Adjunctive treatment of behavioral disorders in patients with cognitive deficit The article provides an overview of the pharmacotherapy of behavioural and psychological symptoms of dementia (BPSD) in the context of evidence-based medicine. Its goal is to provide readers with a practical and educational overview of managing these symptoms. Cognitive disorders, including dementia, result from the disruption of higher cortical functions of the brain. Dementia often manifests not only through cognitive dysfunction but also through BPSD, such as agitation, aggression, anxiety, psychosis, and sleep disturbances. These symptoms affect up to 97% of patients with dementia and significantly reduce the quality of life for both patients and caregivers. BPSD are often more stressful for patients and caregivers than the cognitive symptoms themselves. Behavioural symptoms include a wide range of manifestations from non-aggressive forms such as pacing and repetitive movements to aggressive and agitated behaviour (verbal and physical). Psychological symptoms can include depression, anxiety, and psychotic symptoms such as paranoia and delusions. The causes of BPSD can be varied, as well as their risk factors (including e.g. co-medication, comorbidities, the patient's personality traits, inappropriate communication by caregivers, and environmental influences). The pharmacotherapy of BPSD is complex and often involves the use of antipsychotics, antidepressants, benzodiazepines, or acetylcholinesterase inhibitors and memantine. Due to the diversity of manifestations and causes of BPSD, a unified pharmacotherapeutic approach cannot be applied. Non-pharmacological approaches should always be preferred, except in cases of severe depression, psychosis, or aggression that may endanger the patient or someone else. In practice, many medications indicated for BPSD therapy are used off-label. The pharmacotherapy of BPSD should only begin after ruling out other causes of BPSD. Furthermore, it should only be initiated after considering all risks and potential benefits, starting with low geriatric doses, monitoring side effects, regularly reassessing effectiveness, and administering medications for the shortest possible duration should be also applied.

• Klíčová slova
• behavioural and psychological symptoms of dementia, dementia., psychopharmacology,
• MeSH
• antipsychotika terapeutické užití   MeSH
• demence * komplikace   MeSH
• duševní poruchy farmakoterapie   MeSH
• kognitivní poruchy etiologie   farmakoterapie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antipsychotika MeSH

The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA's blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

• Klíčová slova
• blood monitoring, clozapine, regulation, treatment-resistant schizophrenia,
• MeSH
• agranulocytóza * chemicky indukované   MeSH
• antipsychotika * terapeutické užití   škodlivé účinky   MeSH
• klozapin * terapeutické užití   škodlivé účinky   krev   MeSH
• lidé MeSH
• monitorování léčiv * metody   normy   MeSH
• poradní výbory MeSH
• refrakterní schizofrenie farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antipsychotika * MeSH
• klozapin * MeSH

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial-based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers. METHOD: The study examined drug management decisions for several behavioural disturbances in patients with FTD by 21 experts across European expert centres affiliated with the European Reference Network for Rare Neurological Diseases (ERN-RND). RESULTS: The study revealed the highest consensus on drug treatments for physical and verbal aggression, impulsivity and obsessive delusions. Antipsychotics (primarily quetiapine) were recommended for behaviours posing safety risks to both patients and caregivers (aggression, self-injury and self-harm) and nightly unrest. Selective serotonin reuptake inhibitors were recommended for perseverative somatic complaints, rigidity of thought, hyperphagia, loss of empathy and for impulsivity. Trazodone was specifically recommended for motor unrest, mirtazapine for nightly unrest, and bupropion and methylphenidate for apathy. Additionally, bupropion was strongly advised against in 10 out of the 14 behavioural symptoms, emphasizing a clear recommendation against its use in the majority of cases. CONCLUSIONS: The survey data can provide expert guidance that is helpful for healthcare professionals involved in the treatment of behavioural symptoms. Additionally, they offer insights that may inform prioritization and design of therapeutic studies, particularly for existing drugs targeting behavioural disturbances in FTD.

• Klíčová slova
• drug therapy, expert testimony, frontotemporal dementia, neurobehavioural manifestations, neurodegenerative diseases,
• MeSH
• agrese účinky léků   MeSH
• antipsychotika terapeutické užití   MeSH
• frontotemporální demence * farmakoterapie   MeSH
• impulzivní chování účinky léků   MeSH
• konsensus MeSH
• lidé MeSH
• selektivní inhibitory zpětného vychytávání serotoninu terapeutické užití   MeSH
• vzácné nemoci farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antipsychotika MeSH
• selektivní inhibitory zpětného vychytávání serotoninu MeSH

Drug induced akathisia is classified as an extrapyramidal adverse effect. Although akathisia is quite common extrapyramidal adverse effect, it is often overlooked or mistaken for restlessness or agitation of another etiology. Drugs associated with the risk of extrapyramidal adverse effects (antipsychotics, antiemetics, antidepressants) belong to frequently used pharmacotherapy. The use of these drugs is often complicated by serious condition of a patient and several other comorbidities, which increase the risk of the aforementioned adverse effects. In many situations, akathisia can be more difficult to recognize and more easily attributed to non-drug etiology, especially outside the fields of psychiatry and neurology. The variability of the clinical symptoms and the similarity to other clinical entities that occur frequently (anxiety, delirium, agitated depression, restless legs syndrome, etc.) can lead to difficult determination of the etiology and to the administration of medication, which tends to worsen the problem. At the same time, akathisia can be a source of very strong distress for a patient and fundamentally reduce his quality of life.

• Klíčová slova
• drug-induced movement disorders, akathisia, antipsychotics, antidepressants, antiemetics,
• MeSH
• antipsychotika škodlivé účinky   MeSH
• lidé MeSH
• poléková akatizie * etiologie   diagnóza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antipsychotika MeSH

BACKGROUND: We need to better understand the risk factors and predictors of medication-related weight gain to improve metabolic health of individuals with schizophrenia. This study explores how trajectories of antipsychotic medication (AP) use impact body weight early in the course of schizophrenia. METHODS: We recruited 92 participants with first-episode psychosis (FEP, n = 92) during their first psychiatric hospitalization. We prospectively collected weight, body mass index (BMI), metabolic markers, and exact daily medication exposure during 6-week hospitalization. We quantified the trajectory of AP medication changes and AP polypharmacy using a novel approach based on meta-analytical ranking of medications and tested it as a predictor of weight gain together with traditional risk factors. RESULTS: Most people started treatment with risperidone (n = 57), followed by olanzapine (n = 29). Then, 48% of individuals remained on their first prescribed medication, while 33% of people remained on monotherapy. Almost half of the individuals (39/92) experienced escalation of medications, mostly switch to AP polypharmacy (90%). Only baseline BMI was a predictor of BMI change. Individuals in the top tercile of weight gain, compared to those in the bottom tercile, showed lower follow-up symptoms, a trend for longer prehospitalization antipsychotic treatment, and greater exposure to metabolically problematic medications. CONCLUSIONS: Early in the course of illness, during inpatient treatment, baseline BMI is the strongest and earliest predictor of weight gain on APs and is a better predictor than type of medication, polypharmacy, or medication switches. Baseline BMI predicted weight change over a period of weeks, when other traditional predictors demonstrated a much smaller effect.

• Klíčová slova
• antipsychotics, polypharmacy, predictor, schizophrenia, weight gain,
• MeSH
• antipsychotika * terapeutické užití   škodlivé účinky   MeSH
• dospělí MeSH
• hmotnostní přírůstek * účinky léků   MeSH
• hospitalizace * statistika a číselné údaje   MeSH
• index tělesné hmotnosti * MeSH
• lidé MeSH
• mladý dospělý MeSH
• olanzapin terapeutické užití   MeSH
• polypharmacy MeSH
• prospektivní studie MeSH
• psychotické poruchy * farmakoterapie   MeSH
• risperidon terapeutické užití   škodlivé účinky   MeSH
• rizikové faktory MeSH
• schizofrenie * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH
• olanzapin MeSH
• risperidon MeSH

BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

• Klíčová slova
• AM251, Haloperidol, Kynurenine Pathway, Novel object recognition test, Peripubertal treatment, Schizophrenia,
• MeSH
• antipsychotika farmakologie   MeSH
• haloperidol farmakologie   MeSH
• kognitivní dysfunkce metabolismus   farmakoterapie   MeSH
• krysa rodu Rattus MeSH
• kyselina kynurenová * metabolismus   MeSH
• methylazoxymethanolacetát * analogy a deriváty   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny farmakologie   MeSH
• potkani Sprague-Dawley * MeSH
• prefrontální mozková kůra * metabolismus   účinky léků   MeSH
• pyrazoly farmakologie   MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• schizofrenie * metabolismus   farmakoterapie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AM 251 MeSH Prohlížeč
• antipsychotika MeSH
• haloperidol MeSH
• kyselina kynurenová * MeSH
• methylazoxymethanolacetát * MeSH
• piperidiny MeSH
• pyrazoly MeSH
• receptor kanabinoidní CB1 MeSH

BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.

• Klíčová slova
• Antipsychotic, GLP-1 receptor agonist, Olanzapine, metabolic adverse effects, Schizophrenia,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• antipsychotika farmakologie   škodlivé účinky   MeSH
• benzodiazepiny farmakologie   škodlivé účinky   MeSH
• glukagonu podobné peptidy * analogy a deriváty   farmakologie   MeSH
• hmotnostní přírůstek účinky léků   MeSH
• imunoglobuliny - Fc fragmenty * farmakologie   MeSH
• kalorická restrikce metody   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• olanzapin * farmakologie   škodlivé účinky   MeSH
• potkani Sprague-Dawley * MeSH
• přijímání potravy účinky léků   MeSH
• receptor pro glukagonu podobný peptid 1 metabolismus   MeSH
• rekombinantní fúzní proteiny * farmakologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• antipsychotika MeSH
• benzodiazepiny MeSH
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy * MeSH
• imunoglobuliny - Fc fragmenty * MeSH
• olanzapin * MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny * MeSH

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

• Klíčová slova
• Clozapine/administration and dosage, Clozapine/adverse effects, Clozapine/therapeutic use, Drug labeling, Europe, Eastern, Schizophrenia,
• MeSH
• antipsychotika * škodlivé účinky   MeSH
• databáze faktografické MeSH
• farmakovigilance * MeSH
• klozapin * škodlivé účinky   MeSH
• lidé MeSH
• nežádoucí účinky léčiv epidemiologie   MeSH
• schizofrenie farmakoterapie   MeSH
• systémy pro sběr zpráv o nežádoucích účincích léků statistika a číselné údaje   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• východní Evropa epidemiologie   MeSH
• Názvy látek
• antipsychotika * MeSH
• klozapin * MeSH

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

• Klíčová slova
• Aripiprazole, Olanzapine, Personalised medicine, Pharmacokinetics, Quetiapine, Risperidone,
• MeSH
• antipsychotika * farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• monitorování léčiv * metody   MeSH
• schizofrenie farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Negative symptoms (NS) represent a detrimental symptomatic domain in schizophrenia affecting social and occupational outcomes. AIMS: We aimed to identify factors from the baseline visit (V1) - with a mean illness duration of 0.47 years (SD = 0.45) - that predict the magnitude of NS at the follow-up visit (V3), occurring 4.4 years later (mean +/- 0.45). METHOD: Using longitudinal data from 77 first-episode schizophrenia spectrum patients, we analysed eight predictors of NS severity at V3: (1) the age at disease onset, (2) age at V1, (3) sex, (4) diagnosis, (5) NS severity at V1, (6) the dose of antipsychotic medication at V3, (7) hospitalisation days before V1 and; (8) the duration of untreated psychosis /DUP/). Secondly, using a multiple linear regression model, we studied the longitudinal relationship between such identified predictors and NS severity at V3 using a multiple linear regression model. RESULTS: DUP (Pearson's r = 0.37, p = 0.001) and NS severity at V1 (Pearson's r = 0.49, p < 0.001) survived correction for multiple comparisons. The logarithmic-like relationship between DUP and NS was responsible for the initial stunning incremental contribution of DUP to the severity of NS. For DUP < 6 months, with the sharpest DUP/NS correlation, prolonging DUP by five days resulted in a measurable one-point increase in the 6-item negative symptoms PANSS domain assessed 4.9 (+/- 0.6) years after the illness onset. Prolongation of DUP to 14.7 days doubled this NS gain, whereas 39 days longer DUP tripled NS increase. CONCLUSION: The results suggest the petrification of NS during the early stages of the schizophrenia spectrum and a crucial dependence of this symptom domain on DUP. These findings are clinically significant and highlight the need for primary preventive actions.

• Klíčová slova
• First-episode schizophrenia, duration of untreated psychosis, longitudinal study, negative symptoms, prediction,
• MeSH
• antipsychotika * terapeutické užití   MeSH
• lidé MeSH
• multivariační analýza MeSH
• psychotické poruchy * diagnóza   farmakoterapie   MeSH
• schizofrenie * diagnóza   farmakoterapie   MeSH
• syndrom Nijmegen breakage * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika * MeSH