Letter to the Editor: Rethinking The Cost Of Antipsychotic Treatment: The Average Cost Of The Drugs Used In Turkey In 2020. / Editöre Mektup: Çildirigideren Ilaç Tedavisinde Maliyeti Yeniden Düsünmek: Türkiye'de Kullanilan Ilaçlarin 2020 Yili Ortalama Tedavi Maliyeti.

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 (Yildiz 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 (Yildiz 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 (Yildiz 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 willconstitute 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 Yildiz1, 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, Ulusahin NA (2018) Mental Health and Disorders. 18th Edit. Ankara: Nobel Tip Kitapevleri. (In Turkish) Republic of Turkey Central Bank Exchange Rates. https://www.tcmb.gov.tr/kurlar/kurlar_tr.html Accession date: 10th January 2021. Yildiz M (2005) The cost of treatment of psychotic disorders. Turk Psikiyatri Derg 16:146-7. (In Turkish) Yildiz 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.

Antiemetics improve the tolerance of polyethylene glycol for colonoscopy preparation: A randomized clinical trial.

BACKGROUND: Bowel preparation is essential to the success of colonoscopy. However, many patients cannot finish the preparation due to nausea and vomiting when taking polyethylene glycol (PEG). Dopamine-2 receptor antagonists, such as domperidone and sulpiride, are classical antiemetic drugs. This study aimed to explore the effect of domperidone and sulpiride on reducing the discomforts associated with PEG. METHODS: Patients scheduled for colonoscopy were enrolled and randomly allocated into 3 groups. Patients in the domperidone group (Dom group) or sulpiride group (Sul group) took 2 doses of domperidone or sulpiride before PEG. Patients in the control group (Con group) followed the regular routine of PEG. Discomforts during bowel preparation and the quality of bowel preparation were assessed. RESULTS: A total of 306 patients were enrolled. The participants in the Dom group and Sul group completed PEG better and had fewer abdominal discomforts than those in the Con group. The severity of nausea and abdominal fullness was lower in the Dom group and Sul group. The quality of bowel preparation was better in the Dom group and Sul group than Con group. CONCLUSIONS: Domperidone and sulpiride could reduce the PEG-related discomfort and improve the quality of bowel preparation. This method may be a promising way to improve the satisfaction of bowel preparation for both patients and endoscopists.

Subjective benign paroxysmal positional vertigo in patients with osteoporosis or migraine / Vertigem posicional paroxística benigna subjetiva em pacientes com osteoporose ou migrânea

Abstract Introduction Subjective benign paroxysmal positional vertigo is a form of benign paroxysmal positional vertigo in which during the diagnostic positional maneuvers patients only present vertigo symptoms with no nystagmus. Objective To study the characteristics of subjects with subjective benign paroxysmal positional vertigo. Methods Prospective multicenter case-control study. All patients presenting with vertigo in the Dix-Hallpike test that presented to the participating hospitals were included. The patients were separated into two groups depending on whether nystagmus was present or not. An Epley Maneuver of the affected side was performed. In the follow-up visit, patients were checked to see if nystagmus and vertigo were present. Both groups of patients were compared to assess the success rate of the Epley maneuver and also to compare the presence of 19 variables. Results 259 patients were recruited, of which 64 belonged to the subjective group. Nystagmus was eliminated in 67.2% of the patients with benign paroxysmal positional vertigo. 89.1% of the patients with subjective benign paroxysmal positional vertigo remained unaffected by nystagmus, thus showing a significant difference (p = 0.001). Osteoporosis and migraine were the variables which reached the closest to the significance level. In those patients who were taking vestibular suppressors, the percentage of subjective benign paroxysmal positional vertigo was not significantly higher. Conclusions Subjective benign paroxysmal positional vertigo should be treated using the Epley maneuver. More studies are needed to establish a relationship between osteoporosis, migraine and subjective benign paroxysmal positional vertigo. The use of vestibular suppressants does not affect the detection of nystagmus.

Resumo Introdução A vertigem posicional paroxística benigna subjetiva é um tipo de vertigem posicional paroxística benigna na qual, durante as manobras posicionais diagnósticas, os pacientes apresentam apenas sintomas vertiginosos sem nistagmo. Objetivo Estudar as características de indivíduos com vertigem posicional paroxística benigna subjetiva. Método Estudo prospectivo multicêntrico de caso-controle. Foram incluídos todos os pacientes com vertigem no teste de Dix-Hallpike, que se apresentaram nos hospitais participantes. Os pacientes foram separados em dois grupos, dependeu da presença ou não do nistagmo. Uma manobra de Epley foi realizada no lado afetado. Na consulta de seguimento, os pacientes foram avaliados para verificar a presença ou não do nistagmo e da vertigem. Ambos os grupos de pacientes foram comparados para avaliar a taxa de sucesso da manobra de Epley e também para comparar a presença de 19 variáveis. Resultados Foram recrutados 259 pacientes, dos quais 64 pertenciam ao grupo subjetivo. O nistagmo foi eliminado em 67,2% dos pacientes com vertigem posicional paroxística benigna. Em 89,1% dos casos, os pacientes com vertigem posicional paroxística benigna subjetiva mantiveram-se não afetados pelo nistagmo, mostraram uma diferença significativa (p = 0,001). Osteoporose e enxaqueca foram as variáveis que atingiram o nível mais próximo ao de significância. Nos pacientes que tomavam supressores vestibulares, a porcentagem de vertigem posicional paroxística benigna subjetiva não foi significativamente maior. Conclusões A vertigem posicional paroxística benigna subjetiva deve ser tratada com a manobra de Epley. Mais estudos são necessários para estabelecer uma relação entre osteoporose, enxaqueca e vertigem posicional paroxística benigna subjetiva. O uso de supressores vestibulares não afeta a detecção do nistagmo.

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer.

Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg-1·d-1) or SUL (25, 50 mg·kg-1·d-1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill's function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.

Prolactin Induces IL-2 Associated TRAIL Expression on Natural Killer Cells from Chronic Hepatitis C Patients In vivo and In vitro.

BACKGROUND: Natural killer cells (NKC) are a major component of the innate immune response to HCV, mediating their effects through TRAIL and IFN-γ. However, their function is diminished in chronic HCV patients (HCVp). Prolactin is an immunomodulatory hormone capable of activating NKC. OBJECTIVE: The study aims to explore if hyperprolactinemia can activate NKC in HCVp. METHODS: We treated twelve chronic HCVp (confidence level =95%, power =80%) for 15 days with Levosulpiride plus Cimetidine to induce mild hyperprolactinemia. Before and after treatment, we determined TRAIL and NKG2D expression on peripheral blood NKC, along with cytokine profiles, viral loads and liver function. We also evaluated in vitro effects of prolactin and/or IL-2 on NKC TRAIL or NKG2D expression and IFN-γ levels on cultured blood mononuclear cells from 8 HCVp and 7 healthy controls. RESULTS: The treatment induced mild hyperprolactinemia and increased TRAIL expression on NKC as well as the secretion of IL-1ra, IL-2, PDGF and IFN-γ. Viral loads decreased in six HCVp. IL-2 and TRAIL together explained the viral load decrease. In vitro, prolactin plus IL-2 synergized to increase TRAIL and NKG2D expression on NKC from HCVp but not in controls. CONCLUSION: Levosulpiride/Cimetidine treatment induced mild hyperprolactinaemia that was associated with NKC activation and Th1-type cytokine profile. Also, an increase in TRAIL and IL-2 was associated with viral load decrease. This treatment could potentially be used to reactivate NKC in HCVp.

Amisulpride in the prevention of nausea and vomiting induced by cisplatin-based chemotherapy: a dose-escalation study.

PURPOSE: The purpose of this study was to investigate the antiemetic effect of the dopamine D2- and dopamine D3-receptor antagonist, amisulpride, in patients receiving cisplatin-based chemotherapy. METHODS: This dose-finding, non-comparative study investigated the antiemetic effect and safety of increasing doses (2.5, 7.5 and 20 mg) of amisulpride against acute nausea and vomiting in the period 0-24 h after initiation of cisplatin-based chemotherapy. The 20 mg dose was also investigated in combination with the 5-HT3-receptor antagonist, ondansetron. The primary parameter was complete response (0-24 h), defined as no emesis and no need for rescue antiemetics. Secondary parameters were number of emetic episodes, severity of nausea and time to first emetic episode and start of nausea. RESULTS: A total of 51 patients were enrolled and evaluable. None of the 10 patients in the 2.5 and 7.5 mg groups obtained a CR. In the 20 mg monotherapy cohort, two of the 18 subjects (11%) had a CR, 3/18 (17%) had no emesis and 12/18 (67%) had no significant nausea. Seven subjects (39%) had no nausea at all (a VAS score < 5 mm). In the combination (ondansetron plus amisulpride) cohort, 19/23 (83%; 90% confidence interval: 65-94%) had a CR and 14/23 (61%) had no nausea at all. CONCLUSIONS: Amisulpride has antiemetic effect against cisplatin-induced acute nausea and vomiting. The effect against nausea is of particular interest. Randomised studies are warranted to further explore the effect and safety of amisulpride.

Comparison of the effectiveness of brand-name and generic antipsychotic drugs for treating patients with schizophrenia in Taiwan.

The purpose of this nationwide population-based study is to compare the long-term effectiveness of brand-name antipsychotics with generic antipsychotics for treating schizophrenia. We identified patients with schizophrenia who were prescribed antipsychotics from a random sample of one million records from Taiwan's National Health Insurance database, observed between January 1, 2000 and December 31, 2012. Only those with no prior use of antipsychotics for at least 180days were included. We selected patients who were prescribed brand-name risperidone (N=404), generic risperidone (N=145), brand-name sulpiride (N=334), or generic sulpiride (N=991). The effectiveness of the treatments researched in this study consisted of average daily doses, rates of treatment discontinuation, augmentation therapy, and psychiatric hospitalization. We found that compared to patients treated with generic risperidone, those treated with brand-name risperidone required lower daily doses (2.14mg vs. 2.61mg). However, the two groups demonstrated similar rates of treatment discontinuation, augmentation, and psychiatric hospitalization. On the other hand, in comparison with patients prescribed generic sulpiride, those treated with brand-name sulpiride not only required lower daily doses (302.72mg vs. 340.71mg) but also had lower psychiatric admission rates (adjusted hazard ratio: 0.24, 95% confidence interval: 0.10-0.56). In conclusion, for both risperidone and sulpiride, higher daily doses of the respective generic drugs were prescribed than with brand-name drugs in clinical settings. Furthermore, the brand-name sulpiride is more effective at preventing patients from hospitalization than generic sulpiride. These findings can serve as an important reference for clinical practices and healthcare economics for treating schizophrenic patients.

Tailored therapy guided by multichannel intraluminal impedance pH monitoring for refractory non-erosive reflux disease.

A relevant percentage of non-erosive reflux disease (NERD) is refractory to proton pump inhibitors (PPIs) treatment. Multichannel intraluminal impedance pH (MII-pH) monitoring should give useful pathophysiological information about refractoriness. Therefore, our aim was to assess whether this technique could be useful to guide a 'tailored' therapy in refractory NERD. We retrospectively recruited NERD patients undergoing MII-pH monitoring for unsuccessful treatment. All patients had undergone upper endoscopy, and those with erosive esophagitis were excluded. No patient received PPI during MII-pH monitoring. Subjects were subgrouped into three categories: acid reflux, non-acid reflux and functional heartburn. MII-pH-guided therapy was performed for 4 weeks as follows: patients with acid reflux received PPI at double dose, patients with non-acid reflux PPI at full dose plus alginate four times a day and patients with functional heartburn levosulpiride 75 mg per day. A visual analog scale (VAS) ranging from 0 to 100 mm was administered before and after such tailored therapy to evaluate overall symptoms. Responders were defined by VAS improvement of at least 40%. Sixty-nine patients with refractory NERD were selected (female-male ratio 43 : 26, mean age 47.6±15.2 years). Overall effectiveness of tailored therapy was 84% without statistical difference among subgroups (88.5% acid reflux, 92% non-acid reflux, 66.6% functional heartburn; P=0.06). Univariate analysis showed that therapy failure directly correlated with functional heartburn diagnosis (OR=4.60) and suggested a trend toward a negative correlation with smoking and a positive one with nausea. However, at multivariate analysis, these parameters were not significant. Functional heartburn experienced a lower median percent VAS reduction than acid reflux (52.5% versus 66.6%, P<0.01) even if equal to non-acid reflux (66.6%). In conclusion, a tailored approach to refractory NERD, guided by MII-pH monitoring, demonstrated to be effective and should be promising to cure symptom persistence after conventional therapy failure. Nevertheless, standardized guidelines are advisable.

Amisulpride Augmentation in Acute Catatonia.

Benzodiazepines are the first-line treatment of catatonia, but a substantial number of patients do not respond to them. Amisulpride is one of the atypical antipsychotic that has been effective for negative symptoms of schizophrenia. We examined the effect of augmentation of oral low doses of amisulpride with lorazepam on resolution of catatonic symptoms. Fifteen patients with catatonia were treated with a combination of oral lorazepam (2-4 mg) with amisulpride (100 mg). Catatonic symptoms were rated using the Bush Francis Catatonia Rating Scale at the baseline and daily thereafter. There was complete resolution of catatonic symptoms on the third day in all patients. There was significant reduction of the total Bush Francis Catatonia Rating Scale score over time (F = 181.38, P < 0.001) with a strong effect size (partial η = 0.96). Augmentation of lorazepam with low-dose amisulpride can be a reliable strategy for management of catatonia.

Intravenous Amisulpride for the Prevention of Postoperative Nausea and Vomiting: Two Concurrent, Randomized, Double-blind, Placebo-controlled Trials.

BACKGROUND: Two essentially identical, randomized, double-blind, placebo-controlled, parallel-group phase III studies evaluated the efficacy of intravenous amisulpride, a dopamine D2/D3 antagonist, in the prevention of postoperative nausea and vomiting in adult surgical patients. METHODS: Adult inpatients undergoing elective surgery during general anesthesia and having at least two of the four Apfel risk factors for postoperative nausea and vomiting were enrolled at 9 U.S. and 10 European sites. A single 5-mg dose of amisulpride or matching placebo was given at induction of anesthesia. The primary endpoint was complete response, defined as no vomiting/retching and no use of antiemetic rescue medication in the 24-h postoperative period. Nausea incidence was a secondary endpoint. RESULTS: Across the two studies, 689 patients were randomized and dosed with study medication, of whom 626 were evaluable per protocol. In the U.S. study, 46.9% (95% CI, 39.0 to 54.9) of patients achieved complete response in the amisulpride group compared to 33.8% (95% CI, 26.2 to 42.0) in the placebo group (P = 0.026). In the European study, complete response rates were 57.4% (95% CI, 49.2 to 65.3) for amisulpride and 46.6% (95% CI, 38.8 to 54.6) for placebo (P = 0.070). Nausea occurred less often in patients who received amisulpride than those who received placebo. There was no clinically significant difference in the safety profile of amisulpride and placebo; in particular, there were no differences in terms of QT prolongation, extrapyramidal side effects, or sedation. CONCLUSIONS: One of the two trials demonstrated superiority, while pooling both in a post hoc change to the plan of analysis supported the hypothesis that amisulpride was safe and superior to placebo in reducing the incidence of postoperative nausea and vomiting in a population of adult inpatients at moderate to high risk of postoperative nausea and vomiting.

[Aripiprazole, gambling disorder and compulsive sexuality]. / Aripiprazole, jeu pathologique et sexualité compulsive.

INTRODUCTION: Aripiprazole, an atypical or second-generation antipsychotic, is usually well tolerated. It is an approved treatment for schizophrenia and mania in bipolar disorder type 1. Unlike the other antipsychotics, it has high affinity agonist properties for dopamine D2 and D3 receptors. It has also 5-HT1A partial agonist and 5-HT2A antagonist properties. Aripiprazole is a first or second line treatment frequently used because it has reduced side effects such as weight gain, sleepiness, dyslipidemia, insulin resistance, hyperprolactinemia and extrapyramidal symptoms. CASE-REPORT: We report the case of a 28-year-old male patient diagnosed with schizoid personality disorder. He was a moderate smoker with occasional social gambling habits. After several psychotic episodes, he was first treated with risperidone, but he experienced excessive sedation, decreased libido, erectile dysfunction and was switched to 15 mg aripiprazole. He developed an addiction habit for gambling at casino slot machines. Due to large gambling debts, he requested placement on a voluntary self-exclusion list. Thereafter, he turned his attention towards scratch card gambling. The patient described his experience of gambling as a "hypnotic state". He got several personal loans to obtain money to continue gambling. He was then referred to an addiction unit. Before being treated with aripiprazole, he was an exclusive heterosexual with a poor sexual activity. Under treatment, he switched to a homosexual behavior with hypersexuality, unprotected sex and sadomasochistic practices. The craving for gambling and compulsive sexual behavior ceased two weeks after aripiprazole was discontinued and he was switched to amisulpride. Thereafter, he reported a return to a heterosexual orientation. DISCUSSION: Compulsive behaviors such as gambling, hypersexuality and new sexual orientation are common in patients with Parkinson's disease treated with dopaminergic agonists. These behaviors involve the reward system, with an enhanced dopaminergic activity in the mesolimbic pathways and occur more frequently in young subjects, males with previous gambling habits and tobacco use. A few cases of aripiprazole-induced pathological gambling as well as aripiprazole-induced hypersexuality have been reported. To our knowledge, we are the first to report a case of gambling disorder associated with hypersexuality and change of sexuality orientation. Aripiprazole is the only antipsychotic with agonist properties for the D2 dopamine receptor. It may also act as an enhancer in the mesolimbic dopaminergic pathways. Aripiprazole also has 5-HT1A partial agonist and 5-HT2A antagonist properties that may promote sexual activity. CONCLUSION: Aripiprazole is an antipsychotic associated with reduced side effects compared to other antipsychotics. We report the case of a patient who experienced gambling disorder, hypersexuality and a new sexual orientation under treatment. These side effects are little known. They are usually difficult for patients to mention due to feelings of guilt. The consequences on social life, family and health may be serious. Clinicians and patients should be aware about the possible issue of these behavior disorders with aripiprazole.

Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade.

BACKGROUND: Psychotic symptoms are core clinical features of schizophrenia. We tested recent hypotheses proposing that psychotic, or positive, symptoms stem from irregularities in long-range white matter tracts projecting into the frontal cortex, and we predicted that selective dopamine D2/3 receptor blockade would restore white matter. METHODS: Between December 2008 and July 2011, antipsychotic-naive patients with first-episode schizophrenia and matched healthy controls underwent baseline examination with 3 T MRI diffusion tensor imaging and clinical assessments. We assessed group differences of fractional anisotropy (FA) using voxelwise tract-based spatial statistics (TBSS) and anatomic region of interest (ROI)-based analyses. Subsequently, patients underwent 6 weeks of antipsychotic monotherapy with amisulpride. We repeated the examinations after 6 weeks. RESULTS: We included 38 patients with first-episode schizophrenia and 38 controls in our analysis, and 28 individuals in each group completed the study. At baseline, whole brain TBSS analyses revealed lower FA in patients in the right anterior thalamic radiation (ATR), right cingulum, right inferior longitudinal fasciculus and right corticospinal tract (CT). Fractional anisotropy in the right ATR correlated with positive symptoms (z = 2.64, p= 0.008). The ROI analyses showed significant associations between positive symptoms and FA of the frontal fasciculi, specifically the right arcuate fasciculus (z = 2.83, p= 0.005) and right superior longitudinal fasciculus (z = -3.31, p= 0.001). At re-examination, all correlations between positive symptoms and frontal fasciculi had resolved. Fractional anisotropy in the ATR increased more in patients than in controls (z = -4.92, p< 0.001). The amisulpride dose correlated positively with FA changes in the right CT (t= 2.52, p= 0.019). LIMITATIONS: Smoking and a previous diagnosis of substance abuse were potential confounders. Long-term effects of amisulpride on white matter were not evaluated. CONCLUSION: Antipsychotic-naive patients with schizophrenia displayed subtle deficits in white matter, and psychotic symptoms appeared specifically associated with frontal fasciculi integrity. Six weeks of amisulpride treatment normalized white matter. Potential remyelinating effects of dopamine D2/3 receptor antagonism warrant further clarification.

Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17ß, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17ß to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Galactocele medicamentosa pós-mamoplastia de aumento: relato de caso e revisão da literatura / Galactocele due to drugs prescribed after augmentation mammoplasty: a case report and literature review

A mamoplastia de aumento é um procedimento cirúrgico muito comum e seguro na cirurgia plástica, mas o mesmo não está isento de complicações. A galactocele após mamoplastia de aumento é raramente descrita na literatura. Este relato de caso refere-se a uma paciente de 34 anos de idade, que fazia uso de sulpirida há 2 anos e 4 meses e desenvolveu galactocele cerca de 100 dias após mamoplastia de aumento. O diagnóstico deve ser suspeitado quando se observar uma mama aumentada de volume, associada a calor local, dor ou desconforto mamário no pós-operatório. Acredita-se que a melhor conduta seja a drenagem cirúrgica, a fim de confirmar o diagnóstico de galactocele e excluir a presença de abscesso mamário.

Augmentation mammaplasty is a common and safe plastic surgery procedure, but it is not free from complications. Galactocele after augmentation mammaplasty is rarely described in the literature. We discuss the case of a 34-year-old woman who had been taking sulpiride for 2 years and 4 months and developed galactocele approximately 100 days after augmentation mammaplasty. However, diagnosis should be suspected if breast size increases and it is associated with postoperative local heat, pain or breast discomfort. We believe that the surgeon must surgically drain galactocele to confirm diagnosis, especially to exclude the presence of breast abscess.

Dopamine D2/3 receptor antagonism reduces activity-based anorexia.

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.

Two Cases of Granulomatous Mastitis Caused by Corynebacterium kroppenstedtii Infection in Nulliparous Young Women with Hyperprolactinemia.

Recently, an association between granulomatous mastitis and local infection with Corynebacterium (C.) kroppenstedtii has been suggested. We herein report two cases of granulomatous mastitis resulting from C. kroppenstedtii infection in nulliparous young women with hyperprolactinemia. Both cases involved nulliparous patients with drug-induced hyperprolactinemia, and both individuals received incision and drainage, after which the pus was sent to our laboratory. Corynebacterium spp. grew on blood agar, and 16S rRNA gene sequencing identified the pathogen as C. kroppenstedtii. In conclusion, lactational changes caused by drug-induced hyperprolactinemia may increase the risk of granulomatous mastitis after C. kroppenstedtii infection.

Reversible Amisulpride-induced Elevation of Creatine Kinase (CK): A Case Series from the German AMSP Pharmacovigilance Project.

The elevation of creatine kinase (CK) levels without neuroleptic malignant syndrome has been reported for several antipsychotics. We present here 4 cases with CK elevation induced by amisulpride, which have been registered for the German pharmacovigilance project, Arzneimittelsicherheit in der Psychiatrie (AMSP). The magnitude of the CK elevation ranged between 1, 498 IU/L and 21,018 IU/L. All 4 patients reported myalgia. In each case CK returned to normal after amisulpride discontinuation. In the fourth case, fluids were administered intravenously in order to prevent acute renal failure. None of the cases showed deterioration of renal function. Finally, we present recommendations for clinical practice.

Evaluation of the pressure ulcers risk scales with critically ill patients: a prospective cohort study / Avaliação das escalas de risco para úlcera por pressão em pacientes críticos: uma coorte prospectiva / Evaluación de las escalas de riesgo para úlcera por presión en pacientes críticos: una cohorte prospectiva

AIMS: to evaluate the accuracy of the Braden and Waterlow risk assessment scales in critically ill inpatients. METHOD: this prospective cohort study, with 55 patients in intensive care units, was performed through evaluation of sociodemographic and clinical variables, through the application of the scales (Braden and Waterlow) upon admission and every 48 hours; and through the evaluation and classification of the ulcers into categories. RESULTS: the pressure ulcer incidence was 30.9%, with the Braden and Waterlow scales presenting high sensitivity (41% and 71%) and low specificity (21% and 47%) respectively in the three evaluations. The cut off scores found in the first, second and third evaluations were 12, 12 and 11 in the Braden scale, and 16, 15 and 14 in the Waterlow scale. CONCLUSION: the Braden scale was shown to be a good screening instrument, and the Waterlow scale proved to have better predictive power. .

OBJETIVOS: avaliar a acurácia das escalas de avaliação de risco de Braden e de Waterlow, em pacientes críticos internados. MÉTODO: trata-se de uma coorte prospectiva, com 55 pacientes nas unidades intensivas, por meio de avaliação de variáveis sociodemográficas e clínicas, de aplicação das escalas (Waterlow e Braden), na admissão e a cada 48 horas, da avaliação e classificação das úlceras em categorias. RESULTADOS: a incidência de úlcera por pressão foi de 30,9%, as escalas de Braden e de Waterlow apresentaram, nas três avaliações, alta sensibilidade (41% e 71 %) e baixa especificidade (21% e 47%), respectivamente. Os escores de coorte encontrados na primeira, segunda e terceira avaliações foram de 12, 12 e 11, na escala de Braden, e de 16, 15 e 14 na escala de Waterlow. CONCLUSÃO: a escala de Braden apresentou-se como bom instrumento de triagem, e a de Waterlow com melhor poder preditivo. .

OBJETIVOS: evaluar la precisión de las escalas de evaluación de riesgo de Braden y de Waterlow en pacientes críticos internados. MÉTODO: se trata de una cohorte prospectiva, con 55 pacientes en las unidades intensivas, por medio de evaluación de variables sociodemográficas y clínicas, de aplicación de las escalas (Waterlow y Braden) en la admisión y a cada 48 horas; de la evaluación y clasificación de las úlceras en categorías. RESULTADOS: la incidencia de úlcera por presión fue de 30,9%, las escalas, de Braden y de Waterlow, presentaron, en las tres evaluaciones, alta sensibilidad (41% y 71 %) y baja especificidad (21% y 47%), respectivamente. Los puntajes de corte encontrados en la primera, en la segunda y en la tercera evaluación fueron de 12, 12 y 11, en la escala de Braden, y de 16, 15 y 14, escala de Waterlow. CONCLUSIÓN: la escala de Braden se presentó como un buen instrumento de detección, y la de Waterlow con mejor poder de predicción. .

Current status of atypical antipsychotics for the treatment of fibromyalgia.

The treatment of fibromyalgia requires pharmacological and nonpharmacological therapies. The pharmacological treatment of fibromyalgia is limited to a few drugs that have been demonstrated to be moderately effective in some but not all dimensions of the disease. Therefore, the search for new drugs to treat this condition is warranted. Atypical antipsychotics offered an attractive alternative because they had been shown to be active against several key symptoms of fibromyalgia. The results of open-label studies, however, appear to indicate that atypical antipsychotics are poorly tolerated in patients with fibromyalgia, and only quetiapine XR has been studied in randomized controlled trials. Quetiapine XR has demonstrated effectiveness in treating comorbid major depression, anxiety and sleep disturbance. However, in two randomized controlled trials, quetiapine XR was not differentiated from placebo and failed to demonstrate noninferiority to amitriptyline in terms of improving overall symptomatology. The effect of quetiapine XR on pain and its usefulness as part of a combination pharmacological regimen should be further evaluated. Overall, the use of quetiapine (initiated at a low dose and slowly titrated) in fibromyalgia should be limited to patients with comorbid major depression or patients who are currently receiving other treatments and have unresolved and disabling depressive and/or anxiety symptoms.