[Therapeutic drug monitoring of antipsychotic drugs in routine psychiatric practice]. / Terapevticheskii lekarstvennyi monitoring antipsikhoticheskikh preparatov v povsednevnoi psikhiatricheskoi praktike.

OBJECTIVE: To evaluate the relationship between daily doses of antipsychotic drugs, their serum concentrations, and characteristics of patients treated for schizophrenia or schizophreniform disorder in day-to-day clinical practice. MATERIAL AND METHODS: A total of 187 patients were included in the study, 77 (41.1%) patients were on monotherapy, and 110 (58.9%) patients received two or more antipsychotics. Patients age was 27.8±8.1 years, and their body weight was 79.8±15.6 kg. The sample was represented mainly by young men (93.0%). The proportion of smokers was 37.4%. The appropriate HPLC-MS/MS method was used for the simultaneous analysis of 8 antipsychotics and its active metabolites. Serum concentrations of the drugs aripiprazole (ARI), chlorpromazine (CPZ), haloperidol (HAL), zuclopenthixol (ZUC), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), norclozapine (N-desmethylclozapine, NOR), 9-hydroxyrisperidone (9-OH-RIS), dehydroaripiprazole (DGA) were measured. The serum concentration/dose ratio (C/D) was employed as the primary outcome measure, as doses were not kept constant during the study. The active antipsychotic fraction (drug+active metabolite, active moiety - AM) was also evaluated for RIS and ARI. In addition, the metabolite/parent ratio (MPR) was evaluated for RIS and ARI. RESULTS: A total of 265 biological samples were obtained, 421 and 203 measurements of the concentration of drugs and their metabolites were carried out, respectively. Overall, 48% of antipsychotics levels were in the expected therapeutic ranges, 30% were below therapeutic ranges, and 22% were above them. A total of 55 patients underwent dose adjustments or drug changes due to ineffectiveness or side-effects. It has been found that smoking reduces the level of C/D for CLO (p<0.01, Mann-Whitney test). We have established that comedication with CLO significantly increases the C/D ratio of QUE (p<0.05, Mann-Whitney test). We have not revealed any influence of weight and age of the subjects on the C/D. The dose-concentration regression relationships are formalized for all AP. CONCLUSION: Therapeutical drug monitoring (TDM) is an essential tool to personalize antipsychotic therapy. Careful analysis of TDM data can contribute significantly to the study of the impact of individual patient characteristics on systemic exposure to these drugs.

Predicting psychotic relapse following randomised discontinuation of paliperidone in individuals with schizophrenia or schizoaffective disorder: an individual participant data analysis.

BACKGROUND: Predicting relapse for individuals with psychotic disorders is not well established, especially after discontinuation of antipsychotic treatment. We aimed to identify general prognostic factors of relapse for all participants (irrespective of treatment continuation or discontinuation) and specific predictors of relapse for treatment discontinuation, using machine learning. METHODS: For this individual participant data analysis, we searched the Yale University Open Data Access Project's database for placebo-controlled, randomised antipsychotic discontinuation trials with participants with schizophrenia or schizoaffective disorder (aged ≥18 years). We included studies in which participants were treated with any antipsychotic study drug and randomly assigned to continue the same antipsychotic drug or to discontinue it and receive placebo. We assessed 36 prespecified baseline variables at randomisation to predict time to relapse, using univariate and multivariate proportional hazard regression models (including multivariate treatment group by variable interactions) with machine learning to categorise the variables as general prognostic factors of relapse, specific predictors of relapse, or both. FINDINGS: We identified 414 trials, of which five trials with 700 participants (304 [43%] women and 396 [57%] men) were eligible for the continuation group and 692 participants (292 [42%] women and 400 [58%] men) were eligible for the discontinuation group (median age 37 [IQR 28-47] years for continuation group and 38 [28-47] years for discontinuation group). Out of the 36 baseline variables, general prognostic factors of increased risk of relapse for all participants were drug-positive urine; paranoid, disorganised, and undifferentiated types of schizophrenia (lower risk for schizoaffective disorder); psychiatric and neurological adverse events; higher severity of akathisia (ie, difficulty or inability to sit still); antipsychotic discontinuation; lower social performance; younger age; lower glomerular filtration rate; benzodiazepine comedication (lower risk for anti-epileptic comedication). Out of the 36 baseline variables, predictors of increased risk specifically after antipsychotic discontinuation were increased prolactin concentration, higher number of hospitalisations, and smoking. Both prognostic factors and predictors with increased risk after discontinuation were oral antipsychotic treatment (lower risk for long-acting injectables), higher last dosage of the antipsychotic study drug, shorter duration of antipsychotic treatment, and higher score on the Clinical Global Impression (CGI) severity scale The predictive performance (concordance index) for participants who were not used to train the model was 0·707 (chance level is 0·5). INTERPRETATION: Routinely available general prognostic factors of psychotic relapse and predictors specific for treatment discontinuation could be used to support personalised treatment. Abrupt discontinuation of higher dosages of oral antipsychotics, especially for individuals with recurring hospitalisations, higher scores on the CGI severity scale, and increased prolactin concentrations, should be avoided to reduce the risk of relapse. FUNDING: German Research Foundation and Berlin Institute of Health.

Paliperidone alleviates MK-801-induced damage to prefrontal cortical neurons via the PP2A/PTEN pathway.

BACKGROUND: The putative mechanisms underlying the efficacy of the US Food and Drug Administration-approved antipsychotic drug paliperidone for the treatment of schizophrenia deserve additional investigation, which is the aim of the present animal study. METHODS: The behavioral activities of mice were recorded in the open field test and light-dark box test. The effects of paliperidone on MK-801-induced neuronal damage in the prefrontal cortex were tested by flow cytometry, TUNEL staining assays, and ROS staining assays. The neuroprotective effects of paliperidone on neural dendrites and synapses were evaluated using Golgi staining and Sholl analysis. An adenovirus vector containing a Ca2+ indicator was used to monitor the calcium ion concentration in the prefrontal cortex. The expression levels of protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN) were investigated using Western blotting. RESULTS: The data showed that MK-801 caused stereotyped behavior in mice and induced synaptic damage and dendritic spine impairment compared with the control, whereas paliperidone ameliorated these changes. Moreover, paliperidone reversed MK-801-induced decreases in PP2A and PTEN levels in prefrontal cortical neurons. Furthermore, in primary cultured cortical neurons and HT-22 cells, paliperidone inhibited cell apoptosis caused by MK-801. In particular, pretreatment with the PP2A inhibitor LB-100 significantly restrained the protective effects of paliperidone on MK-801-treated neurons and on locomotor activity and stereotypical behavior of mice. LIMITATIONS: Whether other proteins are involved in this pathway and how the pathway works have not been revealed. CONCLUSION: Our data show that paliperidone alleviates neuronal damage induced by MK-801 via the PP2A/PTEN pathway.

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 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 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.

Eosinophilic Pleural Effusion Induced by Paliperidone Palmitate: Case Report and Literature Review.

BACKGROUND: Eosinophilic pleural effusions are defined by an eosinophil count ≥ 10% in pleural fluid and represent approximately 10% of exudative pleural effusions. They are associated with a large spectrum of etiologies, both benign and malignant. Drug-induced eosinophilic pleural effusions remain rarely described. OBJECTIVE AND METHODS: After ruling out other causes with a careful diagnostic assessment, we retain paliperidone as the etiology, given the disappearance of the pleural effusion after drug discontinuation. RESULTS: We report the first case of eosinophilic pleural effusion induced by paliperidone palmitate treatment. CONCLUSION: After considering other etiologies, drug-induced eosinophilic pleural effusion should be sought.

Precision psychiatry: The complexity of personalizing antipsychotic dosing.

Recently, Salagre and Vieta commented on the complexity of implementing precision medicine in psychiatry. For 25 years, this author has focused on a circumscribed type of precision medicine: personalized dosing using pharmacokinetic mechanisms to stratified patients. This short communication focuses on personalized dosing of three oral antipsychotics (clozapine, risperidone and paliperidone) and presents their maintenance dosing in a table which provides dose-correction factors generated by pharmacokinetic studies. Inhibitors need dose-correction factors < 1 and inducers need correction factors >1. Clozapine maintenance dosing is based on the dose needed to reach 350 ng/ml (the minimum plasma therapeutic concentration in treatment-resistant schizophrenia). Clozapine maintenance dosing is influenced by 3 levels of complexity: 1) ancestry groups (Asians/Native Americans; Europeans and Blacks), 2) sex-smoking subgroups (lowest dose in female non-smokers and highest in male smokers) and 3) presence/absence of poor metabolizer status (due to genetic and non-genetic causes including co-prescription of inhibitors, obesity or inflammation). Risperidone and paliperidone maintenance dosing are based on the dose needed to reach plasma concentrations of 20-60 ng/ml. Risperidone PMs need approximately half the dose, which can be explained by genetics (CYP2D6 PMs) or co-prescription of CYP2D6 inhibitors. Fluoxetine co-prescription may require one fourth the risperidone maintenance dose. Carbamazepine co-prescription may require twice the risperidone maintenance dose. Although not well studied, two groups may need higher doses of oral paliperidone: Koreans may need 1.5 times higher doses while those taking carbamazepine may need 3 times higher paliperidone maintenance doses. Precision dosing in psychiatry requires using blood levels of individuals.

Effects of body weight, smoking status, and sex on plasma concentrations of once-monthly paliperidone palmitate.

OBJECTIVES: Knowledge about the impact of body composition features on pharmacokinetics of newer long-acting injectable antipsychotics is limited. METHODS: We analyzed steady-state plasma concentrations of paliperidone in different body mass index (BMI), age, sex, and smoking status patient subgroups treated with once-monthly paliperidone palmitate (PP1M). Paliperidone plasma concentrations and dose-adjusted-plasma concentrations (C/D) from a therapeutic drug monitoring (TDM) database of PP1M-treated patients were compared among normal BMI, overweight, and obese patients as well as between females vs. males, elderly vs. non-elderly, and smokers vs. non-smokers using non-parametric tests. RESULTS: In a total of 183 PP1M-treated patients, we found highly variable paliperidone plasma concentrations between individuals but no significant effect of PP1M dose or dosing intervals (p> 0.05). C/D ratios were similar in 54 obese, 82 overweight, and 47 normal BMI patients (p> 0.05). Females had 13.7% higher C/D ratios compared to males, yet this difference was not significant (p> 0.05). No differences were found between elderly vs. non-elderly patients or for smokers vs. non-smokers (p> 0.05). CONCLUSION: Our findings suggest that age, sex, smoking, or body weight may not substantially affect pharmacokinetic indices of PP1M. The high interindividual variation of plasma concentrations implies that TDM may be helpful to enhance PP1M efficacy and tolerability.

Protocolo Clínico e Diretrizes Terapêuticas (PCDT) complementares de esquizofrenia no Estado de Goiás - versão 2022 / Clinical protocol and complementary therapeutic guidelines (PCDT) for schizophrenia in the State of Goiás - version 2022

Protocolo estadual que complementa o PCDT do Ministério da Saúde e ambos devem ser considerados como referência diagnóstica e terapêutica pelos profissionais de saúde, em Goiás, para o tratamento de pessoas com o transtorno de esquizofrenia. A esquizofrenia é um transtorno mental grave que ocorre em cerca de 1% da população, independente de nível sociocultural. É caracterizada por períodos de intensas distorções do pensamento e da percepção (surtos) e pela inadequação e embotamento do afeto. Ao longo do tempo, pode aparecer prejuízos cognitivos em uma parcela significativa dos pacientes , principalmente os que não seguem tratamento regular

State protocol that complements the Ministry of Health's PCDT and both should be considered as a diagnostic and therapeutic reference by health professionals in Goiás for the treatment of people with schizophrenia disorder. Schizophrenia is a serious mental disorder that occurs in around 1% of the population, regardless of sociocultural level. It is characterized by periods of intense distortions of thought and perception (outbreaks) and by inadequacy and blunting of affect. Over time, cognitive impairment may appear in a significant portion of patients, especially those who do not follow regular treatment

Pica y traumatismo craneoencefálico en un paciente adolescente: recuperación <> con paliperidona / Pica and traumatic brain injury in an adolescent: complete improvement with paliperidone

Presentamos el caso clínico de un adolescente varón de 15 años derivado a Psiquiatría Infanto-Juvenil por realizar ingestas repetitivas de sustancias no nutritivas como gomas de borrar, escamas psoriásicas o incluso pintura de la pared. Entre sus antecedentes somáticos de interés, conviene destacar la Enfermedad de Kawasaki y psoriasis, además de haber sufrido un traumatismo craneoencefálico (TCE) tras lo cual presentó una exacerbación del cuadro. Tras el fracaso en el manejo conductual realizado por parte de su madre y teniendo en cuenta sus rasgos de personalidad caracterizados por una elevada suspicacia y desconfianza hacia los demás, se decide iniciar tratamiento con paliperidona oral produciéndose una rotunda mejoría clínica. Durante todo el seguimiento posterior hasta su mayoría de edad, se ha mantenido la desaparición de la pica. Presentamos el primer caso clínico publicado en la bibliografía actual de un adolescente con el diagnóstico de pica y un TCE previo y una adecuada respuesta a paliperidon

We present a case report of a 15-year-old male adolescent who was referred to our consultation of Children and Adolescent Psychiatry due to persistent eating of non-nutritive substances like rubber, psoriatic scale or wall paint. The patient had the previous diagnostic of Kawasaki Disease and psoriasis. In addition, he had suffered a traumatic brain injury, after which he presented an exacerbation of the clinic. After behaviour therapy failure realized by his mother and taking into account his personality features with high suspicion and distrust of others, he was prescribed paliperidone oral treatment and pica disappeared. During all subsequent follow-up until the age of majority, the disappearance of pica has been maintained. We describe the first case report in the current bibliography of an adolescent with the diagnosis of pica, a previous traumatic brain injury and a good response to oral paliperidone.

Factors predicting relapse and treatment discontinuation with paliperidone 3-monthly long-acting injection: A 2-year naturalistic follow-up study.

BACKGROUND: Paliperidone 3-monthly (PP3M) long-acting injection has proven efficacy and effectiveness in schizophrenia. Little is known of its effectiveness in other diagnoses. METHODS: All patients starting PP3M were followed up for 2 years. Main outcome measures were relapse and discontinuation from PP3M. Post hoc we examined outcomes in those switched back to one monthly paliperidone (PP1M) long-acting injection. RESULTS: Overall, 186 patients were followed-up. At the 2-year end point, 110 patients (59%) were still receiving PP3M, and 129 (70%) were receiving some form of paliperidone long-acting injection. Discontinuation from paliperidone long-acting injections (PPLAIs) was more likely with a nonschizophrenia diagnosis (hazard ratio [HR] for continuation 0.429 [95% confidence intervals (CI) - 0.21, 0.87 p = 0.018)), and prior clozapine use [in PP3M patients; HR for discontinuation 1.87 [95% CI - 1.05, 3.30 p = 0.032]). Relapse occurred in 20 (11%) of those receiving PP3M. Relapse on PP3M and PPLAIs was more likely in nonschizophrenia diagnosis (HR 0.17 for remaining relapse-free [95% CI - 0.06, 0.50; p = 0.001]; HR 0.21 [95% CI - 0.08, 0.58 p = 0.002], respectively), polypharmacy in PP3M patients (HR for relapse 7.91 [95% CI - 3.73, 22.9; p < 0.001]) and PPLAI patients (HR for relapse 6.45 [95% CI - 2.49, 16.5; p < 0.001]), and prior clozapine use in PP3M patients (HR for relapse 6.11 [95% CI - 1.82, 20.5; p = 0.003]) and PPLAI patients (HR for relapse 4.52 (95% CI - 1.51, 13.5; p = 0.007). CONCLUSIONS: Outcomes with PP3M are excellent in practice, even when used outside its formal license. PP3M was relatively more effective in those with an F20 schizophrenia diagnosis and in those never before considered for or prescribed clozapine.

Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports.

BACKGROUND: Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries). METHODS: We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556. RESULTS: Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference - 5.83, 95% CI - 10.79 to - 0.87, I2 = 8.5%, n = 4 studies, 1131 participants), Paliperidone (- 6.01, 95% CI - 8.7 to - 3.32, I2 = 4.3%, n = 13, 3821) and Paliperidone palmitate (- 7.89, 95% CI - 12.1 to - 3.69, I2 = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity. CONCLUSION: IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.

Patterns and Predictors of Oral Anticancer Agent Use in Diverse Patients With Metastatic Renal Cell Carcinoma.

PURPOSE: Availability of targeted oral anticancer agents (OAAs) has transformed care for patients with metastatic renal cell carcinoma (mRCC). Our objective was to identify patterns and predictors of OAA use within 12 months after mRCC was detected to understand real-world adoption of OAAs. METHODS: We used a novel, North Carolina cancer registry-linked multipayer claims data resource to examine patterns of use of five oral therapies among patients with mRCC diagnosed in 2006-2015, with claims through 2016. Patients were required to have 12 months of continuous enrollment before metastatic index date. Log-Poisson models estimated unadjusted and adjusted risk ratios (RRs) for associations between patient characteristics and OAA use. In sensitivity analyses, we used a competing risk framework to estimate adjusted risk differences in OAA use. RESULTS: Our population-based study of 713 patients demonstrated low (37%) OAA use during the first year after metastatic index date among both publicly and privately insured patients, with shifting patterns of use consistent with regulatory approvals over time. Compared with patients age 18-49 years, patients age 70-74 years were half likely to use OAAs (95% confidence limit [CL], 0.34 to 0.78) and patients age 80+ years were 71% less likely to use OAAs (95% CL, 0.17 to 0.50). Patients with two comorbidities (RR, 0.73; 95% CL, 0.55 to 0.98) and those with 3+ comorbidities (RR, 0.68; 95% CL, 0.50 to 0.91) were less likely to receive OAA than those without comorbidities. Patients with higher frailty also had lower OAA utilization (RR, 0.67; 95% CL, 0.52 to 0.85). CONCLUSION: These findings suggest a need to better understand the system-level and provider-level drivers of OAA underuse, as well as OAA adherence and associated survival.

Pharmacokinetic Correlates of Once-Monthly Paliperidone Palmitate-Related Adverse Drug Reactions.

OBJECTIVE: The objective of this study was to investigate associations between pharmacokinetic correlates and once-monthly paliperidone palmitate (PP1M)-related adverse drug reactions (ADRs). METHODS: Plasma concentrations and dose-adjusted plasma concentrations ('concentration-by-dose' [C/D]) of paliperidone from a naturalistic therapeutic drug monitoring database of PP1M-treated patients were compared between patients with ADRs, classified according to the Udvalg for Kliniske Undersogelser side-effect rating scales categories, and patients without ADRs. Analyses included non-parametric tests and a logistic regression model with a significance level set at 0.05. RESULTS: In 172 patients, we found no differences in sex, age, smoking, body mass index, PP1M dose, paliperidone plasma concentrations, and C/D values (p > 0.05) between 44 patients with and 128 patients without PP1M-related ADRs. We did not detect differences when specifying for different types of ADRs (p > 0.05). Injection intervals were shorter in patients with vs patients without ADRs (p = 0.03). The logistic regression did not report effects for sex, plasma concentrations, or C/D values (p > 0.05). Post hoc analyses in male patients receiving PP1M every 28 weeks reported higher paliperidone concentrations and C/D values in patients with vs without ADRs (p = 0.049 and p = 0.022). Within the group of male patients, we found an odds ratio of 3.07 for PP1M-associated ADRs in patients with C/D values above 7.7 (ng/mL)/(mg/day). CONCLUSIONS: Our findings did not reveal distinct patterns of paliperidone concentrations in patients with PP1M-related ADRs. However, male patients receiving PP1M every 28 days with C/D values higher than 7.7 (ng/mL)/(mg/day) showed a higher risk for ADRs, implying that therapeutic drug monitoring may be useful in assessing the risk of PP1M-related ADRs.

Hepatitis C virus and hepatitis B virus in patients with schizophrenia.

ABSTRACT: This study evaluated the severe hepatic outcome (SHO) in patients with schizophrenia and viral hepatitis who received antipsychotics.Using the nationwide Taiwan National Health Insurance Research Database, patients first diagnosed with schizophrenia between 2002 and 2013 were identified. Patients diagnosed with schizophrenia who had viral hepatitis, including hepatitis B virus (HBV) or hepatitis C virus (HCV), were designated as the viral hepatitis group. A control group without viral hepatitis was matched for age, sex, and index year in a 2:1 ratio. Patients with severe hepatic outcomes before enrollment were excluded. The 2 cohorts were observed until December 31, 2013. The primary endpoint was occurrence of a SHO, including liver cancer, liver failure, liver decompensation, or transplantation.Among the 16,365 patients newly diagnosed with schizophrenia between January 2002 and December 2013, we identified 614 patients with viral hepatitis and 1228 matched patients without viral hepatitis. Of these 1842 patients, 41 (2.22%) developed SHOs, including 26 (4.23%) in the viral hepatitis group and 15 (1.22%) in the control group, during the mean follow-up period of 3.71 ±â€Š2.49 years. Cox proportional hazard analysis indicated that the SHO risk increased by 3.58 (95% confidence interval [CI]: 1.859-6.754; P < .001) in patients with schizophrenia and viral hepatitis. Moreover, patients with schizophrenia having HCV had a higher SHO risk than those without viral hepatitis (hazard ratio: 5.07, 95% CI: 1.612-15.956; P < .0001). Patients having both schizophrenia and viral hepatitis, especially HCV, had a higher risk of SHOs.

Lack of Smoking Effects on Pharmacokinetics of Oral Paliperidone-analysis of a Naturalistic Therapeutic Drug Monitoring Sample.

INTRODUCTION: Major smoking effects have been reported for a series of psychotropic agents, mainly including substrates of CYP450 1A2, although smoking may also affect alternative metabolic pathways. To our knowledge, smoking effects on paliperidone pharmacokinetics have not been assessed yet. METHODS: We compared plasma concentrations of paliperidone as well as dose-corrected-plasma concentrations (C/D) from a naturalistic database between smokers and nonsmokers using nonparametrical tests, such as the Mann-Whitney U-test (MWU). Additionally, we compared light and heavy smokers with nonsmokers separately. RESULTS: Comparing 55 smokers with 37 nonsmokers treated with oral paliperidone, no differences in the percentage of females, age, body weight, body mass index, and daily paliperidone dose were reported (p=0.709 for χ2, p=0.26, p=0.38, p=0.67, and p=0.8 for MWU). No differences were detected in plasma concentrations or C/D values (p=0.50 and p=0.96 for MWU). Likewise, differences in daily dose, plasma concentrations, or C/D values were not significant between light smokers (n=17) and nonsmokers (p=0.61, p=0.81, and p=0.33 for MWU) or heavy smokers (n=22) and nonsmokers (p=0.874, p=0.38, and p=0.59; MWU in all cases). DISCUSSION: Paliperidone is not affected by smoking, and paliperidone dose-adjustments in smokers may not be necessary. This may be seen as an essential difference to risperidone, whose cytochrome-mediated metabolism might be affected by smoking.

High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers / Dos pacientes que tomaban inductores necesitaron dosis altas de medicamentos metabolizados en gran medida por el CYP3A4 para alcanzar concentraciones terapéuticas

ABSTRACT Introduction: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations. Methods: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4. Results: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000 mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction. Conclusions: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.

RESUMEN Introducción: Durante sus últimos 20 años de práctica, el último autor ha identificado estos 2 infrecuentes casos que necesitaban dosis extremadamente altas de medicaciones metabolizadas por el CYP3A4 para alcanzar y mantener concentraciones séricas terapéuticas. Métodos: La gran capacidad metabólica de estos 2 pacientes se demostró por los bajos cocientes entre concentración y dosis (C/D) de varias medicaciones metabolizadas por el CYP3A4. Resultados: El caso 1 se caracterizaba por una historia de altas dosis de carbamazepina (1.500 mg/día) y la necesidad de tomar 170 mg de diazepam en 2 días para facilitar una limpieza dental. La gran actividad de la isoenzima CYP3A4 se manifestó por una gran capacidad metabólica de quetiapina y diazepam, cuya normalización tardó más de 1 año tras la toma de un inductor, fenitoína. El caso 2 tambien era muy sensible a la inducción, lo cual se demuestra por los bajos cocientes C/D de carbamazepina, risperidona y paliperidona. Las dosis de carbamazepina (2.800 mg/día) y risperidona (20 mg/día) de este segundo paciente son las más altas nunca vistas por el último autor. La inducción de risperidona duró muchos meses y su metabolismo era normal 3 años después de interrumpir la carbamazepina. El cociente C/D de olanzapina era normal para la inducción. Conclusiones: Nunca se habían descrito casos similares de dosis tan altas de medicaciones metabolizadas por el CYP3A4. Se especula con que estos pacientes podrían tener unos perfiles genéticos inusuales en los receptores nucleares que regulan la inducción de medicamentos.

Projecting the Long-Term Economic Impact of Once-Monthly Paliperidone Palmitate Versus Oral Atypical Antipsychotics in Medicaid Patients with Schizophrenia.

BACKGROUND: Recent evidence has demonstrated that, over 12 months, pharmacy costs associated with switching nonadherent recently relapsed patients from oral atypical antipsychotics (OAAs) to once-monthly paliperidone palmitate (PP1M) were offset by reduced relapse rates and schizophrenia-related health care costs. In addition, earlier use of PP1M may generate greater cost savings. OBJECTIVE: To project the long-term economic impact when a proportion of nonadherent patients with a recent relapse switch from OAAs to PP1M. METHODS: A 36-month decision-tree model with twelve 3-month cycles was developed from a Medicaid payer's perspective. The target population was nonadherent, recently relapsed OAA patients. At equal adherence, probability of relapse was equal between PP1M and OAAs, and OAA patients were nonadherent until treatment switch. Event rates (adherence, relapse, and switch) and cost inputs (pharmacy and relapse) were based on the literature, and rates remained constant. Outcomes included number of relapses, pharmacy costs, and relapse costs (2017 U.S. dollars) at years 1, 2, and 3. One-way sensitivity (OSA) and probabilistic sensitivity analyses (PSA) evaluated the effect of varying model inputs on health plan and per-patient level costs. RESULTS: Based on a hypothetical health plan of 1 million members, 3,037 OAA patients were recently relapsed and nonadherent. Compared with continuing OAAs, switching 5% of patients (n = 152) to PP1M resulted in net cost savings of $674,975, $723,298, and $562,310 at the plan level; $4,445, $4,764, and $3,703 per patient switched per year; and $0.0562, $0.0603, and $0.0469 per member per month in years 1, 2, and 3, respectively, resulting in total plan-level savings of > $1.9 million over 3 years. A total of 221 relapses were avoided (year 1: 92; year 2: 72; and year 3: 57). In years 1, 2, and 3, respectively, total annual plan-level schizophrenia-related costs were $114.1 million, $107.2 million, and $105.8 million when all patients switched to PP1M before any subsequent relapse (n = 3,037); $123.4 million, $109.6 million, and $106.7 million when patients switched to PP1M after a first subsequent relapse (n = 2,631); and $127.6 million, $121.6 million, and $117.0 million when all patients remained on OAAs. The cost per patient switched to PP1M was lower when all patients received PP1M before a subsequent relapse versus after their first subsequent relapse at all years (year 1: $37,559 vs. $45,089; year 2: $35,288 vs. $36,321; and year 3: $34,826 vs. $35,155). OSA demonstrated consistent net cost savings per patient switched, ranging from $640 to $10,484 (year 1); $1,774 to $9,245 (year 2); and $1,354 to $7,026 (year 3). PSA demonstrated 96.3%, 99.7%, and 99.7% of iterations were cost saving in years 1, 2 and 3, respectively. CONCLUSIONS: Pharmacy costs associated with switching nonadherent OAA patients with a recent relapse to PP1M were offset by reduced relapse rates and health care costs at years 1, 2, and 3, with earlier use of PP1M resulting in increased cost savings at all years. DISCLOSURES: This research was funded by Janssen Scientific Affairs. Pilon, Morrison, Lefebvre, and Shak are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs to conduct this study. El Khoury and Kim are employees of Janssen Scientific Affairs. At the time this study was conducted, Llaneza was an employee of HireGenics, which provided services to Janssen Scientific Affairs for the study. Part of the material in this manuscript was presented at the Academy of Managed Care Pharmacy 2019 Annual Meeting; March 25-29, 2019; San Diego, CA.

Switching from clozapine to paliperidone palmitate-3-monthly improved obesity, hyperglycemia and dyslipidemia lowering antipsychotic dose equivalents in a treatment-resistant schizophrenia cohort.

Clozapine, an antipsychotic developed in 1958, is considered the gold standard and the treatment of choice in treatment-resistant schizophrenia despite its side effects and despite 40-70% of these patients not responding to clozapine. In the last decade, new antipsychotics, such as paliperidone palmitate (PP), have emerged as well as its long acting-injectable (LAI) formulations, available as PP-1-monthly (PP1M) and the newest PP-3-montlhy (PP3M). Despite paliperidone having shown a similar efficacy as others antipsychotics for the treatment of schizophrenia, and that PP3M has been shown to reduce relapses compared to oral formulations, no study has been carried out in treatment-resistant schizophrenia. The aim of our study was to carry out an exploratory evaluation of endocrine and hepatic profiles as well as the concomitant treatments associated to PP3M vs. clozapine, the gold standard, in patients with treatment-resistant schizophrenia. We designed a retrospective study. A total number of 33 patients previously diagnosed as schizophrenics treatment-resistant, who were prescribed clozapine followed by PP1M and PP3M when available, were selected. Demographic data, BMI, hepatic enzymes (glutamic oxaloacetic transaminase, glutamate-pyruvate transaminase and gamma-glutamyl transferase (GGT)], thyroid function (thyroid stimulating hormone), blood platelets and both white and red blood cells as well as the use of concomitant antipsychotics, benzodiazepines and biperiden were compared under treatment with clozapine and PP3M. Antipsychotics and benzodiazepines dosages were compared using by the defined daily dose (DDD) method and haloperidol or diazepam dose equivalents. All statistical analyses were performed using the paired Student t-test for repeated measures. Our data showed that patients under treatment with PP3M showed a significant decrease in BMI (P < 0.01), glucose (P < 0.01), cholesterol (P < 0.05) and triglycerides (P < 0.01) when compared with basal values under treatment with clozapine. Hepatic cholestasis enzyme, GGT, were significantly elevated (P < 0.05) under treatment with clozapine when compared to PP3M. Switching clozapine to PP3M led to a significant lower pharmacological exposure to antipsychotics, by both the DDD (P < 0.05) and haloperidol dose equivalents (P < 0.001) methods without increasing the dose of benzodiazepines while biperiden was more used under PP3M. Finally, antipsychotic monotherapy was higher and less polypharmacy was used with PP3M. In conclusion, our findings suggest that switching clozapine to PP3M improved endocrine and hepatic profile with a lower total exposure to antipsychotics. More studies are needed to truly establish the role of PP3M in treatment-resistant schizophrenia and should be compared against clozapine by using clinical trials.