tanja veselinovic - Academia.edu (original) (raw)
Papers by tanja veselinovic
Journal of Clinical Psychopharmacology, 2019
Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics ... more Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D 2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). Methods: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. Results: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. Conclusions: Our results suggest that high plasma levels and consequently high occupancy at D 2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.
European Neuropsychopharmacology, 2019
Background: The Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium promot... more Background: The Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium promotes collaborative approaches to address the problem of insufficient power and reproducibility in neuroimaging studies [1]. By applying harmonized protocols to existing MRI and genetic samples, ENIGMA maximizes the utility of archival data from around the world [2,3]. Recent projects include some of the world's largest collaborative research efforts in psychiatry, neurogenetics, and neuroimaging, involving more than 900 scientists [3,4]. Methods: ENIGMA's projects contribute to psychiatric neuroimaging research through team science and innovative technical analyses. ENIGMA: 1. Incorporates over 300 sites in a global network spanning 35 countries. The network is cultivated through international leadership and low barriers to participation, promoting collaboration among multidisciplinary scientists. The consortium does not require genetic samples, the forfeit of data, or dedicated funding to become a member. 2. Promotes technical development by curating protocols for analysis and quality control of imaging and genetic data. Protocols are tested by modality-specific working groups and distributed to each site. This model allows raw data to remain at its own site; summary statistics or derived measures allow for meta-analysis or distributed machine learning. 3. Fosters cultural developments in neuroimaging by providing: (a) open-source code, (b) opportunity for investigators to lead without securing prior funding, (c) training for junior researchers in novel techniques, and (d) an environment to build trust for further collaboration.
CNS Drugs
Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the sym... more Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D 2 /D 3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies.
This Dataset holds the results of the manuscript entitled "mGluR5 and GABAA Receptor Specifi... more This Dataset holds the results of the manuscript entitled "mGluR5 and GABAA Receptor Specific Parametric PET Atlas Construction - PET/MR Data Processing Pipeline, Validation and Application". In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non-displaceable binding potential (BPND), and total distribution volume (VT) based on simultaneously acquired bolus-infusion positron emission tomography (PET) and magnetic resonance imaging (MR) data. The pipeline was applied to [11C]ABP688-PET/MR (13 healthy male non- smokers, 26.6 ± 7.0 years) and [11C]Flumazenil-PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as VT and BPND atlases of mGluR5 and GABAA, were generated from these data. An evaluation of PET-to-PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [15O]H2O-template distribute...
International Journal of Neuropsychopharmacology, 2016
in mPFC and DA efflux in dSTR. NGB and Blo improved the scPCP-induced NOR deficit. The combinatio... more in mPFC and DA efflux in dSTR. NGB and Blo improved the scPCP-induced NOR deficit. The combination of SED NGB and Blon improved the NOR deficit. Conclusions: D 3 receptor blockade may contribute to the ability of Blon to increase cortical ACh and DA efflux, as well as to restore NOR in scPCP deficit. D 3 receptor blockade may be an important component of the efficacy of Blon to enhance neurotransmitter efflux and improve cognitive function.
Pharmacopsychiatry, 2015
Objectives: The ability of psychotropic drugs to pass the blood brain- and blood CSF-barrier depe... more Objectives: The ability of psychotropic drugs to pass the blood brain- and blood CSF-barrier depends on several properties of the drugs (e. g. lipophilicity, molecular size). Aim of this study was to investigate the relation of drug concentrations of different antidepressants in plasma and cerebrospinal fluid (CSF) as well as its relation to the administered daily dose of the drugs. Methods: Three groups (venlafaxine [VEN], n = 16, mirtazapine [MIR], n = 16 and citalopram [CIT], n = 20, of both sexes) were analyzed. All patients were on a stable therapy with fixed daily doses for at least seven days in a naturalistic clinical setting and underwent lumbar puncture for medical reasons. The correlation of drug levels in the blood, drug levels in the CSF and the daily dose of the drugs were calculated. Results: A strong correlation could be observed for VEN in plasma and CSF (p < 0.001). MIR in plasma and CSF were just trend-wise correlated (r = 0.441, p = 0.088) and no relation of daily dose and CSF levels of MIR could be observed (r = 0.313, p = 0.238). CIT levels showed a strong correlation between plasma and CSF (r = 0.890, p < 0.001). Conclusion: For the investigated antidepressants a (strong) relation of drug levels in serum and CSF could be observed, but the plasma and CSF concentrations do not reflect the administered daily dose of the drugs proper. These finding indicate that that therapeutic efforts should be driven by serum concentration rather than by dose optimization.
MMW Fortschritte der Medizin, Jan 19, 2008
Pharmacopsychiatry, 2011
Therapeutic Drug Monitoring (TDM) of psychotropic drugs is strongly depending on the validity of ... more Therapeutic Drug Monitoring (TDM) of psychotropic drugs is strongly depending on the validity of recommended therapeutic plasma concentration reference ranges. Rational pharmacotherapy is based on the assumption that plasma concentrations are directly related to target occupancy by the respective drug. Here we show that positron emission tomography (PET) of molecular drug targets in the brain (neuroreceptors and transporters) allows for establishment of these relationships, thereby providing guidance for TDM services. Associations between brain target occupancy, plasma concentrations, and clinical effects and adverse reactions will be discussed for the most commonly used antidepressant and antipsychotic drugs.
Pharmacopsychiatry, 2013
Rationale Many aspects of the neurobiology of schizophrenia, especially the physiological basis o... more Rationale Many aspects of the neurobiology of schizophrenia, especially the physiological basis of the negative symptoms and associated cognitive deficits, remain inadequately understood. Tandon and Greden (1989) postulated a central role of dopaminergic/cholinergic imbalance in schizophrenia. Objective/Methods In light of this hypothesis, we elected to investigate the effects of anticholinergic challenge on psychopathology, cognition and attention in 12 unmedicated patients with schizophrenia and 12 healthy controls. The first examination occurred before any pharmacological intervention; the second examination was carried out immediately following an intravenous infusion of 5 mg biperiden, a centrally acting antimuscarinergic agent. Results The biperiden challenge provoked a considerable increase in PANSS scores in both groups which was significantly more pronounced in patients (repeated measures analysis of variance (ANOVA) (rmANOVA): F(df)=6.4(1,22); p=0.019). The increase in the PANSS scores showed a significant negative correlation with age in patients. Biperiden caused considerable cognitive impairments in both groups. A significant group difference (rmANOVA) could be observed for TMT-B (F(df)=11.29(1,22); p=0.003). Conclusions The anticholinergic intervention caused more pronounced psychopathological and cognitive deteriorating effects in patients suffering from schizophrenia than in healthy volunteers. This could be related to the disrupted cholinergic transmission in schizophrenia. Our findings speak on behalf of the need of a more restrictive use of anticholinergics in psychiatric patients. The age-related attenuation of PANSS score increases in patients could be related to the age-dependent changes in dopamine dynamics and also to the age-associated decline of the availability of muscarinic receptors. Our results emphasise the need for further investigation of cholinergic disturbances in schizophrenia.
![Research paper thumbnail of Elevated D2/3-receptor availability in schizophrenia: A [18F]fallypride study](https://attachments.academia-assets.com/95923826/thumbnails/1.jpg)
](NeuroImage, 2008
Introduction: While post-mortem investigations on D 2/3 receptor (D 2/3-R) densities of patients ... more Introduction: While post-mortem investigations on D 2/3 receptor (D 2/3-R) densities of patients suffering from schizophrenia indicated elevated receptor-concentrations, PET studies show inconsistent results, with most studies demonstrating no change and a few showing elevations in the striatum. The most consistent finding yet is a reduction of D 2/3-R availability in the thalamus. Aim of the present study was to quantify D 2/3-Rs in medication-free patients with schizophrenia (SCZ) and healthy controls (CTL) using the high-affinity ligand [ 18 F]fallypride (FP).
Expert Review of Neurotherapeutics, 2013
Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to ... more Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.
Der Nervenarzt, 2012
Punkte sammeln auf... springermedizin.de/ eAkademie Teilnahmemöglichkeiten Diese Fortbildungseinh... more Punkte sammeln auf... springermedizin.de/ eAkademie Teilnahmemöglichkeiten Diese Fortbildungseinheit steht Ihnen als e.CME und e.Tutorial in der Springer Medizin e.Akademie zur Verfügung.-e.CME: kostenfreie Teilnahme im Rahmen des jeweiligen Zeitschriftenabonnements-e.Tutorial: Teilnahme im Rahmen des e.Med-Abonnements Zertifizierung Diese Fortbildungseinheit ist mit 3 CME-Punkten zertifiziert von der Landesärztekammer Hessen und der Nord rheinischen Akademie für Ärztliche Fort-und Weiterbildung und damit auch für andere Ärzte kammern anerkennungsfähig. Hinweis für Leser aus Österreich Gemäß dem Diplom-Fortbildungs-Programm (DFP) der Österreichischen Ärztekammer werden die in der e.Akademie erworbenen CME-Punkte hierfür 1:1 als fachspezifische Fortbildung anerkannt.
The Lancet Psychiatry, 2022
BACKGROUND Combining antipsychotics is common in schizophrenia treatment, despite evidence-based ... more BACKGROUND Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING German Federal Ministry of Education and Research.
Fortschritte der Medizin, 2008
The International Journal of Neuropsychopharmacology, 2014
Journal of Clinical Psychopharmacology, 2019
Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics ... more Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D 2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). Methods: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. Results: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. Conclusions: Our results suggest that high plasma levels and consequently high occupancy at D 2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.
European Neuropsychopharmacology, 2019
Background: The Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium promot... more Background: The Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium promotes collaborative approaches to address the problem of insufficient power and reproducibility in neuroimaging studies [1]. By applying harmonized protocols to existing MRI and genetic samples, ENIGMA maximizes the utility of archival data from around the world [2,3]. Recent projects include some of the world's largest collaborative research efforts in psychiatry, neurogenetics, and neuroimaging, involving more than 900 scientists [3,4]. Methods: ENIGMA's projects contribute to psychiatric neuroimaging research through team science and innovative technical analyses. ENIGMA: 1. Incorporates over 300 sites in a global network spanning 35 countries. The network is cultivated through international leadership and low barriers to participation, promoting collaboration among multidisciplinary scientists. The consortium does not require genetic samples, the forfeit of data, or dedicated funding to become a member. 2. Promotes technical development by curating protocols for analysis and quality control of imaging and genetic data. Protocols are tested by modality-specific working groups and distributed to each site. This model allows raw data to remain at its own site; summary statistics or derived measures allow for meta-analysis or distributed machine learning. 3. Fosters cultural developments in neuroimaging by providing: (a) open-source code, (b) opportunity for investigators to lead without securing prior funding, (c) training for junior researchers in novel techniques, and (d) an environment to build trust for further collaboration.
CNS Drugs
Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the sym... more Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D 2 /D 3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies.
This Dataset holds the results of the manuscript entitled "mGluR5 and GABAA Receptor Specifi... more This Dataset holds the results of the manuscript entitled "mGluR5 and GABAA Receptor Specific Parametric PET Atlas Construction - PET/MR Data Processing Pipeline, Validation and Application". In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non-displaceable binding potential (BPND), and total distribution volume (VT) based on simultaneously acquired bolus-infusion positron emission tomography (PET) and magnetic resonance imaging (MR) data. The pipeline was applied to [11C]ABP688-PET/MR (13 healthy male non- smokers, 26.6 ± 7.0 years) and [11C]Flumazenil-PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as VT and BPND atlases of mGluR5 and GABAA, were generated from these data. An evaluation of PET-to-PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [15O]H2O-template distribute...
International Journal of Neuropsychopharmacology, 2016
in mPFC and DA efflux in dSTR. NGB and Blo improved the scPCP-induced NOR deficit. The combinatio... more in mPFC and DA efflux in dSTR. NGB and Blo improved the scPCP-induced NOR deficit. The combination of SED NGB and Blon improved the NOR deficit. Conclusions: D 3 receptor blockade may contribute to the ability of Blon to increase cortical ACh and DA efflux, as well as to restore NOR in scPCP deficit. D 3 receptor blockade may be an important component of the efficacy of Blon to enhance neurotransmitter efflux and improve cognitive function.
Pharmacopsychiatry, 2015
Objectives: The ability of psychotropic drugs to pass the blood brain- and blood CSF-barrier depe... more Objectives: The ability of psychotropic drugs to pass the blood brain- and blood CSF-barrier depends on several properties of the drugs (e. g. lipophilicity, molecular size). Aim of this study was to investigate the relation of drug concentrations of different antidepressants in plasma and cerebrospinal fluid (CSF) as well as its relation to the administered daily dose of the drugs. Methods: Three groups (venlafaxine [VEN], n = 16, mirtazapine [MIR], n = 16 and citalopram [CIT], n = 20, of both sexes) were analyzed. All patients were on a stable therapy with fixed daily doses for at least seven days in a naturalistic clinical setting and underwent lumbar puncture for medical reasons. The correlation of drug levels in the blood, drug levels in the CSF and the daily dose of the drugs were calculated. Results: A strong correlation could be observed for VEN in plasma and CSF (p < 0.001). MIR in plasma and CSF were just trend-wise correlated (r = 0.441, p = 0.088) and no relation of daily dose and CSF levels of MIR could be observed (r = 0.313, p = 0.238). CIT levels showed a strong correlation between plasma and CSF (r = 0.890, p < 0.001). Conclusion: For the investigated antidepressants a (strong) relation of drug levels in serum and CSF could be observed, but the plasma and CSF concentrations do not reflect the administered daily dose of the drugs proper. These finding indicate that that therapeutic efforts should be driven by serum concentration rather than by dose optimization.
MMW Fortschritte der Medizin, Jan 19, 2008
Pharmacopsychiatry, 2011
Therapeutic Drug Monitoring (TDM) of psychotropic drugs is strongly depending on the validity of ... more Therapeutic Drug Monitoring (TDM) of psychotropic drugs is strongly depending on the validity of recommended therapeutic plasma concentration reference ranges. Rational pharmacotherapy is based on the assumption that plasma concentrations are directly related to target occupancy by the respective drug. Here we show that positron emission tomography (PET) of molecular drug targets in the brain (neuroreceptors and transporters) allows for establishment of these relationships, thereby providing guidance for TDM services. Associations between brain target occupancy, plasma concentrations, and clinical effects and adverse reactions will be discussed for the most commonly used antidepressant and antipsychotic drugs.
Pharmacopsychiatry, 2013
Rationale Many aspects of the neurobiology of schizophrenia, especially the physiological basis o... more Rationale Many aspects of the neurobiology of schizophrenia, especially the physiological basis of the negative symptoms and associated cognitive deficits, remain inadequately understood. Tandon and Greden (1989) postulated a central role of dopaminergic/cholinergic imbalance in schizophrenia. Objective/Methods In light of this hypothesis, we elected to investigate the effects of anticholinergic challenge on psychopathology, cognition and attention in 12 unmedicated patients with schizophrenia and 12 healthy controls. The first examination occurred before any pharmacological intervention; the second examination was carried out immediately following an intravenous infusion of 5 mg biperiden, a centrally acting antimuscarinergic agent. Results The biperiden challenge provoked a considerable increase in PANSS scores in both groups which was significantly more pronounced in patients (repeated measures analysis of variance (ANOVA) (rmANOVA): F(df)=6.4(1,22); p=0.019). The increase in the PANSS scores showed a significant negative correlation with age in patients. Biperiden caused considerable cognitive impairments in both groups. A significant group difference (rmANOVA) could be observed for TMT-B (F(df)=11.29(1,22); p=0.003). Conclusions The anticholinergic intervention caused more pronounced psychopathological and cognitive deteriorating effects in patients suffering from schizophrenia than in healthy volunteers. This could be related to the disrupted cholinergic transmission in schizophrenia. Our findings speak on behalf of the need of a more restrictive use of anticholinergics in psychiatric patients. The age-related attenuation of PANSS score increases in patients could be related to the age-dependent changes in dopamine dynamics and also to the age-associated decline of the availability of muscarinic receptors. Our results emphasise the need for further investigation of cholinergic disturbances in schizophrenia.
NeuroImage, 2008
Introduction: While post-mortem investigations on D 2/3 receptor (D 2/3-R) densities of patients ... more Introduction: While post-mortem investigations on D 2/3 receptor (D 2/3-R) densities of patients suffering from schizophrenia indicated elevated receptor-concentrations, PET studies show inconsistent results, with most studies demonstrating no change and a few showing elevations in the striatum. The most consistent finding yet is a reduction of D 2/3-R availability in the thalamus. Aim of the present study was to quantify D 2/3-Rs in medication-free patients with schizophrenia (SCZ) and healthy controls (CTL) using the high-affinity ligand [ 18 F]fallypride (FP).
Expert Review of Neurotherapeutics, 2013
Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to ... more Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.
Der Nervenarzt, 2012
Punkte sammeln auf... springermedizin.de/ eAkademie Teilnahmemöglichkeiten Diese Fortbildungseinh... more Punkte sammeln auf... springermedizin.de/ eAkademie Teilnahmemöglichkeiten Diese Fortbildungseinheit steht Ihnen als e.CME und e.Tutorial in der Springer Medizin e.Akademie zur Verfügung.-e.CME: kostenfreie Teilnahme im Rahmen des jeweiligen Zeitschriftenabonnements-e.Tutorial: Teilnahme im Rahmen des e.Med-Abonnements Zertifizierung Diese Fortbildungseinheit ist mit 3 CME-Punkten zertifiziert von der Landesärztekammer Hessen und der Nord rheinischen Akademie für Ärztliche Fort-und Weiterbildung und damit auch für andere Ärzte kammern anerkennungsfähig. Hinweis für Leser aus Österreich Gemäß dem Diplom-Fortbildungs-Programm (DFP) der Österreichischen Ärztekammer werden die in der e.Akademie erworbenen CME-Punkte hierfür 1:1 als fachspezifische Fortbildung anerkannt.
The Lancet Psychiatry, 2022
BACKGROUND Combining antipsychotics is common in schizophrenia treatment, despite evidence-based ... more BACKGROUND Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING German Federal Ministry of Education and Research.
Fortschritte der Medizin, 2008
The International Journal of Neuropsychopharmacology, 2014