication (no treatment group, n=16). Rs-fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared using One-way ANOVA analysis and post analysis.Partial correlation and mediation analyses were performed on ReHo values and the improvement of symptoms scores (gastrointestinal symptom rating scale(GSRS) and hospital anxiety/depression scale (HAD)) in the two medicated groups. Results: No significant differences in ReHo values were observed among the three groups before treatment. Compared with patients on no-medication, patients receiving either PB or PB-FM showed decreased ReHo in the striatum, insular lobe, medial prefrontal cortex (MPFC) and subcallosal gyrus, and increased ReHo in the occipital cortex. In particular, the combined treatment group showed more extensive decreased ReHo in the left thalamus and left temporal pole, and increased in the left precuneus. Compared with the basic treatment group, the combined treatment group showed decreased ReHo in the right putamen, right insula, right MPFC and subcallosal gyrus, and increased ReHo in the left precuneus. In addition, the combined treatment group demonstrated a positive correlation between ReHo values in the left thalamus and the improvement of HAD score (r=0.653, P=0.011) , and a negative correlation between ReHo values in left precuneus and the improvement of GSRS and HAD score (r=-0.771, P=0.001; r=-0.716, P=0.004). ReHo values in the left precuneus were observed to mediate between gastrointestinal symptoms and anxiety-depressive symptoms in the combined treatment group. Conclusions: The efficacy of PB combined with FM is superior to PB alone in the treatment of IBS. In addition to more extensive changes in pain-related brain areas, IBS-D patients treated with anxiolytic/antidepressant also show changes in default network and brain areas related to emotional regulation, and are associated with improvement in gastrointestinal symptoms, anxiety and depression.

Indole and indoxyl sulfate, gut bacteria metabolites of tryptophan, change arterial blood pressure via peripheral and central mechanisms in rats.

Arterial blood pressure (BP) is regulated by a complex network of peripheral and central (brain) mechanisms. Research suggests that gut bacteria-derived compounds may affect the circulatory system. We evaluated hemodynamic effects of indole, a gut bacteria-derived product of tryptophan, and indoxyl sulfate (indoxyl), a liver metabolite of indole. BP and heart rate (HR) were recorded in anesthetized, male, Wistar rats at baseline and after the administration of either a vehicle, indole, or indoxyl into the femoral vein (IV) or into the lateral ventricle of the brain (ICV). Besides, we evaluated the effect of pretreatment with flupentixol, a non-selective D1, D2, α1 and 5 HT2A receptor blocker; pizotifen, a non-selective 5-HT1, 5-HT2A and 5HT2C receptor blocker; and ondansetron, a 5-HT3 blocker, on hemodynamic responses to indole and indoxyl. Vehicle infused IV and ICV did not affect hemodynamics. Indole administered IV produced a dose-dependent increase in BP but not HR. In contrast, the ICV infusion of indole produced a decrease in BP and HR. Indoxyl infused IV produced an increase in BP and HR, whereas indoxyl infused ICV did not affect BP and HR. The hemodynamic effects of indole and indoxyl were inhibited by pretreatment with ondansetron and pizotifen but not flupentixol. In conclusion, indole and indoxyl sulfate affect arterial blood pressure via peripheral and central mechanisms dependent on serotonin signalling. We propose that indole and indoxyl sulfate may be mediators in the interaction between gut bacteria and the circulatory system.

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.

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.

Administration of neuropeptide Y into the rat nucleus accumbens shell, but not core, attenuates the motivational impairment from systemic dopamine receptor antagonism by α-flupenthixol.

Previous research has demonstrated that dopamine and Neuropeptide Y (NPY) promote motivated behavior, and there is evidence to suggest that they interact within neural circuitry involved in motivation. NPY and dopamine both modulate appetitive motivation towards food through direct actions in the nucleus accumbens (NAc), although how they interact in this region to promote motivation is presently unclear. In this study, we sought to further elucidate the relationship between NAc NPY and dopamine and their effects on motivated behavior. Specifically, we examined whether NAc injections of NPY might reverse behavioral deficits caused by reduced dopamine signaling due to systemic dopamine receptor antagonism. Appetitive motivation was measured using a progressive ratio-2 paradigm. Male Sprague Dawley rats were treated with systemic injections of the dopamine antagonist, α-flupenthixol or a saline vehicle. Two hours following injections, they were administered infusions of NPY (at 0, 156, or 235 pmol) into either the NAc shell (n = 12) or the NAc core (n = 10) and were placed in operant chambers. In both groups, α-flupenthixol impaired performance on the PR-2 task. NPY receptor stimulation of the NAc shell significantly increased both breakpoint and active lever presses during the PR-2 task, and dose-dependently increased responding following systemic dopamine receptor blockade. NPY did not affect appetitive motivation when injected into the NAc core. These data demonstrate that NPY in the NAc shell can improve motivational impairments that result from dopamine antagonism, and that these effects are site specific. These results also suggest that upregulation of NPY in neurodegenerative diseases may possibly buffer early motivational deficits caused by dopamine depletion in Parkinson's and Huntington's disease patients, both of which show increased NPY expression after disease onset.

Preadolescent dopamine receptor antagonism increases postadolescent reward-related operant behaviors that may depend on dopamine receptor hypersensitivity.

The dopaminergic system has a long history of being associated with reward-related activities but the developmental consequences of blocking dopamine receptor function on reward-based associative learning has been less studied. To this end, male, Long Evans rats were systemically (i.p.) treated with the dopamine receptor (DAr) antagonist, flupenthixol (0.25 mg/kg), or saline, from postnatal day (P)18 - 24 (preadolescence) then trained on an operant conditioning task from P41 - P45 (postadolescent) without drug treatment. The preadolescent flupenthixol group showed elevated active lever responses and locomotor activity during the drug-free test. Another group of rats was given flupenthixol prior to each acquisition session from P41 - 45 which significantly suppressed both active lever presses and locomotor activity. Separate groups of rats were treated with flupenthixol or saline from P18 - 24 then treated with apomorphine or saline on P41 followed by assessment of c-Fos labeling in the nucleus accumbens. Early flupenthixol treatment was associated with more apomorphine-induced c-Fos labeling in the nucleus accumbens shell than the early saline-apomorphine group, indicating a sensitized response. These findings suggest that preadolescent dopamine receptor blockade may lead to a sensitized postadolescent dopaminergic response that underlies enhanced behavioral responses in the presence of rewarding stimuli.

Hippocampal subfield volumes and change in body mass over 12 months of treatment in first-episode schizophrenia spectrum disorders.

In this study, we explored the relationship between baseline hippocampal subfield volumes and change in body mass over 12 months of treatment in 90 first-episode schizophrenia spectrum disorder patients (66 males, 24 females; mean age= 24.7 ± 6.8 years). Body mass index was assessed in patients at baseline, and at months 3, 6, 9 and 12. Hippocampal subfields of interest were assessed at baseline using a segmentation algorithm included in the FreeSurfer 6.0 software program. Linear regression revealed a significant interactive effect between sex and anterior hippocampus size as predictors of change in body mass over 12 months, adjusting for age, substance use, and treatment duration. In an exploratory post-hoc sub-analysis, partial correlations showed a significant association between weight gain and smaller CA1, CA3 and subiculum volumes in females, but not males, adjusting for age and substance use, with similar trends evident for the CA4 and presubiculum subfields. In conclusion, our findings suggest that smaller anterior hippocampal subfields at baseline are associated with the development of weight gain over the course of treatment in first-episode schizophrenia spectrum disorders in a sex-specific fashion. This may be related to the greater increase in body mass evident for female patients in our study.

Rewarding effects of M4 but not M3 muscarinic cholinergic receptor antagonism in the rostromedial tegmental nucleus.

The rostromedial tegmental nucleus (RMTg) receives inputs from the laterodorsal tegmental and pedunculopontine tegmental nuclei, the two principle brainstem cholinergic nuclei. We tested the effects of RMTg M3 and M4 muscarinic cholinergic receptor antagonism in a conditioned place preference (CPP) paradigm in mice. RMTg infusions of the M3 muscarinic cholinergic receptor antagonist 1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) do not result in the acquisition of CPP but increase locomotor activation. By contrast, RMTg infusions of the M4 muscarinic cholinergic receptor antagonist Tropicamide result in the acquisition of CPP but do not increase locomotor activation. The rewarding effects of RMTg Tropicamide infusions are dopamine-dependent as systemic pre-treatment with the broad-spectrum dopamine receptor antagonist flupenthixol prevents the acquisition of CPP induced by RMTg Tropicamide infusions. Under conditions of systemic dopamine receptor blockade, RMTg Tropicamide infusions significantly increase locomotor activation. These data provide further support for an important role of endogenous cholinergic input to the RMTg in reward function and suggest that the contributions of RMTg cholinergic input to rewarding and locomotor-activating effects involve differential contributions of RMTg M4 and M3 muscarinic receptors, respectively.

Neurological soft signs in first-episode schizophrenia: State- and trait-related relationships to psychopathology, cognition and antipsychotic medication effects.

BACKGROUND: Neurological soft signs (NSS) are proposed to represent both state- and trait-related features of schizophrenia. METHOD: We assessed the course of NSS with the Neurological Evaluation Scale (NES) over 12months of standardised treatment in 126 patients with first-episode schizophrenia, schizophreniform or schizoaffective disorder, and evaluated their state- and trait-related associations with psychopathology, functionality, cognition and antipsychotic treatment. We considered change scores from baseline to be state-related and endpoint scores to be trait-related. RESULTS: Significant effects for time were recorded for all NSS domains. For state-related change-scores greater improvements in sensory integration were predicted by more improvement in working memory (p=0.01); greater improvements in motor sequencing scores were predicted by more improvement in working memory (p=0.005) and functionality (p=0.005); and greater improvements in NES Total score were predicted by more improvement in disorganised symptoms (p=0.02). There were more substantial associations between trait-related endpoint scores than for state-related change scores. For endpoint scores lower composite cognitive score predicted poorer sensory integration (p=0.001); higher Parkinsonism score predicted poorer motor co-ordination (p=0.0001); lower composite cognitive score (p=0.001) and higher Parkinsonism score (p=0.005) predicted poorer motor sequencing; higher Parkinsonism score (p=0.0001) and disorganised symptoms (p=0.04), and lower composite cognitive score (p=0.0007) predicted higher NES total score. CONCLUSIONS: NSS improved with treatment, but were weakly associated with improvements in psychopathology. Studies investigating NSS as trait-markers should ensure that patients have been optimally treated at the time of testing, and should take possible effects of extrapyramidal symptoms into account.

Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer.

In advanced lung cancer, epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have extraordinary clinical efficacy. However, their usefulness is severely compromised by drug resistance mediated by various mechanisms, the most important of which is the secondary EGFR T790M mutation. The mutation blocks the binding of EGFR TKIs to the receptor kinase, thereby abolishing the therapeutic efficacy. In this study, we used our free and open-source protein-ligand docking software idock to screen worldwide approved small-molecule drugs against EGFR T790M. The computationally selected drug candidates were evaluated in vitro in resistant non-small cell lung cancer (NSCLC) cell lines. The specificity of the drugs toward the mutant EGFR was demonstrated by cell-free kinase inhibition assay. The inhibition of EGFR kinase activity and its downstream signaling pathways in NSCLC cells was shown by immunoblot analysis. The positive hints were revealed to be indacaterol, canagliflozin, and cis-flupenthixol, all of which were shown to induce apoptosis in NSCLC cells harboring the EGFR T790M mutation. Moreover, the combination of indacaterol with gefitinib was also found to produce synergistic anticancer effect in NSCLC cells bearing EGFR T790M. The observed synergistic effect was likely contributed by the enhanced inhibition of EGFR and its downstream signaling molecules.

Fine-mapping of antipsychotic response genome-wide association studies reveals novel regulatory mechanisms.

AIM: Noncoding variation has demonstrated regulatory effects on disease treatment outcomes. This study investigated the potential functionality of previously implicated noncoding variants on schizophrenia treatment response. MATERIALS & METHODS: Predicted regulatory potential of variation identified from antipsychotic response genome-wide association studies was determined. Prioritized variants were assessed for association(s) with treatment outcomes in a South African first episode schizophrenia cohort (n = 103). RESULTS: Bioinformatic and association results implicated a relationship between regulatory variants, expression of MANBA, COL9A2 and NFKB1, and treatment response. Three SNPs were associated with poor outcomes (rs230493: p = 1.88 × 10-6; rs3774959: p = 1.75 × 10-5; and rs230504: p = 1.48 × 10-4). CONCLUSION: This study has thoroughly investigated previous GWAS to pinpoint variants that may play a causal role in poor schizophrenia treatment outcomes, and provides potential candidate genes for further study in the field of antipsychotic response.

Dopamine antagonism does not impair learning of Pavlovian conditioned approach to manipulable or non-manipulable cues but biases responding towards goal tracking.

Dopamine's (DA) role in reward-processing is currently discussed as either providing a teaching signal to guide learning or mediating the transfer of incentive salience (i.e. motivational aspects) from unconditioned stimuli (US) to conditioned stimuli (CS). We used a Pavlovian conditioned approach (PCA) procedure to further investigate DAs contribution to these processes. Experiment 1 assessed the acquisition of PCA to a manipulable lever cue for 7days under DA-blockade with Flupenthixol (FLU; 225µg/kg) or Saline (SAL) treatment, followed by 6-days off-drug testing. FLU decreased the number of conditioned responses (CR) during the treatment phase, but cessation of treatment resulted in an immediate increase in CR to levels comparable to SAL controls; notably, CR in FLU-treated rats were restricted to goal tracking behaviour. During continued off-drug testing, rats from the FLU group developed sign tracking with a similar temporal pattern as controls. In experiment 2, acquisition of PCA to a non-manipulable auditory cue was investigated. FLU reduced the number of CR during treatment, and removing DA antagonism resulted in a similar rapid increase of CR as seen in experiment 1. These data complement other reports by demonstrating that, independently from the physical properties of the CS, DA is not required for learning predictive aspects of a CS-US relationship but for the development of behaviour (namely sign tracking) which is based on the motivational aspects of a CS-US relationship.

Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration.

Cocaine has long been known to produce an initial "high" followed by an aversive/anxiogenic "crash". While much is known about the neurobiology of cocaine's positive/rewarding effects, the mechanisms that give rise to the drug's negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15µg/side) or the D2 agonist, sumanirole (0, 5 or 10µg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine.

Changes in body mass and metabolic profiles in patients with first-episode schizophrenia treated for 12 months with a first-generation antipsychotic.

OBJECTIVES: To assess changes in body mass and metabolic profiles in patients with first-episode schizophrenia receiving standardised, assured treatment and to identify predictors and moderators of the effects. METHODS: We investigated the changes in body mass, fasting blood glucose and lipids in 107 largely antipsychotic naïve, first-episode schizophrenia patients who were treated according to a standard algorithm with long-acting injectable flupenthixol decanoate over 12 months. RESULTS: Eighty-three (78%) participants completed the 12 months of treatment, and 104 (97%) received 100% of the prescribed injections during their participation. There were significant increases in BMI (P<.0001), waist circumference (P=0.0006) and triglycerides (P=0.03) and decrease in HDL (P=0.005), while systolic (P=0.7) and diastolic blood pressure (P=0.8), LDL (P=0.1), cholesterol (P=0.3), and glucose (P=0.9) values did not change over time. The triglyceride: HDL ratio increased by 91%. Change in BMI was only correlated with change in triglycerides (P=.008). The only significant predictor of BMI increase was non-substance abuse (P=.002). CONCLUSIONS: The risks of weight gain and metabolic syndrome associated with antipsychotic treatment in first-episode schizophrenia are not restricted to second generation antipsychotics. This is a global problem, and developing communities may be particularly susceptible.

Sex differences in response to amphetamine in adult Long-Evans rats performing a delay-discounting task.

The use of animal models to investigate experimental questions about impulsive behavior can provide valuable insight into problems that affect human health. The delay-discounting paradigm involves subjects choosing between smaller reinforcers delivered immediately and larger reinforcers that are delivered after a delay. This is an important experimental paradigm for examining impulsive choice in both laboratory species and humans. However, a shortcoming of previously published delay-discounting studies in animals is that typically only males were studied, reducing the applicability of these studies to human populations. In the present study, both female and male adult Long-Evans rats were trained to perform a delay-discounting task, with delays of 0, 5, 10, 20 and 40 s before delivery of the larger reinforcer. Because dopaminergic signaling is important in mediating this task, the effects of d-amphetamine and the dopamine receptor antagonist, cis-flupenthixol, on task performance were then examined. The main experimental measure was percent larger-reinforcer choice, which was defined as the percentage of experimental trials at each delay in which the delayed, larger reinforcer was chosen. There was no sex difference in percent larger-reinforcer choice during baseline performance of the task. However, d-amphetamine administration disrupted choice in females, as evidenced by <80% larger-reinforcer choice in half of the females, but none of the males, at 0.5 mg/kg. D-Amphetamine also differentially altered the latency to choose between immediate versus delayed reinforcers in females compared to males. In contrast, cis-flupenthixol did not have a sex-related effect on percent larger-reinforcer choice. These findings parallel the sex differences in response to amphetamine seen in human delay-discounting studies and underscore the importance of evaluating sex-based differences in baseline performance and in response to pharmacologic agents when utilizing animal models.

The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats.

Human cocaine users report that the initial "high" produced by cocaine administration is followed by an anxiogenic "crash". Given that cocaine has such robust and opposing properties, it is likely that both positive and negative effects of cocaine contribute to an individual's motivation to administer the drug. Despite this likelihood, the neurobiology underlying cocaine's dual processes remains unclear. While much literature supports a role for dopamine (DA) in cocaine reward, it is uncertain if DA also contributes to the drug's negative effects. Our laboratory has extensively utilized a modified conditioned place test to explore cocaine's opponent processes. In this paradigm rats develop conditioned place preferences (CPPs) for an environment paired with the immediate/positive effects of cocaine, and conditioned place aversions (CPAs) for an environment paired with the delayed/negative effects present 15-min after i.v. injection. In the current study rats were conditioned to associate an environment with either the immediate or delayed effects of i.v. cocaine (1mg/kg/0.1ml) 3h after i.p. pre-treatment with either the DA D1/D2 receptor antagonist cis-flupenthixol (0.5mg/kg/ml) or saline vehicle. As expected, vehicle-treated control animals developed the normal pattern of CPPs for cocaine's immediate effects or CPAs for the delayed effects of cocaine. However, while DA receptor antagonism prevented the expression of cocaine CPPs it did not alter the expression of cocaine-induced CPAs. These data confirm a role for DA transmission in cocaine reward but suggest that different neural pathways mediate the drug's negative/anxiogenic properties.

Attenuation of acute d-amphetamine-induced disruption of conflict resolution by clozapine, but not α-flupenthixol in rats.

Previous research demonstrates that disruption of forebrain dopamine systems impairs the use of high-order information to guide goal-directed performance, and that this deficit may be related to impaired use of task-setting cues in patients with schizophrenia. Such deficits can be interrogated through conflict resolution, which has been demonstrated to be sensitive to prefrontal integrity in rodents. We sought to examine the effects of acute systemic d-amphetamine administration on the contextual control of response conflict in rats, and whether deficits were reversed through pre-treatment with clozapine or the D1/D2 antagonist α-flupenthixol. Acute d-amphetamine (1.5 mg/kg) disrupted the utilisation of contextual cues; therefore rats were impaired during presentation of stimulus compounds that require conflict resolution. Evidence suggested that this effect was attenuated through pre-treatment with the atypical antipsychotic clozapine (5.0 mg/kg), but not the typical antipsychotic α-flupenthixol (0.25 mg/kg), at doses previously shown to attenuate d-amphetamine-induced cognitive deficits. These studies therefore demonstrate a potentially viable model of disrupted executive function such as that seen in schizophrenia.