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This study aims to analyze the technological impact of papers that Advanced Pharmaceutical Bulletin (APB) has published through patent-to-paper citations analysis. Current research uses a Scientometric approach to analyze patent citations to published papers by the APB. The Lens has been used for collecting patents that cited related papers. Some of the data analysis was conducted using the Lens analytical tool. Results show that APB's patent-to-paper citation rate is 32.39%, above the toxicology field average (6.15%) but below pharmacology (46.33%), indicating significant technological influence. APB contributes to both science and technology, attracting global inventors. The patent citations metric can be used to understand how a journal contributes to technological progress. However, these methods need to be standardized and promoted to understand a journal's real value in technology contribution.
Since the start of the 6-year program in pharmacy education, outcome-based education has progressed, and students' experience of onsite pharmacy practice has increased their awareness of their roles as pharmacists. This progress has been confirmed by student reports submitted at the end of onsite practice. In addition, the results of undergraduate students' graduation research as well as those of clinical research carried out in graduate schools are presented at the annual meetings of the Pharmaceutical Society of Japan (PSJ) and its local branches. Research activity is also promoted by the various divisions of the PSJ that represent a wide range of pharmacy-related fields, including the Division of Clinical Pharmaceutical Sciences. In this way, the PSJ effectively connects researchers in basic and clinical fields, promoting the development of both translational research and reverse-translational research based on needs and ideas brought from the clinic to the basic sciences. Following their presentation at academic meetings, clinical research outcomes are often published in academic journals, including in the three academic journals published by the PSJ: Yakugaku Zasshi, Biological and Pharmaceutical Bulletin, and Chemical and Pharmaceutical Bulletin. Yakugaku Zasshi accepts submissions of case studies, case reports, and survey reports related to clinical pharmacy, which can be submitted in either English or Japanese. As the foundational society for pharmacy and pharmaceutical sciences in Japan, the PSJ is committed to continuing advances in basic and clinical pharmacy research. In the last part of this review, I discuss graduate schools of pharmacy and pharmaceutical sciences.
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Background and Objectives: Menopausal hormone therapy (MHT) is the most efficacious treatment for vasomotor symptoms and genitourinary conditions associated with menopause. Modern menopause care increasingly encompasses women with multimorbidity, renal or hepatic impairment, previous malignancies or thromboembolic disorders, advanced age, and polypharmacy-groups frequently underrepresented in randomized clinical trials. This evidence gap prompts significant inquiries about the relevance of trial-based recommendations to actual clinical practice. Materials and Methods: This narrative review offers a concentrated assessment of prominent worldwide clinical guidelines regarding menopausal hormone therapy through thematic synthesis. We examined position statements from the North American Menopause Society (NAMS), the European Menopause and Andropause Society (EMAS), NICE clinical guidelines, the ACOG Practice Bulletin on menopausal symptom management, the Endocrine Society clinical practice guideline, and pertinent UK guidance from RCOG, BMS, and BGCS. Data from systematic reviews, meta-analyses, and extensive observational studies were analyzed to contextualize guideline recommendations for populations often underrepresented in clinical trials, including women aged ≥65 years and individuals with multimorbidity or polypharmacy. Results: Only the NICE and EMAS recommendations expressly acknowledge clinical vulnerability or complexity (multimorbidity, frailty, and cancer survivorship) as foundational principles. NAMS and ACOG delineate risk categories but fail to offer a cohesive taxonomy of vulnerability. Polypharmacy and drug-drug interactions are inconsistently addressed across guidelines, and there is a deficiency of standardized prescribing algorithms. While routine safety monitoring is universally advocated, the intervals for follow-up and methods for risk categorization differ. Observational evidence consistently indicates route-dependent variations in cardiovascular and thromboembolic risk, with transdermal estrogen linked to a more advantageous safety profile in higher-risk individuals. Conclusions: Present menopausal therapy guidelines are methodologically sound; however, they insufficiently address the complexities of multimorbidity, polypharmacy, and organ dysfunction. A systematic conceptual framework that incorporates areas of clinical vulnerability may facilitate personalized benefit-risk evaluation in practical applications. Future guideline revisions should enhance clarity by incorporating polypharmacy concerns, monitoring strategies, and systematic risk stratification methods for clinically complicated patients.
Better-than-chance guessing of treatment assignment raises concerns about unblinding as this opens efficacy estimates up to being influenced by factors other than the true efficacy of the intervention. However, such accuracy does not necessarily indicate that efficacy estimates are biased. To assess whether unblinding was biasing (impacting on efficacy estimates) or non-biasing (not impacting on efficacy estimates) in a sham-controlled trial of a home-use transcranial direct-current stimulation (tDCS) device, in which treatment allocation guesses at endpoint were unbalanced. Interrelations between i) treatment allocation, ii) treatment allocation guesses, iii) adverse event reports, and iv) depressive symptom severity, as measured by Hamilton Depression Rating Scale, after ten weeks of treatment were examined using linear regression (n = 149). Receiving tDCS was positively associated with a) guessing that one had received tDCS (p = .01704), b) number of adverse events (beta: 0.69, p = .0046), and c) improvement after ten weeks (beta: -2.39, p = .0049). Guessing that one had received tDCS was positively associated with greater improvement (beta: -3.16, p = .0005), whereas the number of reported adverse events correlated negatively with improvement (beta: 0.68, p = .0186). Moreover, among participants who received tDCS, those who reported any of nine examined adverse events consistently showed numerically worse outcomes than those who did not report the same adverse events. In this exploratory analysis, adverse events correlated negatively with HDRS-rated improvement. This is not consistent with a pathway where adverse events lead to unblinding and, subsequently, to improvement via expectancy effects and/or biased ratings.
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but use is constrained by potentially life-threatening neutropenia and mandatory hematological monitoring. Evidence from Western cohorts suggests risk is concentrated early in treatment, yet data from Japan where monitoring is stringent, remain limited. Retrospective study including all patients prescribed clozapine from July 2009-January 2020 in Japan. Mild neutropenia was defined as absolute neutrophil count (ANC) 1.0-1.5 × 109/L, and serious neutropenia as ANC <1.0 × 109/L. Cumulative incidence of first mild and serious neutropenia was estimated using competing-risks methods. Associations with serious neutropenia were examined using Fine-Gray regression, including 2-week titration rate. The cohort comprised 8263 individuals contributing 764 180 blood tests, with a median follow-up of 102 weeks. Overall, 3.0% patients experienced mild neutropenia and 2.2% had serious neutropenia. Among clozapine-naïve patients, cumulative incidence was 1.8% for mild and 1.6% for serious neutropenia at 18 weeks, rising to 3.1% and 2.5% at 104 weeks, respectively. Faster clozapine titration rate was associated with higher incidence of serious neutropenia (sub-distribution hazard ratio [sHR] 1.22, 95% CI, 1.02-1.45 per 50 mg dosage increase at 2-weeks), as was older age (sHR 1.05, 95% CI, 1.04-1.06), while prior clozapine exposure was associated with lower incidence (sHR 0.27, 95% CI, 0.09-0.86). In Japan, neutropenia among clozapine-treated patients accrued predominantly within the first 1-2 years, with faster titration in the first 2-weeks being associated with a 22% increase in serious neutropenia risk per 50 mg. These findings support risk-stratified, less intensive monitoring approaches beyond the first 2 years.
Social media listening is a new approach for gathering insights from social media platforms about users' experiences. This approach has not been applied to analyse discussions about Alzheimer's disease (AD) in China. We aimed to leverage multisource Chinese data to gain deeper insights into the current state of the daily management of Chinese patients with AD and the burdens faced by their caregivers. We searched nine mainstream public online platforms in China from September 2010 to March 2024. Natural language processing tools were used to identify patients and caregivers, and categorise patients by disease stage for further analysis. We analysed the current state of patient daily management, including diagnosis and treatment, choice of treatment scenarios, patient safety and caregiver concerns. A total of 1211 patients with AD (66% female, 82% aged 60-90) and 756 caregivers for patients with AD were identified from 107 556 online sources. Most patients were derived from online consultation platforms (43%), followed by bulletin board system platforms (24%). Among the patients categorised into specific disease stages (n=382), 42% were in the moderate stage. The most frequent diagnostic tools included medical history (97%) and symptoms (84%). Treatment options for patients with AD primarily included cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists and antipsychotics. Both quantitative and qualitative analysis of patients who experienced wandering (n=92) indicated a higher incidence of wandering during the moderate stage of the disease. Most caregivers were family members, with their primary concerns focusing on disease management and treatment (90%), followed by daily life care (37%) and psychosocial support (25%). Online platform data provide a broad spectrum of real-world insights into individuals affected by AD in China. This study enhances our understanding of the experiences of patients with AD and their caregivers, providing guidance for developing personalised interventions, providing advice for caregivers and improving care for patients with AD.
Major depressive disorder (MDD) is a leading cause of disability worldwide, yet its diagnosis relies on clinical symptoms alone. Using the semi-supervised machine learning algorithm, Heterogeneity through Discriminative Analysis (HYDRA), we had identified two neuroanatomical dimensions in deeply phenotyped (i.e., comprehensively assessed across neuroimaging, clinical, and behavioural domains), medication-free participants with MDD from the COORDINATE-MDD consortium. In the present study, we apply this pre-trained HYDRA model to the UK Biobank (UKB) to validate these dimensions in a large general population and a subsample with current depressive symptoms. Dimension 2 (D2), compared to Dimension 1 (D1), is characterized by reduced grey and white matter volumes and limited treatment response to antidepressant and placebo medications. Out-of-sample validation in the UKB general population (n = 37,235) confirms these neuroanatomical features and reveals D2 associations with cognitive impairments, adverse life events, self-harm and suicide attempts, a pro-atherogenic lipid profile, and genetic links to neurodegenerative traits. Similar profiles are observed in the UKB subsample with current depressive symptoms (n = 1455). D1 and D2 represent distinct neurobiological mechanisms underlying MDD. The validation in a general population-based cohort and in a cohort sample with depressive symptoms delineates mechanisms underlying heterogeneity in MDD. Major depressive disorder is a common and disabling condition, but people differ greatly in their symptoms and responses to treatment. We used brain scans and machine learning to identify two patterns of brain structure linked to depression. One pattern showed relatively preserved brain volume and was associated with better treatment response. The other showed widespread reductions in brain volume and was related to poorer memory and thinking skills, greater exposure to adverse life events, increased risk of self-harm, and metabolic and genetic changes. These findings were confirmed in a large general population sample as well as in people with current depressive symptoms. The results suggest that depression includes distinct brain-based subtypes, which may help explain differences in treatment response and guide the development of more personalised approaches.
An understanding of the tumor immune microenvironment is required to improve treatment, especially the selection of immune checkpoint inhibitors (ICIs). In this study, we stratified the immunotypes of tongue squamous cell carcinoma (TSCC) based on the results of comprehensive immune profiling. We enrolled 87 therapy-naïve TSCC and 17 ICI-treated TSCC patients who underwent glossectomy without any other prior therapy. Comprehensive immune profile analyses employed multiplex immunofluorescence and tissue imaging. Based on the hierarchies of 58 immune parameters and the spatial distances between cytotoxic T lymphocytes (CTL) and tumor cells, we stratified five immunotypes: Immunoactive type I, border type II, immunosuppressed type III, immunoisolating type IV, and immunodesert type V. The type I frequency was only 16%. Most TSCCs (~ 70%) were of types III-V. The CTL density (CTL-D) was closely correlated with the PD-L1+ pan-macrophages (panM)-D, and the panM-D closely correlated with the PD-1+ CTL-D. This indicated that PD-1 and PD-L1 expression required macrophages and CTL recruitment in the tumor microenvironment. No ICI-treated TSCC patients, all of whom were recurrent/metastatic cases, were of the type I immunotype, and almost half (47.0%) were of the immunodesert type V. Most cases exhibited an imbalance between T-cell PD-1 and macrophage PD-L1 expression. We defined five TSCC-specific immunotypes based on the results of comprehensive immune profiling analyses. Immunoactive type, which would be sensitive to ICI monotherapy, was rare, and most TSCC cases exhibited immune-regulated immunotypes. Immunotype-based personalized treatments are required to improve clinical outcomes.
Ethyl cellulose (EC), a degradable cellulose derivative, served as a primary component in membranes fabricated by electrospinning for in vitro drug delivery applications. An effective strategy to enhance drug release was incorporating high-surface-area nanomaterials into polymeric drug carriers, which facilitated drug attachment to both the polymer matrix and additive surfaces, promoting release. MXene (Ti3C2Tx) demonstrated promising potential in improving tensile mechanical properties, antibacterial activity, and curcumin (Cur) release performance of EC membrane. Compared to Cur-loaded EC/MXene membranes, the toughness of Cur-loaded EC-based carriers significantly increased by 53.58 %, reaching 3.821 kJ/m3. This composite membrane exhibited exceptional antibacterial efficacy, notably reducing Staphylococcus aureus colonies by 52.4 × 107 CFU/mL after 168 h, through the dilution spread plate method. Using MTT assay, the composite membrane demonstrated biocompatibility, as evidenced by >70 % viability of mouse fibroblast L929 cells with observable cell attachment after 168 h. Importantly, the EC/MXene membrane achieved a Cur release amount of 69.82 % compared to 7.11 % from Cur-loaded EC membranes within 168 h, representing a 62.71 % enhancement in Cur release. The EC/MXene composite membrane is a promising drug delivery candidate, particularly for Cur, by utilizing the sustainability of EC as the primary drug carrier component.
Transcranial direct current stimulation (tDCS) has been proposed as a new treatment in major depressive disorder (MDD). This is a fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of 10-week home-based tDCS in MDD. Participants were 18 years or older, with MDD in current depressive episode of at least moderate severity as measured using the Hamilton Depression Rating Scale (mean = 19.07 ± 2.73). A total of 174 participants (120 women, 54 men) were randomized to active (n = 87, mean age = 37.09 ± 11.14 years) or sham (n = 87, mean age = 38.32 ± 10.92 years) treatment. tDCS consisted of five sessions per week for 3 weeks then three sessions per week for 7 weeks in a 10-week trial, followed by a 10-week open-label phase. Each session lasted 30 min; the anode was placed over the left dorsolateral prefrontal cortex and the cathode over the right dorsolateral prefrontal cortex (active tDCS 2 mA and sham tDCS 0 mA, with brief ramp up and down to mimic active stimulation). As the primary outcome, depressive symptoms showed significant improvement when measured using the Hamilton Depression Rating Scale: active 9.41 ± 6.25 point improvement (10-week mean = 9.58 ± 6.02) and sham 7.14 ± 6.10 point improvement (10-week mean = 11.66 ± 5.96) (95% confidence interval = 0.51-4.01, P = 0.012). There were no differences in discontinuation rates. In summary, a 10-week home-based tDCS treatment with remote supervision in MDD showed high efficacy, acceptability and safety. ClinicalTrials.gov registration: NCT05202119.
Transcranial direct current stimulation (tDCS) is a potential home-based treatment for major depressive disorder (MDD). In our double-blind randomised controlled trial (RCT) (n = 174; UK and USA), a 10-week course of home-based tDCS demonstrated clinical efficacy (clinical response: 58.3 % active treatment arm and 37.8 % sham (p = 0.017). tDCS was delivered in a bifrontal montage, with anode over left dorsolateral prefrontal cortex (DLPFC) and cathode over right DLPFC. Each session was 30 min, with active stimulation at 2 mA and sham at 0 mA, incorporating brief ramp-up and ramp-down phased. Following the 10-week RCT, all participants were offered active tDCS in a 10-week open-label treatment phase, with 111 participants completing this phase. UK cohort (n = 77 MDD) were invited for additional 3-month and 6-month follow-ups, extending the total study period to 11 months post-randomisation. Participants were able to continue using the tDCS device during follow-up. At least one follow-up visit was attended by 42 MDD participants (27 women). Device usage rates were 59 % at 3-month follow-up and 55 % at 6-month follow-up. Clinical response rate was 64 % at 3-month follow-up and 76 % at 6-month follow-up. Among participants who had shown a clinical response after the open-label phase, 90 % maintained their response at the 6-month follow-up. In summary, long-term follow-up showed high and sustained clinical response rates regardless of continued tDCS device use.
To evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines Agency (EMA). Retrospective cohort study. Oncology drugs and their indications approved by the EMA between 1995 and 2020. Added benefit was evaluated using ratings published by seven organisations: health technology assessment agencies from the United States, France, Germany, and Italy, two medical oncology societies, and a drug bulletin. All retrieved ratings were recategorised using a four point ranking scale to indicate negative or non-quantifiable, minor, substantial, or major added benefit. Revenue data were extracted from publicly available financial reports and compared with published estimates of research and development (R&D) costs. Finally, the association between added benefit and revenue was evaluated. All analyses were performed within the overall study cohort, and within subgroups based on the EMA approval pathway: standard marketing authorisation, conditional marketing authorisation, and authorisation under exceptional circumstances. 131 oncology drugs with 166 indications were evaluated for their added benefit by at least one organisation within the required timeframe, yielding a total of 458 added benefit ratings; 189 (41%) were negative or non-quantifiable. The median time to offset the median R&D costs ($684m, £535m, €602m, adjusted to 2020 values) was three years; 50 of 55 (91%) drugs recovered these costs within eight years. Drugs with higher added benefit ratings generally had greater revenues. Negative or non-quantifiable added benefit ratings were more frequent for conditional marketing authorisations and authorisations under exceptional circumstances than for standard marketing authorisations (relative risk 1.53, 95% confidence interval 1.23 to 1.89). Conditional marketing authorisations generated lower revenues and took longer to offset R&D costs than standard marketing authorisations (four years compared with three years). While revenues seem to align with added benefit, most oncology drugs recover R&D costs within a few years despite providing little added benefit. This is particularly true for drugs approved through conditional marketing authorisations, which inherently appear to lack comprehensive evidence. Policy makers should evaluate whether current regulatory and reimbursement incentives effectively promote development of the most effective drugs for patients with the greatest needs.
The aim of this work was to understand how patients with non-alcoholic steatohepatitis (NASH) perceive their disease, unmet needs, and expectations regarding future treatment through online bulletin board (OBB) qualitative research. OBB is an asynchronous online qualitative market research tool that provides an open forum for interactive discussion among participants. Patients with NASH were recruited via physician referral and completed a screener questionnaire to ensure their eligibility and willingness to participate. A trained moderator managed the discussion that allowed open answers and responses to other participants' posts. Patient responses were analyzed using a combination of different qualitative analytical tools. The OBB ran for 4 days and included 16 patients (n = 8, UK; n = 8, US) with NASH (fibrosis stages F1-F3) and comorbidities including diabetes/prediabetes (n = 9) and obesity (n = 12). The key insights were (1) patients with NASH have a poor understanding of the disease, its progression, and management-they feel a lack of adequate educational support from their physicians; (2) diagnosis of NASH is incidental in most cases, mainly because patients fail to spontaneously associate their signs or symptoms with their liver condition; (3) comorbidities (obesity and diabetes) are more concerning to patients than NASH; and (4) patients perceive that NASH impacts their social life and work performance in more advanced stages. This OBB provided valuable patient insights into NASH disease perception and management and revealed unmet need areas. In light of no approved therapies, these patient insights can inform early drug development strategies and stakeholder discussions on NASH. Novartis Pharma AG, Basel.
Cocaine use disorder (CUD) is characterized by the continued use of cocaine despite serious impacts on life. This study focused on understanding the perspective of individuals with current CUD, individuals in CUD remission, and their supporters regarding current therapies, future therapies, and views on clinical trials for CUD. The online bulletin board (OBB) is a qualitative tool where participants engage in an interactive discussion on a virtual forum. Following completion of a screening questionnaire to determine eligibility, individuals in CUD remission and their supporters logged in to the OBB and responded to questions posed by the moderator. Individuals with current CUD participated in a one-time virtual focus group. All individuals with current CUD and 94% of those in CUD remission reported a diagnosis consistent with CUD or substance use disorder during screening. Individuals with current CUD and their supporters were recruited from the United States (US). Individuals in CUD remission were recruited from five countries, including the US. Individuals with current CUD reported hesitation about seeking treatment due to stigma, a lack of privacy, and being labeled as a drug seeker; barriers to therapy included time, cost, and a lack of privacy. Participants wanted a safe therapy to stop cravings and withdrawal symptoms. Seven clinical trial outcomes, including long-term abstinence and craving control, were suggested based on collected insights. This study can help inform the design of clinical trials and emphasize the need for effective, safe, and accessible therapies. Recruiting participants will require significant trust building.
To assess the frequency, clinical features, and outcome of peri-ictal delirium in adult patients experiencing seizures during intensive care. This observational study was conducted at a Swiss intensive care unit from 2015 to 2020. Patients aged ≥ 18 years with seizures were categorized as peri-ictal delirious (Intensive Care Delirium Screening Checklist [i.e., ICDSC] ≥ 4) or not (i.e., ICDSC < 4) within 24 h of seizures. The frequency of peri-ictal delirium and in-hospital death were defined as the primary endpoints. Illness severity and treatment characteristics between delirious and non-delirious patients were secondary endpoints. Logistic regression was used to compare in-hospital death and differences regarding clinical characteristics between delirious and non-delirious patients. 48% of 200 patients had peri-ictal delirium for a median of 3 days. Delirious patients were older (median age 69 vs. 62 years, p = 0.002), had lower Simplified Acute Physiology Scores II (SAPS II; median 43 vs. 54, p = 0.013), received neuroleptics more frequently (31 vs. 5%, p < 0.001), were mechanically ventilated less often (56% vs. 73%, p = 0.013) and shorter (median 3 vs. 5 days, p = 0.011), and had decreased odds for in-hospital death with delirium (OR = 0.41, 95% CI 0.20-0.84) in multivariable analyses. Delirium emerged in every second patient experiencing seizures and was associated with lower SAPS II, shorter mechanical ventilation, and better outcomes, contradicting assumptions that altered cerebral function, from seizures and delirium, are linked to unfavorable outcomes.
Neurological manifestations of coronavirus disease 2019 (COVID-19) are less noticeable than the respiratory symptoms, but they may be associated with disability and mortality in COVID-19. Even though Omicron caused less severe disease than Delta, the incidence of neurological manifestations is similar. More than 30% of patients experienced "brain fog", delirium, stroke, and cognitive impairment, and over half of these patients presented abnormal neuroimaging outcomes. In this review, we summarize current advances in the clinical findings of neurological manifestations in COVID-19 patients and compare them with those in patients with influenza infection. We also illustrate the structure and cellular invasion mechanisms of SARS-CoV-2 and describe the pathway for central SARS-CoV-2 invasion. In addition, we discuss direct damage and other pathological conditions caused by SARS-CoV-2, such as an aberrant interferon response, cytokine storm, lymphopenia, and hypercoagulation, to provide treatment ideas. This review may offer new insights into preventing or treating brain damage in COVID-19.
Dear Editor, The costs of antipsychotic drugs (APDs) used in the treatment of mental disorders with psychosis are mentioned in treatment guidelines (APA 2021, NICE 2014). While the American Psychiatric Association guideline states that every specialist should make decisions according to the rules and conditions of their country and their region, the National Institute of Health and Clinical Excellence guideline emphasizes that drug costs must be taken into consideration in the treatment process. Classical or first-generation antipsychotic drugs (FAPDs) are relatively cheaper in terms of sales prices compared to atypical or second-generation antipsychotic drugs (SAPDs) with a slightly different effect mechanism. The price difference between the two drug groups can be so large that sometimes it may be necessary to consider whether the cost of a second-generation drug is worth its benefit. While deciding on the use of first-generation or second-generation drugs, a multifaceted assessment should be made, such as the patient's level of compliance with the treatment, the possibility of occurrence of side effects, the possible effects of these side effects on body health and treatment compliance, and whether or not the costs are covered. The most important criterion that determines the choice of medication for psychiatrists is of course the multi-dimensional benefit/harm ratio that the drug used will reveal in the long term. We think that in our country, which, in terms of economic indicators is not in a strong position as an importer of pharmaceutical raw materials from abroad, APDs' cost calculation should be considered because drug costs constitute an important part of the direct treatment costs of psychotic disorders in developing countries such as Turkey (Yıldız and Cerit 2006). We calculated the unit (mg) price based on the box prices of the APDs in use in 2020, thinking that it might work when calculating the cost of the illness using APDs as the main component of the treatment and calculated the annual average drug costs with the daily average dosage. Although the daily treatment dose varies with the stage of the illness and the individual characteristics of the patient, the average doses recommended for maintenance treatment were used here (Öztürk and Ulusahin 2018). The daily and annual cost calculations based on the assumption that the average maintenance treatment dose was used with the unit price obtained from (Drug Prices 2020) the drugs in the Turkish pharmaceutical market in September 2020 are shown in Table 1. A similar study was done in 2005 (Yıldız 2005). The purpose of this article is to redetermine the average costs of APDs in the Turkish pharmaceutical market every 15 years and to bring them to the attention of experts in terms of cost-effectiveness studies. When the costs in 2005 are examined, it is seen that the annual costs of the FAPDs were around 450 TRY, and the annual cost of oral preparations of SAPDs was 2,500 TRY (5 times the first generation). In 2005, there was only one depot of SAPD (risperidon consta) that allowed intramuscular (IM) administration, and its average annual cost was 5,400 TRY, 3 times more than the tablet form (1,700 TRY). In 2005, when the price of risperidone consta, which was the first second-generation depot APD, were compared with the prices of the first-generation depot drugs (fluphenazine = 380 TRY, flupentixol = 876 TRY, zuclopentixol = 730 TRY), the cost difference was 6-14 times. This almost-10-fold difference between the cost of the first and second generation APDs was remarkable. It is seen that this difference (risperidone consta = 10,807 TRY, fluphenazine = 916 TRY, flupentixol = 1,007 TRY, zuclopenthixol = 2,372 TRY, and haloperidol deconate 237 TRY) did not change in 2020. In 2020, the average RETHINKING THE COST OF ANTIPSYCHOTIC TREATMENT: THE AVERAGE COST OF THE DRUGS USED IN TURKEY IN 2020 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 146 147 annual cost of oral use preparations of FAPDs is 925 TRY, while the average annual cost of oral forms of SAPDs is 2,580 TRY. The 5-fold difference observed in 2005 between the first and second-generation ones of the oral APDs decreased to 2.5 times in 2020. It is clear that while the difference between the cost of oral use of first- and second-generation drugs was halved in 2020, the difference between the costs of depot preparations applied with IM did not change. In 2005, the average dollar rate was 1.34 TRY, and in 2020 it was 7.02 TRY (Republic of Turkey Central Bank Exchange Rates, 2021). It is understood that the 5-fold increase in dollar exchange rate is not reflected in all drug prices in the same way. For example, there was a 3 to 4-fold increase in the prices of haloperidol, chlorpromazine, fluphenazine, trifluperazine and zuclopenthixol, while a less than two-fold increase in pimozide, flupenthixol, sulpiride, amisulpride and quetiapine and a decrease in the prices of clozapine, olanzapine, ziprasidone and risperidone in the tablet form. There is also a two-fold increase in the price of risperidone consta. The fluctuations in drug prices in 2005 and 2020 are shown in Table 2 in 500, 1,000, 2,000, 3,000 and 5,000 TRY brackets. It is noteworthy that while some drugs have moved into an upper price bracket in terms of annual costs, some have fallen into a lower price bracket. The prices of the second generation long-acting (depot) antipsycotic drugs (LA-APDs), which were not available in the Turkish pharmaceutical market in 2005, are quite high compared to others. In 2020, the annual cost of all of them, including risperidone consta, is over 10 thousand TRY. It is understood that the underlying reason for such price increase is the fact that the drug is wanted/sought after/new/marketed rather than the dollar exchange rate. For example, while there was a certain increase in the price of FAPDs, the increase in the price of some of the SAPDs (sulpiride, amisulpride, quetiapine tablet) was low, while the price of some others (clozapine, olanzapine, ziprasidone, risperidone tablet) decreased. It should also be taken into account that the effect of generic drugs entering the market during this period may have had an impact on price changes. It is noteworthy that while the annual cost of risperidone consta was approximately 3 times higher than the tablet form (5,400 TRY versus 1,700 TRY) in 2005, this difference reached 14 folds (10,807 TRY versus 742 TRY) in 2020. In 2005, the difference between the lowest daily cost (0.07 TRY) and the highest daily cost (14.80 TRY) was 211 times (Yıldız 2005), this difference had receded to 111 times (0.35 TRY versus 38.72 TRY) in 2020. Still a huge difference, isn't it? Table 1. Current Forms, Box Prices, Daily and Annual Costs in For Maintenance Treatment of Antipsychotic Drugs Available in the Pharmaceutical Market in September 2020 in Turkey No Generic name Trade name Dosage forms (mg) BV Price# TRY/Mg ADD Cost/d Cost/y 2005** 1 Haloperidol Norodol 5, 10, 20 tb 5/50 17.57 0.070 5 0.35 127 26 5, 10 amp 5/5 5.35 0.214 5 1.07 390 - 50, 150 LAI 50/1 9.80 0.196 1/15* 0.65 237 - 2 Chlorpromazine Largactil 25,100 tb 100/30 17.92 0.006 300 1.79 653 197 3 Fluphenazine Prolixin 25 LAI 25/1 17.57 0.703 1/7* 2.51 916 380 4 Trifluoperazine Stilizan 1, 2, 5 drj; 1 amp 5/30 14.52 0.096 10 0.97 354 91 5 Pimozide Nörofren 2 tb 2/30 19.33 0.322 4 1.29 470 365 6 Flupenthixol Fluanxol 3 drj 3/50 65.75 0.438 6 2.63 960 526 20 LAI 20/1 19.33 0.966 1/7* 2.76 1,007 876 7 Zuklopenthixol Clopixol 2, 10, 25 tb 2/50 38.65 0.386 20 7.72 2,817 701 200 LAI, 50 acu 200/1 45.55 0.227 1/7* 6.50 2,372 730 8 Sulpirid Dogmatil 200 tb 200/24 23.15 0.005 600 3.00 1,095 876 9 Amisulpirid Solian 200 tb 200/60 146.92 0.012 600 7.20 2,628 2,387 10 Quetiapine Seroquel 25, 50, 100, 200, 300, 400 tb 300/30 137.17 0.015 600 9.00 3,285 2,628 11 Clozapine Leponex 25, 100 tb 100/50 32.56 0.006 400 2.40 876 1,898 12 Olanzapine Zyprexa 5, 10, 20 tb 10/28 152.96 0.546 10 5.46 1,992 2,606 13 Ziprasidone Zeldox 20, 40, 60, 80 tb 60/56 189.89 0.056 120 6.72 2,452 3,541 14 Sertindole Serdolect 4, 12, 16, 20 tb 16/28 453.53 1.012 16 16.19 5,909 - 15 Risperidone Risperdal 1, 2, 3, 4 tb; 1 sol 2/20 20.34 0.508 4 2.03 741 1,719 Ris. Consta 25, 37.5, 50 LAI 37.5/1 444.17 11.840 1/15* 29.61 10,807 5,402 16 Paliperidone Invega 3, 6, 9 tb 6/28 213.15 1.268 6 7.61 2,777 - Xeplion 50, 75, 100, 150 LAI 100/1 1161.56 11.615 1/30* 38.72 14,132 - Trevicta 175, 263, 350, 525 LAI 350/1 3426.95 9.788 1/90* 38.08 13,899 - 17 Aripiprazole Abilify 5, 10, 15, 20 tb; 1 sol 20/28 113.25 0.404 20 8.08 2,949 - Abilify Main. 400 LAI 400/1 971.17 2.420 1/30* 32.37 11,815 - BV: Baseline value (in mg of the form and the number in the box), Price#: Box price of the base value in TRY, TRY/mg: Value per milligram in Turkish Lira, ADD: Average daily dose, Cost/d: Daily cost in TRY, Cost/y: Annual cost in TRY, mg: Milligram, tb: Tablet, drj: Dragee, amp: Ampoule, LAI: Long-acting injectable, acu: Acuphase, d: Day, TRY: Turkish Lira, *LAI per 7,15,30 or 90 days, **Annual cost in TRY in 2005. 148 Received: 14.01.2021, Accepted: 31.03.2021, Available Online Date: 07.01.2022 1Prof., 2Res. Assis., Kocaeli University School of Medicine, Department of Psychiatry, Kocaeli, Turkey. e-mail: myildiz60@yahoo.com https://doi.org/10.5080/u26315 The difference in 2005 between oral FAPDs prices and SAPDs prices seems to have halved in 2020. In 2020, the average daily treatment cost of oral drugs, whether for the first generation or the second generation, is 3 TRY (approximately the same for FAPDs applied with IM), while the daily cost of LA-SAPDs is around 33 TRY. It is seen that the difference between costs is approximately 11 times. This difference increases to 50 times for haloperidol deconate. From here, the following judgment can be made: in order for LA-SAPDs to be preferred, they must be at a value that will constitute at least 11 times higher cost. This cost can and should be taken, especially for patients who are non-adherend with treatment and who do not adapt to LA-FAPDs. Because for clinicians, preventing the multi-dimensional destructiveness of psychosis in the individual, families and the society should be the priority. In this case, calculating the cost should not be a primary consideration. However, it is also known that patients who are non-adherend with treatment gain the ability to understand their illness and make consistent evaluations with its' results. If a psychosocial therapy has been carried out for a patient using IM medication for six months or a year, it is likely that this period provides insight and increases the level of treatment compliance. After one year of IM application, whether or not the patient will comply with oral treatment should be re-evaluated and the transition to oral treatment should be considered. If there is no problem in the patient's oral treatment compliance, it should be taken into account that the benefit of this transition will be at least 11-folds a year with this transition. Naturally, it will be necessary to apply IM for some patients for years. Moreover, there will be patients who need to switch from monthly administration of LA-SAPDs to quarterly usage patterns. However, we can say that most patients using LA-APDs will not need such use after a while, based on our clinical practice, although there is no study done in this field. With this study, we wanted to emphasize that while prescribing drugs used in the treatment of illnesses with psychotic symptoms, they should take into account the side effects of the drugs, as well as the daily, monthly, annual, and lifetime costs of the drugs. The principle of 'using an effective drug recommended for a specific disorder at the required dose, in sufficient time, at the lowest cost' adopted in the rational drug use guidelines should not be forgotten. It is expected that the modification of drug treatments, considering their costs as well as their efficiency, will contribute significantly to the country's economy in the long run. Mustafa Yıldız1, Emre Osman2 REFERENCES American Psychiatric Association (2021) The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Third edition. Washington, DC: American Psychiatric Association. Drug Prices. https://www.ilacrehberi.com/ilac-fihrist/ Accession date: 25th September 2020. National Institute for Health and Clinical Excellence (NICE) (2014) Psychosis and schizophrenia in adults: prevention and management. NICE Guideline CG178; https://www.nice.org.uk/guidance/cg178. Accession date: 4th April 2018. Öztürk MO, Uluşahin NA (2018) Mental Health and Disorders. 18th Edit. Ankara: Nobel Tıp Kitapevleri. (In Turkish) Republic of Turkey Central Bank Exchange Rates. https://www.tcmb.gov.tr/kurlar/kurlar_tr.html Accession date: 10th January 2021. Yıldız M (2005) The cost of treatment of psychotic disorders. Turk Psikiyatri Derg 16:146-7. (In Turkish) Yıldız M, Cerit C (2006) Annual cost of treatment for schizophrenia: Estimation from a university hospital data in Turkey. Bulletin of Clinical Psychopharmacology 16:239-44. Table 2. Comparison of the Annual Costs of Antipsychotic Drugs Calculated By The Daily Standard Average Dose Use, at Certain Price Ranges, for the Years 2005 and 2020 Price bracket (TRY) 2005 2020 500 ↓ Haloperidol tb, amp, Trifluoperazine drj, Chlorpromazine tb, Pimozid tb, Fluphenazine LAI Haloperidol tb, amp, depo, Trifluoperazine drj, Pimozid tb 500-1,000 Flupenthixol drj, LAI, Zuklopenthixol tb, acu, LAI, Sulpirid tb Chlorpromazine tb, Fluphenazine LAI, Flupenthixol drj, LAI, Clozapine tb, Risperidone tb 1,000-2,000 Clozapine tb, Risperidone tb Olanzapine tb, Sulpirid tb 2,000-3,000 Amisulpirid tb, Olanzapine tb, Quetiapine tb Zuklopenthixol tb, acu, LAI, Amisulpirid tb, Ziprasidone tb, Paliperidone tb, Aripiprazole tb 3,000-5,000 Ziprasidone tb Quetiapine tb 5,000-10,000 Risperidone consta Sertindole tb 10,000 ↑ Risperidone consta, Paliperidone monthly, Paliperidone 3 monthly, Aripiprazole maintana tb: Tablet, drj: Dragee, amp: Ampoule, LAI: Long-acting injectable, acu: Acuphase.