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ImportanceAn increasing number of individuals fill antipsychotic prescriptions during pregnancy, and concerns have been raised about prenatal antipsychotic exposure on neurodevelopmental outcomes.ObjectiveTo examine whether maternal prescription fill for antipsychotics during pregnancy was associated with performance in standardized tests among schoolchildren.Design, Setting, and ParticipantsThis 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.ExposuresAntipsychotic prescriptions filled by pregnant individuals were obtained from the Danish National Prescription Register.Main Outcomes and MeasuresDifferences 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.ResultsOf 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 RelevanceIn 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.

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_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.

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.

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

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.

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.

The purpose of this study was to evaluate the co-prescription efficacy of esomeprazole and flupenthixol/melitracen relative to that of solitary esomeprazole on erosive gastritis complicated with negative feelings. 140 erosive gastritis patients complicated with negative feelings enrolled in the present study. Seventy cases in the control group took esomeprazole, and 70 cases in the observation group received esomeprazole plus flupenthixol/Melitracen, both for 4 weeks. We gastroscopically checked the clinical symptoms, mucosal erosion, PGE2 and MDA levels in gastric mucosa, anxiety, depression, and recurrence before and after treatment in the groups. After treatment, the observation group had lower scores of clinical symptoms, mucosal erosions, Hamilton Depression Rating Scale (HAMD), and Hamilton Depression Rating Scale (HAMA) than the control group (p

This case report highlights the risk of development of Neuroleptic Malignant-Like Syndrome secondary to withdrawal of procyclidine with brief withdrawal of L-dopa and long-term typical antipsychotic depot. The patient responded to reintroduction of procyclidine, sedation and supportive treatment. The mechanism and management of NMS and NMLS is also reviewed. This case emphasises that any changes in antipsychotic and antiparkinsonian medications should be undertaken with extreme caution and patient should be closely monitored for development of NMLS after alteration in these medications.

This study aimed to analyze the use of antidepressants in non-psychiatric departments. The data of patients treated with antidepressants in non-psychiatric departments of the First Affiliated Hospital of Xi 'an Jiaotong University, were collected from 2014 to 2018. The average annual growth rate of antidepressants use was 22.83%. According to the number of patients at discharge, the classification descending order was: SSRIs, Flupenthixol-TCA, SNRIs, TCAs, SARIs, and NaSSA. Sertraline and flupenthixol-melitracen were the main drugs used in SSRIs and Flupenthixol-TCA, respectively. Neurology, Cardiology, and Geriatrics were the main departments prescribing SSRIs, Flupenthixol-TCA and SNRIs. The antidepressants used by all patients were mainly SSRIs according to drug classification, but the specific drug use in unclear diagnosis group was dominated by flupenthixol-melitracen, while it was sertraline in clear diagnosis group. The proportion of Flupenthixol-TCA in anxiety state group was higher than that in depression state group, While the situation in SSRIs is the opposite. More guidelines should be formulated to improve the recognition of comorbidities between specialized diseases and psychiatric disorders. Also, multi-level training should be implemented to perform the standard diagnosis and medication of mental disorders in clinical practice.

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.

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.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.Флупентиксол длительно применяется в России в психиатрической практике, тем не менее встречаются случаи его передозировки и отравления им. В литературе отсутствуют систематические исследования по выявлению флупентиксола при диагностике острых отравлений.Анализ распределения флупентиксола во внутренних органах лабораторных животных при острых отравлениях. Исследования проводили на крысах линии Wistar обоего пола. Пробоподготовку и изолирование флупентиксола из модельных проб и внутренних органов лабораторных животных осуществляли по предложенным нами методикам. Разработали методику обнаружения флупентиксола в извлечениях из внутренних органов лабораторных животных с помощью тонкослойной хроматографии. В качестве подтверждающего метода и для количественного определения флупентиксола в извлечениях использовали высокоэффективную жидкостную хроматографию и метод жидкостной масс-спектрометрии. Во всех масс-спектрах извлечений из внутренних органов присутствовал выраженный молекулярный ион флупентиксола. В масс-спектре извлечения из почек на 30-й минуте обнаружили молекулярный ион метаболита (629,13 m/z), соответствующего глюкурониду флупентиксола. После острого отравления лабораторных животных флупентиксол в максимальном количестве присутствовал в печени, селезенке и мозге, в меньших количествах — в желудке, кишечнике с содержимым и почках.

Lihua Wu,1,2,* Chang Xu,1,2,* Guolan Wu,1,2 Huili Zhou,1,2 Duo Lv,1,2 You Zhai,1,2 Yujie Huang,1,2 Wenling Tang,3 Fangqiong Li,4 Jianzhong Shentu1–3 1Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Clinical Research Department, Haisco Pharmaceutical Group, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianzhong ShentuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236560Fax +86 571 87214223Email stjz@zju.edu.cnPurpose: A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation.Methods: The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs).Results: The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0–t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.Keywords: bioequivalence, melitracen, flupentixol, pharmacokinetics, fixed-dose combination tablet

First-episode psychosis (FEP) patients are more sensitive to neuroleptic side-effects such as hyperprolactinemia. We examined the prolactin levels of previously minimally treated patients with first episode schizophrenia over their first year of treatment with flupenthixol decanoate and the relationship between prolactin levels, gender and clinical features of schizophrenia. Prolactin levels were assessed at three monthly intervals in 126 patients with first-episode schizophrenia in a single-site study conducted over 12 months during treatment with flupenthixol decanoate according to a fixed protocol. The mean prolactin level for the total sample was 11.91 ng/ml (standard deviation [SD]15.52) at baseline. Women had higher levels of prolactin than men at month 3, 6 and 12, reaching statistical significance at month 12 (p = 0.02). At 12 months more women than men had hyperprolactinemia (defined as more than 20 ng/ml for males, and as more than 25 ng/ml for females (p = 0.007). Using a mixed effect model, there was a significant association between prolactin change scores over 12 months and gender (p = 0.025) as well as Positive and Negative Syndrome Scale (PANSS) total scores (p = 0.001). In addition female gender (p = 0.04) and age (p = 0.02) correlated with the risk of hyperprolactinemia as categorical variable. In this study treatment with flupenthixol decanoate was associated with relatively low levels of hyperprolactinemia, likely owing to flupenthixol's relatively atypical mode of action, as well as to the low doses used in our study. We found an inverse correlation between total PANSS scores and prolactin levels, which could support the suggested theory of prolactin having antipsychotic properties. Our study confirms the importance of gender on the prolactin raising effects of antipsychotic treatment.

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

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is hyperactivated in lung cancer and regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. Thus PI3K is considered a promising target for therapy. To date, PI3K inhibitors have not been approved for lung cancer. Recent studies showed that the antipsychotic agent flupentixol induced apoptosis of lung cancer cell, however the anti-tumor mechanism of flupentixol remains unclear. Methods: (1) The idock software simulated the molecular docking between the PI3Kα protein and flupentixol. (2) Inhibition of PI3Kα by the flupentixol was examined by in vitro kinase assays. (3) The cytotoxicity of flupentixol on the NSCLC cell lines was tested by MTT assays. (4) We treated A549 and H661 cells with flupentixol and then measured the percentage of apoptotic cells by the Annexin V/PI analysis. (5) We investigated the effect of flupentixol on the expression of critical PI3K/AKT signaling pathway proteins, further analyzed on the cleavage of PARP and caspase-3 by Western blotting. (6) BALB/C nude mice were subcutaneously injected with A549 cells to evaluate the effect of flupentixol on the growth of lung carcinoma. Results: Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3Kα. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kα kinase activity. Flupentixol exhibited cytotoxicity in lung cancer cell lines A549 and H661 in a dose- and time-dependent manner. Furthermore, flupentixol more strongly inhibited the phosphorylation of AKT (T308 and S473) and the expression of its downstream target gene Bcl-2 than two known PI3K inhibitors (BYL719 and BKM120). Flupentixol induced apoptosis as measured by PARP and caspase-3 cleavage. Finally, flupentixol significantly suppressed A549 xenograft growth in BALB/C nude mice. Conclusions: Flupentixol could be docked to the PI3Kα protein and specifically inhibit the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. As an old drug, flupentixol is a new PI3K inhibitor that may be used for the treatment of lung cancers.

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.

While insight in schizophrenia improves with treatment, significant impairments often persist. The degree of persistence is not well characterised.We assessed patient and clinician-rated changes in insight in acutely ill, minimally treated first-episode schizophrenia spectrum disorder patients over 24 months of standardised treatment with a depot antipsychotic.This single arm open label longitudinal cohort study included 105 participants with first-episode schizophrenia, schizophreniform or schizoaffective disorder. Insight was assessed at months 0, 6, 12 and 24 using the patient-rated Birchwood Insight Scale (BIS) and clinician-rated global insight item of the Positive and Negative Syndrome Scale (PANSS). Changes in insight over time were assessed using linear mixed-effect models for continuous repeated measures. Relationships between insight and psychopathology, functionality, cognition and quality of life were assessed with regression models.There was significant improvement over time for the PANSS insight item (p 0.0001). However, the only significant improvement for the BIS was with the Need for Treatment subscale (p = 0.01). There were no significant improvements noted for the Symptom Attribution (p = 0.7) and Illness Awareness (p = 0.2) subscales, as well as the BIS Total score (p = 0.6). Apart from depressive symptoms at baseline, there were no significant predictors of patient-rated insight.Clinicians should note that, even when treatment is assured and response is favourable, fundamental impairments in patient-rated insight persist.