Papers by Dr. István Laszlovszky
Bioorganic & Medicinal Chemistry Letters, 2012
Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyrid... more Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D 3 /D 2 compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D 3 and D 2 receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012.
European Neuropsychopharmacology, Oct 1, 2016
P.3.d. Psychotic disorders and treatment − Treatment (clinical) Results: The majority of patients... more P.3.d. Psychotic disorders and treatment − Treatment (clinical) Results: The majority of patients were discharged from hospital with second-generation antipsychotics: 115 (65.7%) patients with LAI second-generation antipsychotics and 141 (80.6%) with second generation oral antipsychotics. The minority of patients were discharged from hospital with first generation antipsychotics: 35 (57.4%) with LAI, and 53 (86.9%) with first generation oral antipsychotics. Sixty-three (33.7%) patients were treated with monotherapy, 119 (63.6%) with combination of two antipsychotics and 5 (2.7%) with combination of three antipsychotics. Sixty-six (35.3%) patients had clozapine in prescriptions throughout the treatment, but it was combined with other drugs for psychosis in the majority of cases. Drugs were generally prescribed in their recommended doses, with clozapine being prescribed at the lower end of its therapeutic range. 95% of patients received psychiatric co-medications such as anxiolytics or antidepressants. Rehospitalization rate during the first 12 months was 36.4% (95% CI 29.5-43.1). The main reason for the hospital readmission was relapse in 38 (57.6%) patients (95% CI 45.9-68.6), followed by non-compliance in 15 (22.7%) patients (95% CI 13.3-32.9), social reasons in 5 (7.6%) patients (95% CI 1.8-14.5), side effects in 4 (6.1%) patients (95% CI 45 1.4-12.1), and suicide attempt in 1 (1.5%) patient (95% CI 0.0-10.3). Conclusion: Use of oral and LAI second-generation antipsychotics in Psychiatric Hospital "Sveti Ivan" is extensive. More than half of the patients participating in this study were on a LAI. Contrary to recommendations in the literature, combination of two drugs for psychosis was the most common pattern of use, while the prescription frequency for antipsychotic monotherapy was low. Also, most patients received psychiatric co-medications such as anxiolytics or antidepressants. Rehospitalization rate during the first 12 months was similar to those reported in literature [1]. The findings of this study contribute to mapping of the use of drugs for psychosis and therefore may improve treatment outcomes.
S419 with an asthenic constitution. The identification of indices of the Tanner index at baseline... more S419 with an asthenic constitution. The identification of indices of the Tanner index at baseline can play the role of a predictive factor for the development of visceral obesity in schizophrenic patients in case of planned use of quetiapine as a basic therapy. In the case of high risk of development of this unwanted phenomenon it is preferable to use antipsychotics that do not cause weight gain, such as ziprasidone and aripiprazole, especially in first-episode schizophrenia when patients are especially vulnerable to developing neuroleptic obesity. Thus, by means of anthropometric examination with the monitoring of the fatty composition of the body in schizophrenic patients the frequency of unwanted phenomena such as visceral obesity and metabolic syndrome can be reduced and the risk of developing cardiovascular endocrine diseases lowered, and quality of life of patients and their social functioning improved. Acknowledgement: The study was performed with support of Russian Science Foundation grant no. 18-15-00011 "Schizophrenia combined with metabolic syndrome: clinical-constitutional factors and molecular markers".
P.3.d. Psychotic disorders and treatment − Treatment (clinical) Results: The majority of patients... more P.3.d. Psychotic disorders and treatment − Treatment (clinical) Results: The majority of patients were discharged from hospital with second-generation antipsychotics: 115 (65.7%) patients with LAI second-generation antipsychotics and 141 (80.6%) with second generation oral antipsychotics. The minority of patients were discharged from hospital with first generation antipsychotics: 35 (57.4%) with LAI, and 53 (86.9%) with first generation oral antipsychotics. Sixty-three (33.7%) patients were treated with monotherapy, 119 (63.6%) with combination of two antipsychotics and 5 (2.7%) with combination of three antipsychotics. Sixty-six (35.3%) patients had clozapine in prescriptions throughout the treatment, but it was combined with other drugs for psychosis in the majority of cases. Drugs were generally prescribed in their recommended doses, with clozapine being prescribed at the lower end of its therapeutic range. 95% of patients received psychiatric co-medications such as anxiolytics or antidepressants. Rehospitalization rate during the first 12 months was 36.4% (95% CI 29.5-43.1). The main reason for the hospital readmission was relapse in 38 (57.6%) patients (95% CI 45.9-68.6), followed by non-compliance in 15 (22.7%) patients (95% CI 13.3-32.9), social reasons in 5 (7.6%) patients (95% CI 1.8-14.5), side effects in 4 (6.1%) patients (95% CI 45 1.4-12.1), and suicide attempt in 1 (1.5%) patient (95% CI 0.0-10.3). Conclusion: Use of oral and LAI second-generation antipsychotics in Psychiatric Hospital "Sveti Ivan" is extensive. More than half of the patients participating in this study were on a LAI. Contrary to recommendations in the literature, combination of two drugs for psychosis was the most common pattern of use, while the prescription frequency for antipsychotic monotherapy was low. Also, most patients received psychiatric co-medications such as anxiolytics or antidepressants. Rehospitalization rate during the first 12 months was similar to those reported in literature [1]. The findings of this study contribute to mapping of the use of drugs for psychosis and therefore may improve treatment outcomes.
European Psychiatry, Apr 1, 2021
Natural caregivers of patients with schizophrenia are often subjected to stigma by virtue of thei... more Natural caregivers of patients with schizophrenia are often subjected to stigma by virtue of their association with patients. Affiliate stigma expose caregivers to community rejection, isolation and may have a negative impact on their psychological wellbeing. Objectives: This study aimed to assess perceived stigma and burden in a Tunisian population of natural caregivers of patients with schizophrenia and to identify risk factors for developing such disorders. Methods: We conducted a cross-sectional, descriptive and analytical study, including 80 natural caregivers of patients with schizophrenia. We used the Stigma Devaluation Scale (SDS) to assess stigma and the Zarit Burden Interview (ZBI) to evaluate burden. Results: The average age of natural caregivers was 55.7 years. The sex ratio (M/F) was 0.86. The mean score of perceived stigma in patients was 24.7. That of perceived stigma in caregivers was 15.34. Assessing the burden on caregivers estimated an average score of 58, corresponding to a severe burden. Medium to high burden was found in 78% of participants. Perceived stigma scores were significantly higher among illiterate caregivers, those linking schizophrenia to hereditary causes, among parents, and in case of daily contact with the patient. Scores of perceived stigma in caregivers were also significantly correlated with burden score. Conclusions: Natural caregivers of patients with schizophrenia are exposed to affiliate stigma and experience an important level of burden. Our findings emphasize the need to support natural caregivers of persons with schizophrenia and to develop strategies to combat stigmatization among patients as well as their natural caregivers.
European Psychiatry, Apr 1, 2021
glucose and insulin. The visceral fat level was determined through the non-invasive bioimpedance ... more glucose and insulin. The visceral fat level was determined through the non-invasive bioimpedance analysis with an "Omron BF508" scale and body composition monitor. Suicide risk was assessed using Beck Hopelessness Inventory. There were identified two groups of examined: with MetS and without MetS. In both groups were distinguished two subgroups: patients with normal range of hopelessness and patients with mild and moderate hopelessness. Subgroups were compared among themselves for a number of anthropometric, biochemical and clinical indicators. Statistical analysis was conducted using Mann-Whitney U-test. Reliability level corresponded to p<0.05. This study was supported by a grant from the Russian Science Foundation 18-15-00011. Results: Waist circumference, body weight and BMI in subgroup with normal hopelessness range in the group of patients with MetS were significantly higher (figure 1). Conclusions: We were able to establish a negative relationship between the waist circumference, body weight and BMI with suicide risk in schizophrenia patients. It can be assumed that adipose tissue can play a "protective" role in the suicidal behavior of schizophrenia patients.
Background: How to use antipsychotic medication in young patients with schizophrenia continues to... more Background: How to use antipsychotic medication in young patients with schizophrenia continues to be a first-line subject for psychiatric specialists. Based on developmental theory, early intervention through antipsychotic treatment is beneficial, beyond symptom control, for neuroprotection and the prevention of potential cognitive deterioration in patients with schizophrenia. Impairment of global functionality and cognitive capacity has a substantial impact on the family, society and the actual costs of the disease. Each reactivation of the symptomatology involves significant personal and socioeconomic costs and is a negative prognostic factor of the disorder. [1] Aims: This research aims to emphasize the importance of the initiation of antipsychotic treatment since the first episode in patients with schizophrenia and implicitly the need for early diagnosis by observing the diagnosis criteria (ICD 10 and DSM 5). At the same time, beyond the early initiation of antipsychotic therapy, the study aims to emphasize the importance of therapeutic adherence to maintain good overall functionality in schizophrenia. Methods: The present study is retrospective, assuming a batch of 100 patients hospitalized between January 2015 and January 2016 at Socola Institute of Psychiatry in Iasi, Romania, in the first psychotic episode with symptoms of schizophrenia. The observation sheets of these patients were analysed taking into account the presence of a premorbid eventual personality, the mode of manifestation of the symptoms, with the dominance of the positive / negative / cognitive symptoms and the antipsychotic used in initiating the psychopharmacological treatment. In order to avoid the occurrence of parasite variables only male patients aged between 18 and 25 years residing in Iasi were selected. These patients were searched in the hospital database by December 2017, following the number of emergency relatives that coincided with new recurrences of symptomatology. In the case of relapsed patients, the new observation sheets were analysed in order to underline the therapeutic adherence of each individual. Results: The present study shows that 82% of patients with first psychotic episodes with symptoms of schizophrenia were treated with atypical antipsychotics, 58% with done's, 32% with pine's and 10% with aripiprazole. All patients in the batch received prescription for antipsychotic treatment. Of the 18% of patients treated with first-generation antipsychotics, 88.8% experienced relapse during the follow-up pe
European Neuropsychopharmacology, Oct 1, 2014
P.3.d. Psychotic disorders and treatment − Treatment (clinical) significant differences in antips... more P.3.d. Psychotic disorders and treatment − Treatment (clinical) significant differences in antipsychotic treatment were found in relation to withdrawal (lower for aripiprazole), and relapse (greater for aripiprazole in monotherapy, lower for polytherapy). These findings were also significant in the Cox Regression analyses adjusted for gender, substance use, CGI, GAF, antipsychotic doses and subtype of FEP diagnosis. We did not find differences between antipsychotics in the risk of admission. Treatment with LAIA was not associated with a lower risk of relapse or admission. Conclusions: In pragmatic conditions, although aripiprazole seems to be the better tolerated antipsychotic drug, it is associated with a higher risk of relapse. Polytherapy is used in a significant proportion of FEP patients and it is associated with a lower risk of relapse. Disclosure statement: AC, LG, DB, SS, AM, AR, MDM and JL have received honoraria for lectures or advisory boards from Janssen-Cilag. LG, AM, SS, and JL have received honoraria for lectures or advisory boards from Otsuka and Lundbeck. Although the need of conducting a pragmatic study about antipsychotic treament and outcome of first episode of psychosis was originated from a meeting of several researchers attending to an advisory board from Janssen-Cilag ("Proyecto Vive"), our study has not been funded or received support by Janssen-Cilag or any other pharmacological company. Moreover, pharmaceutical industry has not participated in the design or development of the study, the statistical analysis, presentation of results or the discussion.
International Clinical Psychopharmacology, Nov 1, 2017
Cariprazine, a potent dopamine D 3 and D 2 receptor partial agonist antipsychotic with preferenti... more Cariprazine, a potent dopamine D 3 and D 2 receptor partial agonist antipsychotic with preferential binding to D 3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients who received ≥ 1 dose of study drug) and modal daily dose subgroups (1.5-3, 4.5-6, and 9-12 mg/day). These exploratory findings were summarized using descriptive statistics. Cariprazine was generally well tolerated. The incidence of treatmentemergent adverse events versus placebo was similar for cariprazine 1.5-3 mg/day and higher for cariprazine 4.5-6 and 9-12 mg/day; a dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. The mean changes in metabolic parameters were generally similar in cariprazine-treated and placebo-treated patients. There was no prolactin level increase or QTc value greater than 500 ms; small increases in mean body weight (∼1 to 2 kg) versus placebo were observed. Within the Food and Drug Administrationapproved dose range (1.5 − 6 mg/day), cariprazine was generally safe and well tolerated in patients with schizophrenia.
European Neuropsychopharmacology, Dec 1, 2019
Background: Abnormalities within hypothalamus-pituitaryadrenal (HPA) axis might interact with oth... more Background: Abnormalities within hypothalamus-pituitaryadrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adoles
Naunyn-schmiedebergs Archives of Pharmacology, Jun 13, 2008
RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl]-3-... more RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl]-3-pyridinesulfonic amide dihydrochloride) displayed subnanomolar affinity to human and rat dopamine D3 receptors (pKi 10.49 and 9.42, respectively) and nanomolar affinity to human and rat D2 receptors (pKi 8.23 and 7.62, respectively). No apparent interactions were found with the other 44 receptors and four channel sites tested in this study. RG-15 inhibited dopamine-stimulated [35S]GTPgammaS binding in membranes from rat striatum, in murine A9 cells expressing human D2L receptors and in CHO cells expressing human D3 receptors (IC50 values were 21.2, 36.7 and 7.2 nM, respectively). In these tests RG-15 showed the highest affinity toward D3 receptors when compared to amisulpride, haloperidol and SB-277011. RG-15, similar to haloperidol and amisulpride, dose-dependently inhibited in vivo [3H]raclopride binding in mouse striatum, enhanced dopamine turnover and synthesis rate in mouse and rat striatum and olfactory tubercle. SB-277011 did not change [3H]raclopride binding in mouse striatum nor biosynthesis or turnover rates in either region in mice or rats. RG-15 and haloperidol, but not SB-277011, antagonised dopamine synthesis inhibition induced by the D3/D2 full agonist 7-OH-DPAT in GBL-treated mice. RG-15, but not SB-277011, elevated plasma prolactin levels. In vitro receptor binding and functional experiments demonstrated that RG-15 had an antagonist profile on both D3 and D2 receptors. with high selectivity for dopamine D3 receptors over D2 receptors. However, in vivo, its neurochemical actions were similar to those of D2 receptor antagonists. Neurochemical comparison of RG-15 with antagonists having a different affinity and selectivity toward D3 and D2 receptors indicate that D3 receptors have little, if any, role in the control of presynaptic dopamine biosynthesis/release in dopaminergic terminal regions.
European Neuropsychopharmacology, Oct 1, 2014
Purpose of the study: Bipolar disorder (BD) is characterized by episodes of depression and mania ... more Purpose of the study: Bipolar disorder (BD) is characterized by episodes of depression and mania or hypomania interspaced by phases of euthymia. Meta-analyses suggest that attention/speed, memory, and executive functions are markedly reduced in euthymic BD. Whereas morphological changes have been found in BD, the linkage between structural abnormalities and cognitive impairment is unclear. Thus, other methods may contribute to advancing the understanding of the pathophysiology of cognition in BD. Recent studies have investigated the pathophysiology of bipolar disorder using cerebrospinal biomarkers [1−2]. Alterations in CSF concentrations suggest impairment in amyloid precursor protein metabolism and axonal damage. The current study aimed to investigate if CSF biomarkers used to study neurodegenerative processes [total and phosphorylated tau, amyloid beta (Ab)1−42, ratios of Ab42/40 and Ab42/38, soluble amyloid precursor protein a and b] and axonal damage (neurofilament light chain protein) predict cognitive functioning in euthymic bipolar disorder. Methods: Patients with bipolar disorder type I and II were recruited from the St. Göran Bipolar Project, a clinically based longitudinal study. To address whether associations were unique to BD we also included healthy age-and gender-matched controls that were randomly selected from the general population. Only patients (N = 82, Age M=38.3±12.6, M/F 34/48) and controls (N = 71, Age M=37.8±14.6, M/F) that had completed sampling of CSF and undergone a comprehensive neuropsychological examination were included in this study. We applied linear regression models to account for cognitive performance in five domains (memory/learning, speed/attention, executive, visuospatial, and verbal functions) using CSF biomarkers as predictors. The following variables were included as covariates for patients: bipolar subtype, age, CGI BP total score, YMRS, MADRS, mood stabilizers, lithium, antidepressants, antipsychotics, benzodiazepines, anticonvulsants, and anxiolytics. Models were repeated in the healthy age-and gender-matched controls. Summary of results: In patients, the CSF biomarkers accounted for a significant proportion of the variance (15−36%, p = 0.002 − <0.0005) in all cognitive domains independently of covariates. The largest variance was accounted for in the visuospatial functions domain whereas the smallest variance explained was in the memory/learning domain. The ratios of Ab42/40 and Ab42/38 were consistently associated with altered cognitive functioning. The CSF biomarkers specifically reflecting Alzheimer-like brain changes, i.e., Ab1−42 and P-tau, did not account for any of the
European Neuropsychopharmacology, Oct 1, 2017
, delusions, conceptual disorganization, and hallucinatory behavior [5]. Sustained remission was ... more , delusions, conceptual disorganization, and hallucinatory behavior [5]. Sustained remission was defined as meeting remission criteria at the current visit and all prior double-blind visits; the percentage of patients with sustained remission for at least a 6-month duration was also evaluated. Time to loss of sustained remission was estimated using Kaplan-Meier analysis. Hazard ratio (HR, 95% confidence interval [CI]) estimate was based on a Cox proportional hazards regression model. Results: At randomization, 169/200 (84.5%) patients met symptomatic remission criteria. During double-blind treatment, 60.5% of cariprazine-treated patients and 34.9% of placebo-treated patients sustained remission through the final visit (number needed to treat = 4). Time to loss of sustained remission was significantly longer for cariprazine versus placebo (HR [95% CI]: 0.51 [0.33, 0.79]; P = 0.002). Among all randomized patients, 39.6% of cariprazine-treated patients and 21.2% of placebo-treated patients had sustained remission at their final visit and for ≥6 months prior with an odds ratio (OR [95% CI]) that was significant in favor of cariprazine (2.44 [1.30, 4.55]; P = 0.006). The proportion of patients with sustained remission for ≥6 consecutive months at any time during double-blind treatment was also significantly greater for patients treated with cariprazine (41.6%) versus placebo (27.3%) (OR [95% CI] = 1.90 [1.05, 3.44]; P = 0.038). Conclusion: Cariprazine was associated with significantly higher rates and longer duration of sustained remission. The likelihood of sustaining remission for ≥6 consecutive months during double-blind treatment was generally greater for cariprazine versus placebo, suggesting that cariprazine was effective in maintaining stable remission in patients with schizophrenia.
European Neuropsychopharmacology, Sep 1, 2015
P.3.d. Psychotic disorders and treatment − Treatment (clinical) the total antipsychotics dose, PP... more P.3.d. Psychotic disorders and treatment − Treatment (clinical) the total antipsychotics dose, PP dose, the total benzodiazepine dose and the PP administration period. However, in the 3 cases of QTc interval prolongation, they had a common factor which was female sex, and in addition dyslipidemia or diabetes was a risk factor for cardiovascular system. Conclusions: In the analysis of the ECG across all patients, no significant correlation factors with ECG changes were found. However, factors which are a common background were observed in patients with QTc interval prolongation. In the future, use of a larger sample is needed, including the inclusion of detailed genetic background.
Journal of Affective Disorders, 2018
Background We evaluated the safety/tolerability of longer-term open-label treatment with caripraz... more Background We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania. Methods In this multinational, multicenter study, open-label, flexible-dose, cariprazine 3-12 mg/d was administered for up to 16 weeks to patients (18-65 years) with bipolar mania. Safety evaluations
Bipolar Disorders, Feb 1, 2015
Objectives: Cariprazine, an orally active and potent dopamine D 3 and D 2 receptor partial agonis... more Objectives: Cariprazine, an orally active and potent dopamine D 3 and D 2 receptor partial agonist with preferential binding to D 3 receptors, is being developed for the treatment of schizophrenia and bipolar mania. This Phase II trial evaluated the efficacy, safety, and tolerability of cariprazine versus placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. Methods: This was a multinational, randomized, double-blind, placebocontrolled, flexible-dose study of cariprazine 3-12 mg/day in patients with acute manic or mixed episodes associated with bipolar I disorder. Following washout, patients received three weeks of double-blind treatment. The primary and secondary efficacy parameters were change from baseline to Week 3 in Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively. Posthoc analysis evaluated changes on YMRS single items. Results: In each group, 118 patients received double-blind treatment; 61.9% of placebo and 63.6% of cariprazine patients completed the study. The overall mean daily dose of cariprazine was 8.8 mg/day. At Week 3, cariprazine significantly reduced YMRS and CGI-S scores versus placebo, with least square mean differences of À6.1 (p < 0.001) and À0.6 (p < 0.001), respectively. On each YMRS item, change from baseline to Week 3 was significantly greater for cariprazine versus placebo (all, p < 0.05). A significantly greater percentage of cariprazine patients than placebo patients met YMRS response (48% versus 25%; p < 0.001) and remission (42% versus 23%; p = 0.002) criteria at Week 3. Adverse events (AEs) led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic parameters were similar between groups, with the exception of fasting glucose; increases in glucose were significantly greater for cariprazine versus placebo (p < 0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale scores, more cariprazine than placebo patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms (parkinsonism) (cariprazine: 16%; placebo: 1%). Conclusion: Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.
Ukraïnsʹkij vìsnik psihonevrologìï, Oct 14, 2020
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Papers by Dr. István Laszlovszky