Search

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.

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.

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.

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. [ABSTRACT FROM AUTHOR]

BackgroundSequential reward-seeking actions are readily learned despite the temporal gap between the earliest (distal) action in the sequence and the reward delivery. Fast dopamine signaling is hypothesized to mediate this form of learning by reporting errors in reward prediction. However, such a role for dopamine release in voluntarily initiated action sequences remains to be demonstrated.MethodsUsing fast-scan cyclic voltammetry, we monitored phasic mesolimbic dopamine release, in real time, as rats performed a self-initiated sequence of lever presses to earn sucrose rewards. Before testing, rats received either 0 (n = 11), 5 (n = 11), or 10 (n = 8) days of action sequence training.ResultsFor rats acquiring the action sequence task at test, dopamine release was strongly elicited by response-contingent (but unexpected) rewards. With learning, a significant elevation in dopamine release preceded performance of the proximal action and subsequently came to precede the distal action. This predistal dopamine release response was also observed in rats previously trained on the action sequence task, and the amplitude of this signal predicted the latency with which rats completed the action sequence. Importantly, the dopamine response to contingent reward delivery was not observed in rats given extensive pretraining. Pharmacological analysis confirmed that task performance was dopamine-dependent.ConclusionsThese data suggest that phasic mesolimbic dopamine release mediates the influence that rewards exert over the performance of self-paced, sequentially-organized behavior and sheds light on how dopamine signaling abnormalities may contribute to disorders of behavioral control.

Previous studies have suggested that food restriction can modify performance in the conditioned place preference (CPP) paradigm. In the present study, we tested the hypotheses that food restriction would enhance the development of a CPP to low-calorie sucrose pellets and that peripheral leptin replacement in food-restricted animals would reverse this effect. Using a range of 45-mg sucrose pellets (0-15 pellets) as a reward, we observed that a significant place preference was conditioned in food-restricted, but not ad libitum-fed rats. This CPP was reversed either by treatment of food-restricted rats with the dopamine receptor antagonist alpha-flupenthixol (200 microg/kg ip) during the training protocol or by chronic subcutaneous replacement of leptin (125 microg/kg/day) that attenuated the food restriction-induced decrease of circulating leptin. We conclude that dopaminergic signaling and the fall of plasma leptin concentrations contribute to the CPP of food-restricted rats. This finding suggests that in addition to metabolic adaptations, hypoleptinemia results in behavioral adaptations during states of energy deprivation.

Dopamine (DA), one of the biogenic amines, has been suggested to regulate the motor activities of various animals. In honey bees, it has been reported to promote locomotor activity in queens, workers, and males, and to regulate the flight activity of workers and males. The role of DA in the flight activity of queens, however, has not yet been investigated. In this study, we tested the roles of DA in the flight activity of virgin queens. We first injected the DA receptor antagonist flupenthixol (10−2 M or 10−3 M) into the abdomens of 6-day-old virgin queens and measured the time to flight initiation. The same experiment was performed in workers, to confirm previous findings and compare them to the virgin queens. We then injected 10−2 M flupenthixol into the queens and quantified their flight activity using a flight mill. The workers were deemed unsuitable for this round of experimentation. In both queens and workers, flupenthixol injection significantly delayed flight initiation. In flight mill experiments, flupenthixol decreased the flight performance of the queens in terms of distance, duration, and velocity. These results suggest the involvement of DA in the flight activity of virgin queens and workers, and indicate that DA is a key neuroactive substance in motor system activation with conserved effects among honey bee queens, workers, and males. [ABSTRACT FROM AUTHOR]

This study retrospectively assessed the effects of Jiawei Yiqihuoxue decotion (JWYQHXD) for the treatment of post stroke depression and anxiety (PSDA). This retrospective study included 72 patients who had undergone PSDA. All patients received flupentixol and melitracen and were divided into treatment (n = 36) and control (n = 36) groups. In addition, all the patients in the treatment group underwent JWYQHXD treatment. All patients in both groups were treated for 8 weeks. The primary outcomes were depression (assessed by Hamilton Depression Scale scores) and anxiety (evaluated by Hamilton anxiety scale scores). The secondary outcomes were quality of life (assessed using the 36-item short form health survey) and adverse events. We collected and analyzed the outcome data before and after treatment. After treatment, patients in the treatment group did not show greater relief on depression (Hamilton depression scale, P > .05) or anxiety (Hamilton anxiety scale, P > .05) than those in the control group. However, there were significant differences in quality of life 36-item short form health survey (physical function, P = .02; physical role, P = .01; and general health, P = .04) between the 2 groups after treatment. This study found that the JWYQHXD may help improve the quality of life of patients with PSDA. Future prospective studies are warranted to confirm these findings., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The aim of this study was to evaluate the efficacy and tolerability of the combination of two long-acting injectable antipsychotics (LAIA) in psychiatric disorders, especially in schizophrenia., Patients and Methods: Eighty-three patients treated with dual LAIA were included in the study by retrospective screening from the hospital registration system. The present study was designed as an observational, retrospective, naturalistic mirror-image study. The number of hospitalizations before and after switching to dual LAIA was compared in patients who received oral antipsychotics and single LAIA during the study period. In addition, it was analyzed which was the preferred dual antipsychotic combination., Results: Of the patients, 44.6% had schizophrenia, 41.0% had schizoaffective disorder, and 14.4% had other psychiatric disorders. The number of patients receiving oral treatment prior to dual LAIA use was 80 (96.4%). Data on dual LAIA regimens showed that 31.3% were receiving paliperidone and aripiprazole, 24.1% were receiving paliperidone and flupenthixol, 18.1% were receiving paliperidone and zuclopenthixol, and 26.5% were receiving the other combinations. After dual LAIA treatment, there was a significant decrease in the number of hospitalizations compared to before (from 5.95 to 0.99, p<0.001). In addition, while the number of patients who did not require hospitalization in the pre-treatment period was 10.8%, it reached 48.1% in the post-treatment period (p<0.001). No significant adverse effect related to the use of dual LAIA was observed in any patient during the treatment period., Conclusions: The use of dual LAIA instead of oral antipsychotics or single LAIA in chronic psychotic patients with poor social support and irregular medication use is thought to reduce hospitalization and related treatment costs and regularize medication use.

Copyright of Chinese Journal of Clinical Healthcare is the property of Chinese Journal of Clinical Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

BackgroundProgressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported.MethodsWe 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).ResultsExcessive 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.ConclusionsBrain 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. [ABSTRACT FROM PUBLISHER]

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 7 days under DA-blockade with Flupenthixol (FLU; 225 μg/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. [ABSTRACT FROM AUTHOR]

The noncompetitive NMDA receptor antagonist (+)-5-methyl-10,l 1-dihydro-5H-dibenzo [a,d] cyclohepten-5-10-imine maleate (MK-801) has been shown to increase the probability of operant responding during extinction and reduce infralimbic prefrontal cortical activation, possibly modeling the cognitive dysfunction symptomology, and underlying cause, in patients with schizophrenia. The present study sought to determine if typical and/or atypical antipsychotics would attenuate the MK-801-induced behavioral perseveration and whether this would be associated with concomitant changes in phosphorylated ERK1/2 (pERKl/2) labeling in the infralimbic cortex (IL). Male, Long Evans rats were pretreated with the typical antipsychotic, Flupenthixol (0, 0.125, 0.25 or 0.5 mg/kg) or the atypical antipsychotic, aripiprazole (0. 0.3, 1.0, 3.0 mg/kg), then given 0.1 mg/kg MK-801 followed by a 60-min appetitive operant extinction session. Flupenthixol produced a dose-dependent decrease in MK-801-induced bar pressing behavior and locomotor activity and a dose-dependent increase in IL pERKl/2 labeling. Aripiprazole produced a U-shaped dose-response curve on MK-801-induced bar pressing behavior, a dose-dependent decrease in locomotor activity but no changes in IL pERKl/2 labeling. The attenuation of the MK-801-induced behavioral (bar pressing, locomotion) profile by Flupenthixol indicates a clear dopaminergic contribution to this behavior. The behavioral effect of aripiprazole may be due to its a) binding to presynaptic dopamine receptors at the midrange dose decreasing dopamine output and b) binding to postsynaptic dopamine receptors at the higher dose increasing dopamine tone. While both classes of antipsychotics can normalize perseverative behavioral symptoms, the underlying prefrontal cortical dysregulation seems to persist. [ABSTRACT FROM AUTHOR]

Torsades de pointes is ventricular tachycardia due to prolongation of the heart rate-corrected QT interval (QTc). It is caused by multiple factors. Here we present a case of self terminating torsades de pointes due to antipsychotic drug Flupenthixol in a permanently paced patient at slow heart rate who developed torsades de pointes only after one episode of loose stool. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 40s 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 0.5mg/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. [Copyright &y& Elsevier]

Drosophila melanogaster, the fruit fly, is an excellent model organism for studying dopaminergic mechanisms and simple behaviors, but methods to measure dopamine during behavior are needed. Here, we developed fast-scan cyclic voltammetry (FSCV) to track in vivo dopamine during sugar feeding. First, we employed acetylcholine stimulation to evaluate the feasibility of in vivo measurements in an awake fly. Next, we tested sugar feeding by placing sucrose solution near the fly proboscis. In the mushroom body medial tip, 1 pmol acetylcholine and sugar feeding released 0.49±0.04 μM and 0.31±0.06 μM dopamine, respectively but sugar-evoked release lasted longer than with acetylcholine. Administering the dopamine transporter inhibitor nisoxetine or D2 receptor antagonist flupentixol significantly increased sugar-evoked dopamine. This study develops FSCV to measure behaviorally evoked release in fly, enabling Drosophila studies of neurochemical control of reward, learning, and memory behaviors., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Importance: An increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on neurodevelopmental outcomes., Objective: To examine whether maternal prescription fill for antipsychotics during pregnancy was associated with performance in standardized tests among schoolchildren., Design, Setting, and Participants: This register-based cohort study included 667 517 children born in Denmark from January 1, 1997, to December 31, 2009, and who were attending public primary and lower secondary school. All children had completed at least 1 language (Danish) or mathematics test as part of the Danish National School Test Program between 2010 and 2018. Data were analyzed from November 1, 2021, to March 31, 2022., Exposures: Antipsychotic prescriptions filled by pregnant individuals were obtained from the Danish National Prescription Register., Main Outcomes and Measures: Differences in standardized test scores (range, 1-100; higher scores indicate better test results) in language and mathematics between children of mothers with and without antipsychotic prescription fills during pregnancy were estimated using linear regression models. Seven sensitivity analyses, including a sibling-controlled analysis, were performed., Results: Of the 667 517 children included (51.2% males), 1442 (0.2%) children were born to mothers filling an antipsychotic prescription during pregnancy. The mean (SD) age of children at the time of testing spanned from 8.9 (0.4) years in grade 2 to 14.9 (0.4) years in grade 8. Maternal prescription fill for antipsychotics was not associated with performance in language (crude mean test score: 50.0 [95% CI, 49.1-50.9] for the exposed children vs 55.4 [95% CI, 55.4-55.5] for the unexposed children; adjusted difference, 0.5 [95% CI, -0.8 to 1.7]) or in mathematics (crude mean test score: 48.1 [95% CI, 47.0-49.3] for the exposed children vs 56.1 [95% CI, 56.1-56.2] for the unexposed children; adjusted difference, 0.4 [95% CI, -1.0 to 1.8]). There was no evidence that results were modified by the timing of filling prescriptions, classes (first-generation and second-generation) of antipsychotics, or the most commonly prescribed antipsychotic monotherapies, including chlorprotixene, flupentixol, olanzapine, zuclopenthixol, quetiapine, perphenazine, and methotrimeprazine. The results remained robust across sensitivity analyses, including sibling-controlled analyses, negative control exposures analyses, and probabilistic bias analyses., Conclusions and Relevance: In this register-based cohort study, maternal prescription fill for antipsychotics during pregnancy did not appear to be associated with standardized test scores in the offspring. The findings provide further reassuring data on offspring neurodevelopmental outcomes associated with antipsychotic treatment during pregnancy.

Abstract: Hippocampal rhythmic slow activity (RSA, theta) is regulated by many brainstem structures, including the midbrain ventral tegmental area (VTA). This work aimed at assessing the role of the dopaminergic (DA) transmission of the VTA in this regulation. Male Wistar rats (n=35) in urethane anaesthesia received an intra-VTA microinjection of either flupenthixol (FLU; doses of 5.0, 2.5, 1.25 and 0.625μg) or amphetamine (AMPH; 2.5 and 5.0μg) following control solvent microinjection. Peak power (P max) and corresponding peak frequency (F max) for delta and theta bands were extracted from EEG recording. Flupenthixol at a dose of 1.25μg evoked long-lasting theta, continuing for 32.0min on average, with a mean latency of 7.1min. Other doses of FLU caused an increase of P max theta and reduction of P max delta without generating visually recognizable, regular theta rhythm. 5μg of AMPH evoked theta continuing for 24.4min on average, with a mean latency of 9.7min. The lower dose was much less effective, with its outcome resembling the one after the less active FLU doses. During pharmacologically induced theta rhythm, both after FLU and AMPH, brief episodes of asynchronous activity appeared periodically, and they were more frequent and longer in AMPH groups. AMPH may act locally on multiple sites, inhibiting DA cells in somatodendritic region but also increasing dopamine release in target structures, and this, depending on AMPH dose, can lead to induction of theta rhythm. Locally administered DA antagonist on the other hand, when used at a proper dose, can produce theta most likely by the mechanism of inhibiting autoreceptors. [Copyright &y& Elsevier]

Dear Editor, The costs of antipsychotic drugs (APDs) used in the treatment of mental disorders with psychosis are mentioned in treatment guidelines (APA 2021, NICE 2014). While the American Psychiatric Association guideline states that every specialist should make decisions according to the rules and conditions of their country and their region, the National Institute of Health and Clinical Excellence guideline emphasizes that drug costs must be taken into consideration in the treatment process. Classical or first-generation antipsychotic drugs (FAPDs) are relatively cheaper in terms of sales prices compared to atypical or second-generation antipsychotic drugs (SAPDs) with a slightly different effect mechanism. The price difference between the two drug groups can be so large that sometimes it may be necessary to consider whether the cost of a second-generation drug is worth its benefit. While deciding on the use of first-generation or second-generation drugs, a multifaceted assessment should be made, such as the patient's level of compliance with the treatment, the possibility of occurrence of side effects, the possible effects of these side effects on body health and treatment compliance, and whether or not the costs are covered. The most important criterion that determines the choice of medication for psychiatrists is of course the multi-dimensional benefit/harm ratio that the drug used will reveal in the long term. We think that in our country, which, in terms of economic indicators is not in a strong position as an importer of pharmaceutical raw materials from abroad, APDs' cost calculation should be considered because drug costs constitute an important part of the direct treatment costs of psychotic disorders in developing countries such as Turkey (Yıldız and Cerit 2006). We calculated the unit (mg) price based on the box prices of the APDs in use in 2020, thinking that it might work when calculating the cost of the illness using APDs as the main component of the treatment and calculated the annual average drug costs with the daily average dosage. Although the daily treatment dose varies with the stage of the illness and the individual characteristics of the patient, the average doses recommended for maintenance treatment were used here (Öztürk and Ulusahin 2018). The daily and annual cost calculations based on the assumption that the average maintenance treatment dose was used with the unit price obtained from (Drug Prices 2020) the drugs in the Turkish pharmaceutical market in September 2020 are shown in Table 1. A similar study was done in 2005 (Yıldız 2005). The purpose of this article is to redetermine the average costs of APDs in the Turkish pharmaceutical market every 15 years and to bring them to the attention of experts in terms of cost-effectiveness studies. When the costs in 2005 are examined, it is seen that the annual costs of the FAPDs were around 450 TRY, and the annual cost of oral preparations of SAPDs was 2,500 TRY (5 times the first generation). In 2005, there was only one depot of SAPD (risperidon consta) that allowed intramuscular (IM) administration, and its average annual cost was 5,400 TRY, 3 times more than the tablet form (1,700 TRY). In 2005, when the price of risperidone consta, which was the first second-generation depot APD, were compared with the prices of the first-generation depot drugs (fluphenazine = 380 TRY, flupentixol = 876 TRY, zuclopentixol = 730 TRY), the cost difference was 6-14 times. This almost-10-fold difference between the cost of the first and second generation APDs was remarkable. It is seen that this difference (risperidone consta = 10,807 TRY, fluphenazine = 916 TRY, flupentixol = 1,007 TRY, zuclopenthixol = 2,372 TRY, and haloperidol deconate 237 TRY) did not change in 2020. In 2020, the average RETHINKING THE COST OF ANTIPSYCHOTIC TREATMENT: THE AVERAGE COST OF THE DRUGS USED IN TURKEY IN 2020 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 146 147 annual cost of oral use preparations of FAPDs is 925 TRY, while the average annual cost of oral forms of SAPDs is 2,580 TRY. The 5-fold difference observed in 2005 between the first and second-generation ones of the oral APDs decreased to 2.5 times in 2020. It is clear that while the difference between the cost of oral use of first- and second-generation drugs was halved in 2020, the difference between the costs of depot preparations applied with IM did not change. In 2005, the average dollar rate was 1.34 TRY, and in 2020 it was 7.02 TRY (Republic of Turkey Central Bank Exchange Rates, 2021). It is understood that the 5-fold increase in dollar exchange rate is not reflected in all drug prices in the same way. For example, there was a 3 to 4-fold increase in the prices of haloperidol, chlorpromazine, fluphenazine, trifluperazine and zuclopenthixol, while a less than two-fold increase in pimozide, flupenthixol, sulpiride, amisulpride and quetiapine and a decrease in the prices of clozapine, olanzapine, ziprasidone and risperidone in the tablet form. There is also a two-fold increase in the price of risperidone consta. The fluctuations in drug prices in 2005 and 2020 are shown in Table 2 in 500, 1,000, 2,000, 3,000 and 5,000 TRY brackets. It is noteworthy that while some drugs have moved into an upper price bracket in terms of annual costs, some have fallen into a lower price bracket. The prices of the second generation long-acting (depot) antipsycotic drugs (LA-APDs), which were not available in the Turkish pharmaceutical market in 2005, are quite high compared to others. In 2020, the annual cost of all of them, including risperidone consta, is over 10 thousand TRY. It is understood that the underlying reason for such price increase is the fact that the drug is wanted/sought after/new/marketed rather than the dollar exchange rate. For example, while there was a certain increase in the price of FAPDs, the increase in the price of some of the SAPDs (sulpiride, amisulpride, quetiapine tablet) was low, while the price of some others (clozapine, olanzapine, ziprasidone, risperidone tablet) decreased. It should also be taken into account that the effect of generic drugs entering the market during this period may have had an impact on price changes. It is noteworthy that while the annual cost of risperidone consta was approximately 3 times higher than the tablet form (5,400 TRY versus 1,700 TRY) in 2005, this difference reached 14 folds (10,807 TRY versus 742 TRY) in 2020. In 2005, the difference between the lowest daily cost (0.07 TRY) and the highest daily cost (14.80 TRY) was 211 times (Yıldız 2005), this difference had receded to 111 times (0.35 TRY versus 38.72 TRY) in 2020. Still a huge difference, isn't it? Table 1. Current Forms, Box Prices, Daily and Annual Costs in For Maintenance Treatment of Antipsychotic Drugs Available in the Pharmaceutical Market in September 2020 in Turkey No Generic name Trade name Dosage forms (mg) BV Price# TRY/Mg ADD Cost/d Cost/y 2005** 1 Haloperidol Norodol 5, 10, 20 tb 5/50 17.57 0.070 5 0.35 127 26 5, 10 amp 5/5 5.35 0.214 5 1.07 390 - 50, 150 LAI 50/1 9.80 0.196 1/15* 0.65 237 - 2 Chlorpromazine Largactil 25,100 tb 100/30 17.92 0.006 300 1.79 653 197 3 Fluphenazine Prolixin 25 LAI 25/1 17.57 0.703 1/7* 2.51 916 380 4 Trifluoperazine Stilizan 1, 2, 5 drj; 1 amp 5/30 14.52 0.096 10 0.97 354 91 5 Pimozide Nörofren 2 tb 2/30 19.33 0.322 4 1.29 470 365 6 Flupenthixol Fluanxol 3 drj 3/50 65.75 0.438 6 2.63 960 526 20 LAI 20/1 19.33 0.966 1/7* 2.76 1,007 876 7 Zuklopenthixol Clopixol 2, 10, 25 tb 2/50 38.65 0.386 20 7.72 2,817 701 200 LAI, 50 acu 200/1 45.55 0.227 1/7* 6.50 2,372 730 8 Sulpirid Dogmatil 200 tb 200/24 23.15 0.005 600 3.00 1,095 876 9 Amisulpirid Solian 200 tb 200/60 146.92 0.012 600 7.20 2,628 2,387 10 Quetiapine Seroquel 25, 50, 100, 200, 300, 400 tb 300/30 137.17 0.015 600 9.00 3,285 2,628 11 Clozapine Leponex 25, 100 tb 100/50 32.56 0.006 400 2.40 876 1,898 12 Olanzapine Zyprexa 5, 10, 20 tb 10/28 152.96 0.546 10 5.46 1,992 2,606 13 Ziprasidone Zeldox 20, 40, 60, 80 tb 60/56 189.89 0.056 120 6.72 2,452 3,541 14 Sertindole Serdolect 4, 12, 16, 20 tb 16/28 453.53 1.012 16 16.19 5,909 - 15 Risperidone Risperdal 1, 2, 3, 4 tb; 1 sol 2/20 20.34 0.508 4 2.03 741 1,719 Ris. Consta 25, 37.5, 50 LAI 37.5/1 444.17 11.840 1/15* 29.61 10,807 5,402 16 Paliperidone Invega 3, 6, 9 tb 6/28 213.15 1.268 6 7.61 2,777 - Xeplion 50, 75, 100, 150 LAI 100/1 1161.56 11.615 1/30* 38.72 14,132 - Trevicta 175, 263, 350, 525 LAI 350/1 3426.95 9.788 1/90* 38.08 13,899 - 17 Aripiprazole Abilify 5, 10, 15, 20 tb; 1 sol 20/28 113.25 0.404 20 8.08 2,949 - Abilify Main. 400 LAI 400/1 971.17 2.420 1/30* 32.37 11,815 - BV: Baseline value (in mg of the form and the number in the box), Price#: Box price of the base value in TRY, TRY/mg: Value per milligram in Turkish Lira, ADD: Average daily dose, Cost/d: Daily cost in TRY, Cost/y: Annual cost in TRY, mg: Milligram, tb: Tablet, drj: Dragee, amp: Ampoule, LAI: Long-acting injectable, acu: Acuphase, d: Day, TRY: Turkish Lira, *LAI per 7,15,30 or 90 days, **Annual cost in TRY in 2005. 148 Received: 14.01.2021, Accepted: 31.03.2021, Available Online Date: 07.01.2022 1Prof., 2Res. Assis., Kocaeli University School of Medicine, Department of Psychiatry, Kocaeli, Turkey. e-mail: myildiz60@yahoo.com https://doi.org/10.5080/u26315 The difference in 2005 between oral FAPDs prices and SAPDs prices seems to have halved in 2020. In 2020, the average daily treatment cost of oral drugs, whether for the first generation or the second generation, is 3 TRY (approximately the same for FAPDs applied with IM), while the daily cost of LA-SAPDs is around 33 TRY. It is seen that the difference between costs is approximately 11 times. This difference increases to 50 times for haloperidol deconate. From here, the following judgment can be made: in order for LA-SAPDs to be preferred, they must be at a value that will constitute at least 11 times higher cost. This cost can and should be taken, especially for patients who are non-adherend with treatment and who do not adapt to LA-FAPDs. Because for clinicians, preventing the multi-dimensional destructiveness of psychosis in the individual, families and the society should be the priority. In this case, calculating the cost should not be a primary consideration. However, it is also known that patients who are non-adherend with treatment gain the ability to understand their illness and make consistent evaluations with its' results. If a psychosocial therapy has been carried out for a patient using IM medication for six months or a year, it is likely that this period provides insight and increases the level of treatment compliance. After one year of IM application, whether or not the patient will comply with oral treatment should be re-evaluated and the transition to oral treatment should be considered. If there is no problem in the patient's oral treatment compliance, it should be taken into account that the benefit of this transition will be at least 11-folds a year with this transition. Naturally, it will be necessary to apply IM for some patients for years. Moreover, there will be patients who need to switch from monthly administration of LA-SAPDs to quarterly usage patterns. However, we can say that most patients using LA-APDs will not need such use after a while, based on our clinical practice, although there is no study done in this field. With this study, we wanted to emphasize that while prescribing drugs used in the treatment of illnesses with psychotic symptoms, they should take into account the side effects of the drugs, as well as the daily, monthly, annual, and lifetime costs of the drugs. The principle of 'using an effective drug recommended for a specific disorder at the required dose, in sufficient time, at the lowest cost' adopted in the rational drug use guidelines should not be forgotten. It is expected that the modification of drug treatments, considering their costs as well as their efficiency, will contribute significantly to the country's economy in the long run. Mustafa Yıldız1, Emre Osman2 REFERENCES American Psychiatric Association (2021) The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Third edition. Washington, DC: American Psychiatric Association. Drug Prices. https://www.ilacrehberi.com/ilac-fihrist/ Accession date: 25th September 2020. National Institute for Health and Clinical Excellence (NICE) (2014) Psychosis and schizophrenia in adults: prevention and management. NICE Guideline CG178; https://www.nice.org.uk/guidance/cg178. Accession date: 4th April 2018. Öztürk MO, Uluşahin NA (2018) Mental Health and Disorders. 18th Edit. Ankara: Nobel Tıp Kitapevleri. (In Turkish) Republic of Turkey Central Bank Exchange Rates. https://www.tcmb.gov.tr/kurlar/kurlar&#95;tr.html Accession date: 10th January 2021. Yıldız M (2005) The cost of treatment of psychotic disorders. Turk Psikiyatri Derg 16:146-7. (In Turkish) Yıldız M, Cerit C (2006) Annual cost of treatment for schizophrenia: Estimation from a university hospital data in Turkey. Bulletin of Clinical Psychopharmacology 16:239-44. Table 2. Comparison of the Annual Costs of Antipsychotic Drugs Calculated By The Daily Standard Average Dose Use, at Certain Price Ranges, for the Years 2005 and 2020 Price bracket (TRY) 2005 2020 500 ↓ Haloperidol tb, amp, Trifluoperazine drj, Chlorpromazine tb, Pimozid tb, Fluphenazine LAI Haloperidol tb, amp, depo, Trifluoperazine drj, Pimozid tb 500-1,000 Flupenthixol drj, LAI, Zuklopenthixol tb, acu, LAI, Sulpirid tb Chlorpromazine tb, Fluphenazine LAI, Flupenthixol drj, LAI, Clozapine tb, Risperidone tb 1,000-2,000 Clozapine tb, Risperidone tb Olanzapine tb, Sulpirid tb 2,000-3,000 Amisulpirid tb, Olanzapine tb, Quetiapine tb Zuklopenthixol tb, acu, LAI, Amisulpirid tb, Ziprasidone tb, Paliperidone tb, Aripiprazole tb 3,000-5,000 Ziprasidone tb Quetiapine tb 5,000-10,000 Risperidone consta Sertindole tb 10,000 ↑ Risperidone consta, Paliperidone monthly, Paliperidone 3 monthly, Aripiprazole maintana tb: Tablet, drj: Dragee, amp: Ampoule, LAI: Long-acting injectable, acu: Acuphase.

Learning about predictive relationships depends on surprise. For example, in Kamin's blocking paradigm learning about the association between one stimulus (X) and a footshock is attenuated when X→footshock training occurs in the presence of a good predictor (A) of that footshock. Establishing the neural processes that underlie this effect has generated considerable interest in recent years. Here, an infusion of the dopamine antagonist cis-(z)-Flupenthixol into the amygdala prtor to compound (AX) conditioning attenuated the blocking effect, but had no effect on controls. This effect of dopamine antagonism in the amygdala immediately prior to compound conditioning was obtained irrespective of whether infusions occurred prior to the first, second or both compound conditioning trials. These results provide evidence for the involvement of amygdaloid dopamine in regulating surprise in fear and therefore predictive learning via a direct outcome processing mechanism. [ABSTRACT FROM AUTHOR]

Male rats display a conditioned preference to ejaculate with a female bearing an odor paired previously with copulation to ejaculation. The present study examined the role of endogenous opioid and dopamine systems in this preference. Male rats received saline, the opioid receptor antagoinst naloxone, or the dopamine receptor antagonist flupenthixol prior to 10 conditioning trials in a pacing chamber with an almond-scented female. On the final test, all males were injected with saline and given access to 2 females, I scented and the other unscented, in an open field. Only males injected with naloxone during training failed to manifest a conditioned ejaculatory preference. These findings suggest that activation of opioid, but not dopamine, systems during sexual interaction are necessary for conditioned ejaculatory preference in male rats. [ABSTRACT FROM AUTHOR]

Abstract: Systemic treatments with acetylcholine (ACh) or dopamine (DA) receptor antagonists during hours 0–4 but not during hours 5–8 following training on a radial arm maze (RAM) or lesions of the dorsal striata impair learning. This suggested that intra-striatal infusions of ACh or DA receptor antagonists during hours 0–4 following training may impair learning. Rats were randomly assigned to groups (ns=5–11) receiving dorsal striatal infusions of the ACh receptor antagonist scopolamine (0–18μg/μL at 0 and 2h or at 4 and 6h after training), the DA receptor antagonist cis-flupenthixol (0–25μg/μL at 0, 4 or 12h after training) or the inactive isomer trans-flupenthixol (6μg/μL at 0h after training). Scopolamine and cis-flupenthixol impaired the habit-learning version of the task. Given after hours 0–4 following training, the effects of scopolamine were diminished but those of cis-flupenthixol were not. Trans-flupenthixol produced less impairment than cis-flupenthixol. Results suggest that ACh and DA receptors in the dorsal striatum during hours 0–4 following training play a role in habit learning. [Copyright &y& Elsevier]

Abstract: The antipsychotic thioxanthene flupenthixol, possessing a trifluoromethyl substituent at position 2, exhibited a distinct antibacterial property against 352 strains of bacteria from 3 Gram-positive and 13 Gram-negative genera. The minimum inhibitory concentration (MIC) of flupenthixol was determined by the National Committee for Clinical Laboratory Standards agar dilution method. MICs ranged from 10–100μg/mL in most of the strains, whilst some strains were inhibited at even lower concentrations. The mode of action of this drug was found to be bacteriostatic against Staphylococcus aureus and Vibrio cholerae. In the in vivo experiments, this drug was capable of contributing significant protection (P <0.001) to a Swiss strain of white mice challenged with 50 median lethal dose of a mouse-virulent strain at a drug concentration of 15μg/mouse. In addition, flupenthixol remarkably reduced the number of viable bacteria in organ homogenates and blood of mice treated with this drug. [Copyright &y& Elsevier]

Summary ¶A study recently finished by our research group elucidated the effectiveness of flupenthixol decanoate (FLX) in maintaining abstinence in detoxified alcoholics. Flupenthixol decanoate is an established antipsychotic drug, which is well known for its mild antidepressant and anxiolytic activity as well as for its minimal sedation at low doses. It blocks dopamine binding at a number of receptor subtypes, primarily at D-1, D-2, D-3 and with less affinity at D4-receptors. It also affects serotonin binding at 5-HT2A and 5-HT2C receptors. In a double-blind placebo-controlled multicenter trial, 77 women and 204 men suffering from moderate or severe DSM-II-R alcohol dependence were randomly assigned to either 10 mg FLX or placebo both injected every second week over a period of 24 weeks (treatment phase) succeeded by a medication-free 24-weeks follow-up period. In the overall analysis the number of patients relapsed after 24 weeks of treatment (=main criterion of efficacy) was significantly higher in the FLX treated group (85.2%) than under placebo (65.5%). However, when differentiating this result according to sex the analysis revealed a gender-related discrepancy: while male patients had an almost 4-fold higher risk to relapse under FLX than under placebo (OR=3.95) this risk was barely elevated for female patients (OR=1.51). A significantly negative outcome due to FLX treatment was restricted to male alcoholics solely. In conclusion, gender-related differences to pharmacological relapse prevention with FLX have probably contributed to a better treatment outcome in women than in men. [ABSTRACT FROM AUTHOR]

A specific reversed phase-high pressure liquid chromatography (RP-HPLC) method has been developed for the simultaneous determination of clozapine (CZP), loxapine (LXP), zuclopenthixol (ZPT) and flupenthixol (FPT) in plasma. These four antipsychotic drugs are frequently used for the treatment of schizophrenia and other neuropsychiatric diseases. Carpipramine, a dihydrodibenzazepine, was used as an internal standard (I.S.). A liquid–liquid procedure was used to extract the drugs from human plasma. The analysis was performed on a XTerra™ MS C18 column with UV detection. Calibration curves were linear in the range 50–1000 μg/l. The limit of quantification (LOQ) was 15 μg/l for clozapine and loxapine and 20 μg/l for zuclopenthixol and flupenthixol. The coefficient of variation (CV) for intra- and inter-day precision was 7.2% or less with accuracies within 10% for the three concentrations.This isocratic and rapid method (run time<10 min) is useful for the management of acute intoxication. [Copyright &y& Elsevier]

Substance use, especially alcoholism, has been recognized as a significant problem in schizophrenic patients, though only a few studies on the effects of pharmacotherapy in these patients have been conducted so far. The thioxanthene neuroleptic flupenthixol, which can be given intramuscularly (i.m.) for improving compliance, has been studied as a possible anti-craving drug both in animal models of alcoholism and some clinical studies. Pilot studies suggest that comorbid schizophrenics with substance use may benefit from treatment with flupenthixol. Efficacy of flupenthixol (10-60 mg i.m.) in reducing alcohol consumption of dual diagnosis patients was studied in an open 6-month clinical trial in 27 schizophrenics with comorbid alcoholism. Twenty-one patients entered the intention-to-treat analysis. Fourteen subjects were completers, 13 dropped out. Six patients completely abstained from alcohol during treatment. Alcohol consumption was significantly reduced compared to baseline (4 weeks before treatment as measured by timeline follow-back interview). In general, while patients showed a marked improvement concerning alcohol consumption, only a slight improvement in psychopathology was recorded. Overall tolerability was good. These data indicate a probable beneficial effect of flupenthixol in schizophrenic patients with comorbid alcoholism. Although the efficacy of flupenthixol as an anti-craving drug in dual diagnosis patients has to be explored in further studies, the drug may be considered a promising medication for these patients. [ABSTRACT FROM AUTHOR]

Objective: The primary aim of this paper was to compare the effects of flupenthixol and risperidone on subjective quality of life and attitude towards medication in chronic schizophrenic patients with mainly negative symptoms. In a spectrum ranging from its typical end ‘haloperidol’ to its atypical end ‘clozapine’, flupenthixol has typical and atypical characteristics. Methods: The effects of flupenthixol versus risperidone were investigated in a multicenter, double-blind trial, whereas subjective quality of life was assessed by means of the EuroQuol-Visual Analogue Scale and the patient satisfaction questionnaire. The attitude towards medication was assessed by means of the Drug Attitude Inventory-30 (DAI-30). Results: Mean daily dose of study medication was 6.6 (SD 2.9) mg/day flupenthixol and 3.6 (SD 1.2) mg/day risperidone. Both groups showed a significant improvement regarding subjective quality of life and positive attitude towards medication. Especially the categories ‘control of their thoughts’, concentration and ‘feeling better in general’ ameliorated in both groups. In the flupenthixol group, the ‘ability to cope with stress’, ‘feel more relaxed’ and the ‘ability to achieve something’ improved significantly more than in the risperidone group. Conclusions: (1) The spectrum of schizophrenia can be treated effectively with different neuroleptic treatments. (2) Flupenthixol especially improves the ability to cope with stress, the ability to achieve something and feeling more relaxed. (3) Subjective quality of life significantly increased with no difference between the groups.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Flupenthixol is an antipsychotic drug with known mood-elevating properties. Its propensity to induce manic symptoms has not been investigated. Methods and results. We describe six patients, four with schizophrenia and two with bipolar disorder, in whom flupenthixol treatment was associated with emergence of manic symptoms. Conclusions. Patients treated with flupenthixol should be carefully monitored for the emergence of manic symptoms. [Copyright &y& Elsevier]

In the present study, we investigated the long-term effects of treatment with amisulpride, a substituted benzamide derivative, as compared with the effects of treatment with flupenthixol, a thioxanthene, on the prolactin levels in schizophrenic patients. After completing 6 weeks of medication with either amisulpride or flupenthixol, the patients entered a long-term maintenance treatment with amisulpride 200–600 mg/day or flupenthixol 5–15 mg/day for a maximum of 12 months with a subsequent drug-free follow-up until month 15. Eighteen initially included patients were still participating in the study at month 6. In the flupenthixol group, only 1 patient treated reached month 12, and none of the patients reached month 15. For the amisulpride treatment group, months 12 and 15 were completed by 9 and 6 patients, respectively. After 1, 3, 6, and 12 months of treatment, and finally 3 months after cessation of treatment, the basal and thyrotropin-releasing hormone-stimulated secretions of prolactin were investigated. The prolactin plasma levels were elevated in both treatment groups during the course of maintenance treatment with a maximum effect at month 1. Flupenthixol treatment initially raised the prolactin levels about two- or threefold, and a subsequent decline during months 3 and 6 occurred. However, only the changes for month 1 reached the level of a statistical trend. The prolactin secretion was initially increased over tenfold by amisulpride. The prolactin levels at months 1, 3, 6, and 12 were significantly elevated as compared with the baseline values. A continuous decline of prolactin levels in both treatment groups occurred over the course of the next months. The prolactin response after the thyrotropin-releasing hormone challenge was not significantly changed over the long-term course. Notably, in the amisulpride group, 3 months after cessation of treatment at month 12, the elevated levels of prolactin returned to baseline at month 15. In summary, amisulpride demonstrated more pronounced effects than flupenthixol on the prolactin levels. However, the findings indicate also that treatment with amisulpride at clinically effective doses can be achieved at significantly lower prolactin levels during the long-term maintenance phase than during the prior acute phase.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A considerable number of animal studies on the effects of dopaminergic agents on alcohol intake behavior have been performed. Acute alcohol administration in rats induces dopamine release in the caudate nucleus and in the nucleus accumbens, an effect related among others to reinforcement. It has been repeatedly suggested that D[sub 1] and D[sub 2] receptor activation mediates reward. As alcohol consumption and dopaminergic transmission seem to have a close relationship, all kinds of dopaminergic agents may be regarded as putative therapeutics for preventing relapse. In a prospective European double-blind multicenter clinical trial, comparing the D[sub 1] , D[sub 2] , D[sub 3] antagonist flupenthixol and placebo in 281 chronic alcohol-dependent patients (27.4% women), the application of the Lesch typology made an outcome differentiation possible. It could be shown in which patients flupenthixol administration was followed by a significantly higher relapse rate and in which patient groups no differences were found when compared to placebo.Copyright © 2001 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

As outlined in the companion paper, many of the changes in functional activity produced by acute intragastric ethanol administration as determined by the quantitative autoradiographic 2-[14C]deoxyglucose method occur in structures of the mesocorticolimbic and nigrostriatal dopamine circuits. In this study, a dopaminergic antagonist, flupenthixol, was used to determine the contribution of dopamine to the ethanol-induced increases in functional activity. To assess the ability of flupenthixol to block dopaminergic-induced increases in glucose utilization, it was first examined in conjunction with the indirect dopaminergic agonist methylphenidate. Pretreatment with flupenthixol significantly reduced methylphenidate-induced increases in glucose utilization in structures of the mesocorticolimbic and nigrostriatal dopamine circuits. These findings indicate that this is an effective strategy for the determination of the neurochemical contributions to the changes in CNS functional activity. Flupenthixol pretreatment blocked many of the ethanol-induced increases in glucose utilization at the 0.25 g/kg dose, particularly in mesocorticolimbic and nigrostriatal structures. At the 1.0 and 2.0 g/kg ethanol doses, however, pretreatment with flupenthixol did not reverse the increases in glucose utilization in several brain regions, suggesting that dopaminergic activity is not responsible for the observed increases in glucose utilization and further, that these increases involve other neurotransmitter systems. In some regions, however, flupenthixol pretreatment resulted in augmented levels of glucose utilization above those rates produced by the administration of higher doses of ethanol alone. These findings suggest that the contribution of dopamine to the increases in functional activity are more complex at higher doses of ethanol. [ABSTRACT FROM AUTHOR]

Flupenthixol (FP), nortriptyline (NT) and zuclopenthixol, (ZCP) were determined in breast milk and plasma from 2 puerperal, lactating women with psychiatric disorders. The milk concentrations were equal to, higher and lower than those in plasma for FP, NT and ZCP, respectively. Variation in milk triglyceride concentration, but not milk pH, could partly explain between-breast differences in the milk concentrations. The study demonstrates the need for appropriate and representative milk sampling procedures. The estimated daily infant exposure averaged 0.5, 2.3 and 0.3% of the corresponding maternal weight related doses of FP, NT and ZCP. FP was also detectable in infant plasma. These drugs are not known to be harmful in small doses to breast-fed infants. However, concern about the effect of dopamine blocking agents on neurobehavioral mechanisms in animals warrants caution. If neuroleptics are required for a long period this risk must be weighed against the benefits of breast-feeding, also considering the psychological effects of the latter. [ABSTRACT FROM AUTHOR]

Several drugs have been shown to exert antipsychotic effects, yet they display an atypical profile with respect to standard neuroleptic drug screens. Low doses of traditional neuroleptics are known to increase self-administration of psychomotor stimulants; we sought to determine whether these atypical drugs would cause a comparable effect. Sulpiride, metoclopramide and thioridazine produced a dose-dependent increase in cocaine intake similar to that found for chlorpromazine, haloperidol, pimozide and flupenthixol. This effect was found to correlate ( r=0.94) with daily clinical dose. Clozapine, however, produced a dose-dependent decrease in cocaine intake. The advantages and disadvantages of using this measure as a screening procedure for neuroleptic drugs are discussed. [ABSTRACT FROM AUTHOR]

On the basis of results obtained from passive avoidance studies, we have argued that the neuropeptide vasopressin could act on arousal, rather than memory processes in rats (Sahgal et al. 1982). In this report, we examine the effects of substances that are known to increase ( d-amphetamine) or decrease (chlordiazepoxide) behavioural arousal, and compare the data with those obtained after vasopressin or oxytocin treatment. All four substances yielded broadly similar bimodal results (although the oxytocin data failed to reach significance). We argue for an arousal interpretation which suggests that performance and arousal are related in an 'inverted-U' manner. The data also indicate that care must be taken in selecting appropriate statistical tests. [ABSTRACT FROM AUTHOR]

The number of nerve cells in two different areas of the corpus striatum (i.e., ventrolateral and dorsomedial) was estimated in rat brain after long-term (36 weeks) treatment with the neuroleptic flupenthixol. Nine rats were given weekly injections of 4 mg/kg flupenthixol dissolved in Viscoleo i.m., and seven rats received Viscoleo alone. Fourteen to 18 weeks after the last drug injection, the animals were decapitated and half of each brain was fixated with formalin for cellcount analysis and the remaining half used for a biochemical analysis (Nielsen, 1977). Separate cell counts in the ventrolateral and dorsomedial corpus striatum yielded a significant cell loss of approximately 10%, but only in the ventrolateral striatum of treated animals. These results suggest at least one concrete anatomical basis for the behavioral and biochemical deficits found in the same animals, as reported earlier. The results further suggest that persistent irreversible anatomical changes can follow long-term neuroleptic treatment. The inconsistencies of results regarding cell loss in the corpus striatum may be due to neglect of dorsal-ventral structural differences in corpus striatum. [ABSTRACT FROM AUTHOR]

The effects of long-term treatment (36 weeks) with a neuroleptic drug (flupenthixol) were investigated behaviourally and biochemically in rats. Sixteen rats were trained on a DRL (differential reinforcement of low rate) 15-s schedule until stable responding was obtained. During the following 36 weeks 9 rats were injected weekly with flupenthixol dissolved in Viscoleo® [4 mg/kg (i.m.)] and seven rats received Viscoleo® alone. During this perod the animals were not run on the DRL schedule. Retesting on DRL 7 weeks after the last drug injection yielded highly significant differences between the flupenthixol-treated animals and the controls. Thorough neurological examinations of the animals just preceding the retesting period also revealed some deficits in the flupenthixol-treated animals. At sacrifice, 14-18 weeks after the last drug injection, levels of homovanillic acid (HVA) were measured in the corpus striatum and total 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rest of the forebrain. The results indicate a nonsignificant increase of 25% in the dopamine metabolite HVA, while the noradrenergic metabolite MOPEG was significantly decreased by 14% in experimental animals. The possibility of persistent functional and biochemical effects produced by prolonged treatment with a neuroleptic drug is highlighted in the results presented here. [ABSTRACT FROM AUTHOR]

α-Flupenthixol and α-flupenthixol decanoate were tested in mice against methylphenidate-induced stereotyped gnaw-compulsions. The effect of both α-flupenthixol, and α-flupenthixol decanoate disappeared 2 days after administration. In addition, the influence of α-flupenthixol and α-flupenthixol decanoate on the apomorphine-induced behaviour in mice was followed over a period of 12 days. Under these conditions apomorphine-induced compulsive gnawing was seen on the days on which the methylphenidate antagonistic effect had subsided. The apomorphine-induced compulsive gnawing seen in α-flupenthixol and α-flupenthixol decanoate pretreated animals could be antagonized by additional small doses of α-flupenthixol given 2 h before apomorphine. The interference of the neuroleptic drugs with dopaminergic receptors is discussed. [ABSTRACT FROM AUTHOR]

Gene expression has been studied in post-mortem frontal cortex samples from patients who had suffered from schizophrenia and depressive illness. mRNA was extracted and characterised by translation and separation of the products by 2D gel electrophoresis. Post-mortem artefacts and the agonal experience did not affect the size distribution or amount of specific translation products. Four expression products were specifically reduced in samples from schizophrenics compared with normals. The expression of six products was altered in affective disorder, one in common with schizophrenia, two the same as schizophrenia but increased. cDNA libraries were produced from the mRNA samples and 5 clones present at abnormal levels in schizophrenia identified by differential screening, isolated and sequenced. All the sequences encode mitochondrial transcripts; four encode mitochondrial rRNA and one the amino acid sequence of cytochrome oxidase sub-unit II. Increased cytochrome oxidase transcripts were found in a further set of mRNA extracts from schizophrenic patients including two who had not received neuroleptic medication. The effects of neuroleptic administration as exemplified by α-flupenthixol compared with the ineffective β-flupenthixol were studied in experimental animals. It was found that 13 out of 28 clones whose levels were altered were mitochondrial in origin including rRNA, COX I & II and the NADH-Q reductase. Those encoding respiratory enzymes were at abnormally low levels as a result of α-flupenthixol administration. Measurements of the enzymic activity of cytochrome c oxidase in post-mortem frontal cortex of schizophrenics did not indicate any differences in overall activity but there was a decreased sensitivity to azide that was abolished by neuroleptics. Studies on NADH-cytochrome c reductase showed that schizophrenics whether medicated or not had a reduced rotenone sensitive activity that was compensated for by increased rotenone insensitive activity. We conclude that changes in mitochondrial gene expression are involved in schizophrenia and probably other functional psychoses. [ABSTRACT FROM AUTHOR]

Two groups of 5 patients were given tritium labelled flupenthixol orally or tritium labelled flupenthixol decanoate in oil intramuscularly. The patients were schizophrenics, who had been treated with one of the two drugs for at least 6 months prior to the study. Blood samples were drawn from the patients at different times after administration. From the flupenthixol decanoate group was also drawn a sample of cerebrospinal fluid 11 days after administration. Total radioactivity was measured in serum and cerebrospinal fluid. After oral administration of flupenthixol peak concentrations were seen at 3-8 h after administration. After injection of flupenthixol decanoate the maximum values were found at 11 to 17 days after injection. A plateau with a duration of 2-3 weeks surrounded the maximum. The concentrations in the samples of cerebrospinal fluid were estimated to 29-55% of the corresponding serum values. The study indicates that the depot preparation given with intervals of 2-3 weeks can replace the normal oral flupenthixol treatment. In addition the study support the clinical impression of drug sparing effect seen when changing from oral tablet treatment to injection of the depot preparation. The discrepancies between the present study and the clinical impression of flupenthixol decanoate are discussed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gabapentin and baclofen are recommended for the treatment of chronic refractory cough (CRC). We investigated the efficacy of flupentixol/melitracen in patients unresponsive to these neuromodulators. METHODS: A total of 101 patients with CRC who failed to respond to gabapentin and baclofen were recruited, and treated with flupentixol/melitracen. The prevalence of cough resolution and changes in the Cough Symptom Score (CSS), cough thresholds to capsaicin, Hull Airway Reflux Questionnaire (HARQ), Leicester Cough Questionnaire (LCQ), Generalized Anxiety Disorder-7, Hamilton Anxiety Rating Scale, Patient Health Questionnaire-9, and Hamilton Depression Rating Scale-24 were evaluated after treatment. RESULTS: Ninety-eight patients (97.0%) completed the study. The overall successful cough resolution rate was 62.4% (63/101). Cough resolution was accompanied by an obvious decrease in the CSS and HARQ score and a remarkable increase in cough thresholds to capsaicin challenge and LCQ score, whereas anxiety and depression scores did not change significantly. The prevalence of adverse effects (e.g., insomnia and dizziness) was 21.8%. The prevalence of cough recurrence within 2 weeks after treatment cessation was 17.8%. CONCLUSION: Flupentixol/melitracen may be an efficacious option for CRC unresponsive to other neuromodulators.

• Preadolescent flupenthixol elevated active lever responses and locomotor activity during postadolescence. • Postadolescent flupenthixol suppressed both active lever presses and locomotor activity. • Preadolescent flupenthixol was associated with elevated apomorphine-induced c-Fos labeling in the nucleus accumbens. • Preadolescent dopamine receptor blockade leads to a sensitized postadolescent dopaminergic responses. 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. [ABSTRACT FROM AUTHOR]

• RMTg Tropicamide but not 4-DAMP induces CPP. • RMTg 4-DAMP but not Tropicamide increases locomotion. • RMTg Tropicamide CPP is dopamine-dependent. • Flupenthixol pretreatment reveals RMTg Tropicamide locomotor effects. 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. [ABSTRACT FROM AUTHOR]

Aims: To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose-adjusted serum concentrations in the perphenazine-treated patients., Methods: Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP-genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose-adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses., Results: Mean dose-adjusted serum concentrations of perphenazine (564 samples) were 3.9-fold and 1.6-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .001 and P < .01). For zuclopenthixol (658 samples), mean dose-adjusted serum concentrations were about 1.5-fold and 1.3-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .01 and P < .001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose-adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function)., Conclusions: This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles., (© 2020 British Pharmacological Society.)

Background: Tension-type headache (TTH), also called muscle contraction headache or neurological headache, is mainly characterized by chronic and persistent bilateral headache in the neck and a severe sense of restraint in the head. This study aims to analyze the effect of warming acupuncture and moxibustion at temples combined with Deanxit on tension headache., Methods: A total of 252 patients with anxiety and tension headache were randomly divided into routine group and study group. The study group was treated with Dailixin on the basis of warm acupuncture and moxibustion. The headache score, pericranial muscle tenderness score, therapeutic effect, tension headache attack times and duration, HAMD and HAMA scores were analyzed before and after treatment., Results: The effective cure rate of the study group was significantly higher than that of the routine group. The pericranial muscle tenderness scores of the study group were significantly lower than those of the routine group. Furthermore, the headache degree score, number of attacks, and duration of the study group after treatment were significantly lower than those of the routine group. And the HAMD and HAMA scores in the study group was significantly lower than those in the routine group., Conclusions: The use of warming acupuncture and moxibustion at temples combined with Deanxit in the treatment of tension headache significantly reduces the number and duration of headache attacks and decreases the degree of headache.

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.

Seventy consecutive patients presenting with a clinical diagnosis of chronic muscle contraction headache over a two-year period were evaluated for depression and anxiety scores, along with other possible aetiological factors in this form of headache. Fifty-five of these patients (33 from a hospital neurology clinic and 22 from a local general practice) completed a double-blind study to evaluate flupenthixol 0.5 mg twice daily, diazepam 5 mg twice daily and placebo as prophylactic agents. Patients evaluated in the hospital neurology clinic had more frequent headaches of longer duration, higher analgesic consumption and higher depression, but no higher anxiety scores than those in general practice. Flupenthixol and diazepam were both significantly superior to placebo in reducing headaches and analgesic consumption. The trend was for flupenthixol to be superior to diazepam without reaching statistical significance. Flupenthixol was significantly better than diazepam and placebo in the reduction of Hamilton depression scores. This effect was independent of the effect on headache and analgesic reduction. [ABSTRACT FROM AUTHOR]