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

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

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

• MeSH
• antipsychotika * terapeutické užití   MeSH
• lidé MeSH
• psychotické poruchy * farmakoterapie   prevence a kontrola   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH

AIM: Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders. METHODS: In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats. RESULTS: Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM. CONCLUSION: Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.

• Klíčová slova
• adipokine, antipsychotic, lipid profile, methylazoxymethanol, schizophrenia,
• MeSH
• antipsychotika * terapeutické užití   MeSH
• haloperidol * toxicita   MeSH
• krysa rodu Rattus MeSH
• lipidy MeSH
• methylazoxymethanolacetát toxicita   analogy a deriváty   MeSH
• modely nemocí na zvířatech MeSH
• olanzapin toxicita   MeSH
• potkani Sprague-Dawley MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika * MeSH
• haloperidol * MeSH
• lipidy MeSH
• methylazoxymethanol MeSH Prohlížeč
• methylazoxymethanolacetát MeSH
• olanzapin MeSH

Dose-response relationships are not fully understood for antipsychotics. Especially in the case of multimodal antipsychotics, these relationships cannot be simplified to the level of dopaminergic receptor occupancy alone. In general, for most antipsychotics, there is no linear dose-response relationship. Reasons for this include, among others, pharmacokinetic factors affecting plasma levels. Based on meta-analyses, the doseresponse curve appears to be bell-shaped. However, in the case of some antipsychotics, it appears that even increasing the dose beyond the recommended range could yield further increases in efficacy. It should be stressed that this is an off-label procedure and cannot generally be recommended and there is not enough valid information for general conclusions for these antipsychotics either. Mini-invasive sampling and alternative matrices such as saliva or dry blood spots could open the way to more frequent monitoring of antipsychotics and a better understanding of doseresponse relationships.

• Klíčová slova
• Safety, Therapeutic drug monitoring, dose- response relationship, efficacy, lurasidone, safety,
• MeSH
• antipsychotika * terapeutické užití   MeSH
• lidé MeSH
• lurasidon hydrochlorid terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH
• lurasidon hydrochlorid MeSH

Dose-response relationships are not fully understood for antipsychotics. Especially in the case of multimodal antipsychotics, these relationships cannot be simplified to the level of dopaminergic receptor occupancy alone. In general, for most antipsychotics, there is no linear dose-response relationship. Reasons for this include, among others, pharmacokinetic factors affecting plasma levels. Based on meta-analyses, the doseresponse curve appears to be bell-shaped. However, in the case of some antipsychotics, it appears that even increasing the dose beyond the recommended range could yield further increases in efficacy. It should be stressed that this is an off-label procedure and cannot generally be recommended and there is not enough valid information for general conclusions for these antipsychotics either. Mini-invasive sampling and alternative matrices such as saliva or dry blood spots could open the way to more frequent monitoring of antipsychotics and a better understanding of doseresponse relationships.

• Klíčová slova
• Safety, Therapeutic drug monitoring, dose- response relationship, efficacy, lurasidone, safety,
• MeSH
• antipsychotika * terapeutické užití   MeSH
• lurasidon hydrochlorid terapeutické užití   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika * MeSH
• lurasidon hydrochlorid MeSH