Publications by authors named "Manfred Gerlach"

144 Publications

[The Pharmacological Management of Emergencies in Child and Adolescent Psychiatry].

Z Kinder Jugendpsychiatr Psychother 2021 Oct 20. Epub 2021 Oct 20.

Zentrum für Psychische Gesundheit (ZEP), Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg, Würzburg.

The Pharmacological Management of Emergencies in Child and Adolescent Psychiatry Emergencies in child and adolescent psychiatry are highly prevalent and often pose significant challenges to physicians, since substantial danger to the patient or others must be avoided through the application of largely moderate interventions. Besides using de-escalating strategies and exploiting psychotherapeutic options, the physician frequently employs psychopharmacological interventions. because of a lack of systematically assessed data, however, in emergencies in child and adolescent psychiatry most administrations of psychotropic drugs occur "off label." This review deduces practice-relevant recommendations for the pharmacological management of occurring child and adolescent emergencies such as acute suicidality, acute psychotic episodes, delirium, disorders of consciousness, acute intoxication, and alcohol withdrawal syndrome. We discuss the issue of quality and safety in pharmacological emergency strategies.
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http://dx.doi.org/10.1024/1422-4917/a000833DOI Listing
October 2021

Determination of Guanfacine in Oral Fluid and Serum of Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: A Short Communication.

Ther Drug Monit 2021 Jul 30. Epub 2021 Jul 30.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.

Background: Guanfacine, a selective α2A-adrenoreceptor agonist, is a second-line medication for treating children and adolescents with attention-deficit/hyperkinetic disorder (ADHD). The dosage administered as milligram per body weight to balance the potential benefits and risks of treatment. Therapeutic drug monitoring (TDM) is useful for identifying a patient's therapeutic window to optimize individual drug dosing and reduce the risk of adverse drug reactions. However, in children and adolescents, intravenous sample collection is especially stressful and thus remains a primary challenge, restricting the use of TDM. Therefore, evaluating alternative specimens to facilitate TDM is a worthwhile task. The aim of this study was to assess the feasibility of using oral fluid for TDM of guanfacine in children and adolescents.

Methods: Herein, nine patients (median age 8.1 years; 6 boys, 3 girls) undergoing treatment with guanfacine were included. Simultaneously collected oral fluid and serum samples were deproteinized using methanol containing a stable isotope-labeled internal standard prior to the determination of guanfacine by liquid chromatography-tandem mass spectrometry. Pearson's correlation and paired t-test were used for statistical analysis.

Results: The mean serum guanfacine concentration was three times higher than that detected in oral fluid (7.47 ng/mL vs. 2.36 ng/mL; t (8) = 5.94; P < 0.001). A strong positive linear correlation (r = 0.758, P = 0.018) was identified between oral fluid and serum concentrations. A strong but non-significant negative correlation (r = -0.574, P = 0.106) was detected between the oral fluid pH and oral fluid-to-serum concentration ratio.

Conclusions: The strong correlation between oral fluid and serum concentration and the probable small effect of oral fluid pH on oral fluid-to-serum concentration ratio supports guanfacine as a suitable candidate for TDM in oral fluid.
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http://dx.doi.org/10.1097/FTD.0000000000000917DOI Listing
July 2021

The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder.

Neurosci Biobehav Rev 2021 09 4;128:789-818. Epub 2021 Feb 4.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Wuerzburg, Germany. Electronic address:

Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.

Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.

Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents.

Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
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http://dx.doi.org/10.1016/j.neubiorev.2021.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328933PMC
September 2021

Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?

J Neural Transm (Vienna) 2021 01 23;128(1):115-120. Epub 2020 Dec 23.

Department of Neurology, CBBM, University of Luebeck, Luebeck, Germany.

Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.
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http://dx.doi.org/10.1007/s00702-020-02289-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815570PMC
January 2021

Dose-Corrected Serum Concentrations and Metabolite to Parent Compound Ratios of Venlafaxine and Risperidone from Childhood to Old Age.

Pharmacopsychiatry 2021 May 8;54(3):117-125. Epub 2020 Dec 8.

Department Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Objective: Comparative pharmacokinetic data about the antidepressant venlafaxine (VEN) and the antipsychotic drug risperidone (RIS) over the lifespan and especially in children and adolescents is lacking. This is the first cross-sectional study that aimed to investigate differences in dose-corrected serum concentrations (CDs) and metabolite to parent compound ratios (MPRs) of VEN and RIS across the lifespan.

Methods: Patients treated with VEN and RIS at the University Hospital of Würzburg, Germany were included in the study. Serum level determinations were performed during clinical routine care. Patients with CYP2D6 influencing co-medication were excluded from analyses.

Results: In 953 patients (12-93 years) treated with VEN and 552 patients (7-92 years) treated with RIS, children/adolescents (<18 years) showed 11% and 19%, and 44% and 42% lower CDs of the active moieties (CDs) of VEN and RIS than adults and elderly (≥60 years) (Kruskal-Wallis tests; p ≤ 0.001). However, when CDs were normalized to body weight, a different pattern emerged. Gender differences, with higher CDs in females were present in adults and elderlies but not in children/adolescents. No gender- or age-dependent difference in MPRs was found; however, 80% of MPRs of RIS in children/adolescents were below the range of "normal" CYP2D6 function for adults.

Conclusions: We suggest a higher clearance as a reason for lower CDs of VEN and RIS in children/adolescents compared to adults/elderlies. Metabolism of VEN or RIS by CYP2D6, characterized by MPRs, was not associated with age. However, MPRs of RIS were lower in children/adolescents, possibly due to a higher renal clearance of 9-OH-risperidone.
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http://dx.doi.org/10.1055/a-1302-8108DOI Listing
May 2021

Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson's Disease.

Cells 2020 12 2;9(12). Epub 2020 Dec 2.

Medizinisches Proteom-Center, Medical Faculty, Ruhr-University Bochum, 44801 Bochum, Germany.

The pathological hallmark of Parkinson's disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes.
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http://dx.doi.org/10.3390/cells9122580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761546PMC
December 2020

Relationship Between Amphetamine Concentrations in Saliva and Serum in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

Ther Drug Monit 2021 08;43(4):564-569

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg; and.

Background: Therapeutic drug monitoring (TDM) is a valid tool for the optimization of psychopharmacotherapy; however, in child and adolescent psychiatry, uncomfortable intravenous sample collection is the main challenge and restricts the use of TDM. Therefore, it is important to evaluate alternate specimens to facilitate TDM. The aim of this study was to evaluate the feasibility of using saliva for the TDM of amphetamine in children and adolescents with attention-deficit/hyperactivity disorder.

Methods: In this study, 28 patient samples (mean age, 11.3 years; boys, 23; and girls, 5) treated with lisdexamfetamine were included. The active compound amphetamine was extracted and derivatized before quantification by high-performance liquid chromatography with fluorescence detection. Nonparametric Spearman rank correlations were used for correlation analyses; for clinical validation, Bland-Altman analysis was applied.

Results: The median amphetamine concentrations in saliva were 2.7 times higher (range 0.7-23.6) than those in serum (257.8 ng/mL versus 77.2 ng/mL; z = -4.51, P < 0.001). A strong positive linear correlation was observed between saliva and serum concentrations (ρ = 0.628, P < 0.001). The ratio of saliva-to-serum concentration was strongly pH dependent (ρ = -0.712, P < 0.001). Therefore, a transformation formula, factoring in salivary pH, to calculate serum concentrations from the measured saliva concentrations was applied. Theoretical and measured serum amphetamine concentrations were subjected to Bland-Altman analysis. Using an acceptance limit of 20%, only 21% (n = 6) of samples fulfilled this criterion.

Conclusions: Amphetamine paired saliva-to-serum concentrations were highly variable and strongly affected by salivary pH, indicating that saliva is an inappropriate sampling matrix for TDM of amphetamine. Furthermore, Bland-Altman analysis did not support saliva as a suitable matrix for TDM.
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http://dx.doi.org/10.1097/FTD.0000000000000831DOI Listing
August 2021

Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain.

Front Neuroanat 2020 23;14:558435. Epub 2020 Sep 23.

Department of Neurology, University of Rostock, Rostock, Germany.

The major catecholamines-dopamine (DA) and norepinephrine (NE)-are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM2 cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM2 cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM2 cell counts) with their NE levels ( = -0.932; < 0.001), but not their DA levels ( = 0.440; = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development.
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http://dx.doi.org/10.3389/fnana.2020.558435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538673PMC
September 2020

Therapeutic drug monitoring of children and adolescents treated with aripiprazole: observational results from routine patient care.

J Neural Transm (Vienna) 2020 12 30;127(12):1663-1674. Epub 2020 Sep 30.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center for Mental Health, University Hospital of Wuerzburg, Wuerzburg, Germany.

Although aripiprazole is one of the most used antipsychotics, knowledge about serum concentrations in children and adolescents is scarce and age-specific therapeutic ranges have not been established yet. Data of a routine therapeutic drug monitoring service were analyzed in order to evaluate the relationship between dose and serum concentration of aripiprazole in children and adolescents. The study also aimed to evaluate whether the therapeutic reference range defined for adults with schizophrenia (100-350 ng/ml) is applicable for minors. Data from 130 patients (aged 7-19 years) treated with aripiprazole for different indications in doses of 2-30 mg/day were evaluated. Patient characteristics, doses, serum concentrations and therapeutic outcome were assessed by standardized measures. A positive mean correlation between body weight-corrected daily dose and aripiprazole concentration was found (r = 0.59, p < 0.001) with variation in dose explaining 35% of the variability in serum concentrations. Girls had on average 41% higher dose-corrected concentrations than boys (244.9 versus 173.4 mg/l; p = 0.006). Aripiprazole concentrations did not vary with co-medication (p = 0.22). About 70% of all measured serum concentrations were within the recommended therapeutic range for adults. Using a calculation method in all responding patients with an ICD-10 F2 diagnosis for a rough estimation of a preliminary therapeutic window also demonstrated a similar therapeutic range of aripiprazole in minors (105.9-375.3 ng/ml) than for adults. If confirmed in larger samples and more controlled study designs, these data may contribute to the definition of a therapeutic range of aripiprazole concentrations in children and adolescents.
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http://dx.doi.org/10.1007/s00702-020-02253-4DOI Listing
December 2020

Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche.

Stem Cells 2020 09 25;38(9):1188-1201. Epub 2020 Jun 25.

Department of Neurology, University of Rostock, Rostock, Germany.

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.
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http://dx.doi.org/10.1002/stem.3232DOI Listing
September 2020

Psychotropic drug concentrations and clinical outcomes in children and adolescents: a systematic review.

Expert Opin Drug Saf 2020 Jul 7;19(7):873-890. Epub 2020 Jul 7.

Department of Hospital Pharmacy, Erasmus Medical Center , Rotterdam, The Netherlands.

Introduction: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known.

Areas Covered: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated.

Expert Opinion: In order to better support routine TDM in child- and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentration-effect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159.
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http://dx.doi.org/10.1080/14740338.2020.1770224DOI Listing
July 2020

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents.

Clin Pharmacokinet 2020 11;59(11):1393-1405

Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Background: Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist.

Objectives: The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations.

Methods: Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages.

Results: In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th-75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0-180.5 µg/L]) than in non-responders (58.0 µg/L [14.9-105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders.

Conclusions: Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100-400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account.
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http://dx.doi.org/10.1007/s40262-020-00894-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658071PMC
November 2020

Dose-Related Concentrations of Neuroactive/Psychoactive Drugs Expected in Blood of Children and Adolescents.

Ther Drug Monit 2020 04;42(2):315-324

Department Child and Adolescent Psychiatry, University Hospital of Würzburg, Würzburg; and.

Purpose: Therapeutic drug monitoring is highly recommended for children and adolescents treated with neurotropic/psychotropic drugs. For interpretation of therapeutic drug monitoring results, drug concentrations (C/D) expected in a "normal" population are helpful to identify pharmacokinetic abnormalities or nonadherence. Using dose-related concentration (DRC) factors obtained from pharmacokinetic data, C/D ranges expected under steady state can be easily calculated by multiplication of DRC by the daily dose. DRC factors, however, are defined only for adults so far. Therefore, it was the aim of this study to estimate DRC factors for children and adolescents and compare them with those of adults.

Methods: To obtain pharmacokinetic data (apparent total clearance of drugs from plasma after oral administration, elimination half-life, area under the curve, and minimum serum drug concentration) from children and adolescents treated with psychotropic drugs, a systematic review of published literature was performed, and the pharmaceutical companies that market these drugs were contacted. Available information was used for the calculation of DRC factors.

Results: Fourteen of 26 drugs had similar DRC factors to those reported for adults; 8 and 4 had higher and lower factors, respectively. The antidepressants citalopram, clomipramine, fluvoxamine, and imipramine and the antipsychotics haloperidol and olanzapine showed higher DRC factors than those calculated for adults. The DRC factors of amphetamine and methylphenidate were higher in children (6-12 years) but not in adolescents (13-17 years). On the contrary, the antipsychotic quetiapine and the mood-stabilizing antiepileptics lamotrigine, oxcarbazepine, and topiramate showed lower DRC factors than those calculated for adults.

Conclusions: It was concluded that concentrations of neuroactive/psychoactive drugs to be expected in blood for a given dose may differ between adults and children or adolescents, most probably owing to age-dependent differences in the elimination of these drugs.
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http://dx.doi.org/10.1097/FTD.0000000000000685DOI Listing
April 2020

Spiked human proteome data set for use as a spectral library for protein modelling and protein mapping.

Data Brief 2019 Apr 7;23:103711. Epub 2019 Mar 7.

Medizinisches Proteom-Center, Ruhr-Universität Bochum, Bochum, Germany.

This article describes a mass spectrometric data set generated from human tissue that was spiked with iRT peptides. The data set can be used as a spectral library for analysis of the human brain; especially for analysis of human , for example, in the context of Parkinson's disease. Obtaining a sufficient amount of high-quality tissue is the key limiting factor for establishing a brain region-specific spectral library. Hence, combining existing spectral libraries for data-independent acquisition analysis (DIA) can overcome this major limitation. Moreover, these data can be used to map brain region-specific proteins and to model brain region-specific pathways. Both can improve our understanding of the functioning of the brain in greater depth. In addition, these data can also be used to determine the optimal settings for measuring proteins and peptides of interest. To create the -specific spectral library, the tissue was first homogenized and then fractionated different types of SDS gel electrophoresis, resulting in 18 fractions. These fractions were analysed in triplicate by nanoHPLC-ESI-MS/MS, resulting in 54 data files. The data files generated from the described workflow are hosted in the public repository ProteomeXchange with the identifier PXD011076.
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http://dx.doi.org/10.1016/j.dib.2019.103711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660433PMC
April 2019

Family-based association study on functional α-synuclein polymorphisms in attention-deficit/hyperactivity disorder.

Atten Defic Hyperact Disord 2019 Mar 29;11(1):107-111. Epub 2019 Mar 29.

Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Tübingen, Tübingen, Germany.

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, p = 1 p = 1) and rs356219 (OR 1.28; p = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, p = 0.020), which survived Bonferroni correction (p = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, p = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.
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http://dx.doi.org/10.1007/s12402-019-00286-8DOI Listing
March 2019

Guidelines for the standardized collection of blood-based biomarkers in psychiatry: Steps for laboratory validity - a consensus of the Biomarkers Task Force from the WFSBP.

World J Biol Psychiatry 2019 06 25;20(5):340-351. Epub 2019 Mar 25.

s Department of Psychiatry , Melbourne Medical School, University of Melbourne , Melbourne , VIC , Australia.

Recently, there has been a major shift in the field of psychiatry towards the exploration of complex relationships between blood-based biomarkers and the pathophysiology of psychiatric and neuropsychiatric disorders. However, issues with study reproducibility, validity and reliability have hindered progress towards the identification of clinically relevant biomarkers for psychiatry. The achievement of laboratory validity is a crucial first step for the posterior development of clinical validity. There is evidence that the variability observed in blood-based research studies may be minimised with the implementation of standardised pre-analytical methods and uniform clinical protocols (i.e., pre-venipuncture). It has been documented that errors made in the pre-analytical phase account for 46-68.2% of laboratory testing errors. Thus, standardising clinical assessment, ethical procedures and pre-analytical phase of clinical research is essential for the reproducibility, validity and reliability of blood marker assessment, and reducing the risk of invalid test results. Various other areas of research have already moved towards guidelines for the standardised collection of blood-based biomarkers. Here we aim to provide a set of guidelines that we believe would improve biomarker research: (1) pre-venipuncture information and documentation, (2) ethics of participant consent and (3) pre-analytical methods. Ultimately, we hope this will assist study planning and will improve data comparison across studies allowing for the discovery of biomarkers in psychiatry with both laboratorial and clinical validity.
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http://dx.doi.org/10.1080/15622975.2019.1574024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728424PMC
June 2019

Special edition on the occasion of Jan K. Buitelaar's 65th anniversary.

Atten Defic Hyperact Disord 2019 Mar;11(1):1-3

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre of Mental Health, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.

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http://dx.doi.org/10.1007/s12402-019-00290-yDOI Listing
March 2019

Long-term cardiovascular safety of psychostimulants in children with attention deficit hyperactivity disorder.

Int J Psychiatry Clin Pract 2019 Jun 21;23(2):157-159. Epub 2019 Jan 21.

a Department of Psychiatry, Psychosomatics and Psychotherapy , University Hospital of Tübingen , Tübingen , Germany.

Side effects are a concern during psychostimulant treatment. Unfortunately, many previous studies only investigated short-term effects of psychostimulants in laboratory settings which lack clinical daily routines. We examined 1042 patient records of patients with attention deficit hyperactivity disorder (ADHD) who were referred to a pediatric-psychiatry practice over 12 years. Data analysis was based on 466 children with ADHD who were newly treated with psychostimulants and who were not in treatment for elevated blood pressure. We analysed blood pressure percentiles, heart rate and BMI percentiles. There was a decrease in systolic and diastolic blood pressure percentiles. Heart rate was not affected. BMI slightly declined in girls. In general psychostimulants were safe. To further elucidate negative effects of psychostimulants, long-term controlled and randomized studies in naturalistic settings are of interest.
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http://dx.doi.org/10.1080/13651501.2018.1519078DOI Listing
June 2019

[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP].

Nervenarzt 2019 May;90(5):463-471

Klinische Pharmakologie, Institut AGATE, Pentling, und Klinische Pharmakologie am Lehrstuhl für Pharmakologie und Toxikologie, Universität Regensburg, Regensburg, Deutschland.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.
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http://dx.doi.org/10.1007/s00115-018-0643-9DOI Listing
May 2019

[Polypharmacy of psychotropic drugs in child and adolescent psychiatry in Germany - rather the rule than the exception].

Z Kinder Jugendpsychiatr Psychother 2019 May 13;47(3):193-202. Epub 2018 Nov 13.

1 Zentrum für Psychische Gesundheit (ZEP), Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg, Würzburg.

Polypharmacy of psychotropic drugs in child and adolescent psychiatry in Germany - rather the rule than the exception Polypharmacy increases the risk of interactions and enhances the chance of adverse drug reactions (ADRs). Hence, child and adolescent psychiatrists generally try to avoid polypharmacy with psychotropic drugs. However, only little data regarding the frequency of polypharmacy in child and adolescent psychiatry are available. This study analyzes clinical data on polypharmacy and the possible association with a higher risk of ADRs in Germany, with a focus on antidepressants and antipsychotics. We investigated a total of 940 datasets from descriptive studies on therapeutic drug monitoring (TDM) of pediatric patients treated with different psychotropic drugs. The frequency of polypharmacy ranged up to 45.6 % (escitalopram) and 72.1 % (olanzapine). In 17.4 % of the cases, polypharmacy consisted of four or more psycho-/neuropharmacological substances. No increased incidence of ADRs was reported with polypharmacy of antipsychotics compared to monotherapy. Polypharmacy with sertraline was associated with a higher number of ADRs. There is a high prevalence of polypharmacy with psychotropic drugs in child and adolescent psychiatry in Germany. Conclusions concerning individual drugs should be drawn with care since the subsample sizes were relatively small. However, our results do provide an indication of the prevalence of polypharmacy, although the validity of the data is limited. There is an urgent need to analyze data from larger and more homogeneous groups under more controlled conditions.
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http://dx.doi.org/10.1024/1422-4917/a000632DOI Listing
May 2019

Editors must be vigilant to guarantee the quality and credibility of published scientific work.

Authors:
Manfred Gerlach

Atten Defic Hyperact Disord 2018 Dec;10(4):245-246

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

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http://dx.doi.org/10.1007/s12402-018-0275-8DOI Listing
December 2018

Editors must be vigilant to guarantee the quality and credibility of published scientific work.

Authors:
Manfred Gerlach

Atten Defic Hyperact Disord 2018 Dec;10(4):245-246

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Centre of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

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http://dx.doi.org/10.1007/s12402-018-0275-8DOI Listing
December 2018

TDM in psychiatry and neurology: A comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians.

World J Biol Psychiatry 2018 04 1;19(3):162-174. Epub 2018 Mar 1.

j Clinical Pharmacology, Department of Psychiatry and Psychotherapy and Department of Pharmacology and Toxicology , University of Regensburg , Regensburg , Germany.

Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions.

Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated.

Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine.

Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.
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http://dx.doi.org/10.1080/15622975.2018.1439595DOI Listing
April 2018

[Does methylphenidate cause liver damage? An analysis of ad hoc reports to the "Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)"].

Z Kinder Jugendpsychiatr Psychother 2018 Jul 14;46(4):342-348. Epub 2017 Dec 14.

1 Zentrum für Psychische Gesundheit, Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg.

Does methylphenidate cause liver damage? An analysis of ad hoc reports to the "Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)" Abstract. Ad hoc reports to the "Bundesinstitut für Arzneimittel und Medizinprodukte" (BfArM, the German Federal Institute for Drugs and Medical Devices) were analyzed concerning liver injuring stemming from therapy with methylphenidate (MPH). Clinical criteria were used to assess suspected cases of causal association. The BfArM database on adverse drug reactions (ADRs) recorded suspected cases from Germany over the period from 1 January 2006 to 23 May 2016. Using the Standardized MedDRA Queries (SMQ) search strategy, we searched the database for "MPH" and its potential ADRs "Hepatic Disorder." The ad hoc reports were checked for completeness and assessed clinically according to the Uppsala Monitoring Centre criteria. 60 suspected cases of liver damages by MPH were recorded in the database. In 15 thereof, an assessment was not possible because of insufficient documentation; in 25 cases, a link between the intake of MPH and the occurrence of liver injury was considered "unlikely." A "possible" causality was assessed in 11 cases, a "probable/likely" causality in 9 cases: 1 patient with fulminant hepatitis, 1 with increased size of benign liver tumor, and 18 cases of (reversible) hepatic enzyme elevation. According to our evaluation, MPH is well-tolerated with regard to liver and gall bladder diseases. For patients with hepatic impairment or other risk factors, regular monitoring of liver values is recommended.
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http://dx.doi.org/10.1024/1422-4917/a000565DOI Listing
July 2018

Transcranial sonography in psychiatry as a potential tool in diagnosis and research.

World J Biol Psychiatry 2018 10 30;19(7):484-496. Epub 2017 Oct 30.

a Center of Mental Health, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy , University Hospital of Würzburg , Würzburg , Germany.

Objectives: During the last two decades transcranial sonography (TCS) of the brain parenchyma evolved from a pure research tool to a clinical relevant neuroimaging method especially in Parkinson's disease and related movement disorders. The aim of this systematic review is to update and summarise the published TCS findings in psychiatric disorders and critically address the question whether TCS may be a valuable tool for the diagnosis or differential diagnosis of psychiatric disorders similarly to the field of movement disorders.

Methods: This paper provides detailed information about the perspectives and limitations of TCS, including guidelines for the scanning procedures, assessment of midbrain structures and discusses the potential causes of the ultrasound abnormalities in psychiatric disorders.

Results: Changes in the echogenicity of subcortical brain structures were detected in different disorders, such as obsessive-compulsive disorder, autism spectrum disorder, schizophrenia, panic disorder, attention-deficit/hyperactivity (ADHD), bipolar disorder and depressive disorder. Although the physical properties of brain tissue underlying the echogenic features in TCS are largely unknown, no alternative technique provides the same insight into the specific central nervous structural characteristics.

Conclusions: Urgent research questions to further clarify the underlying pathophysiological and structural alterations are further outlined to bring this promising technique to the clinic.
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http://dx.doi.org/10.1080/15622975.2017.1386325DOI Listing
October 2018

Relationship Between Daily Dose, Serum Concentration, and Clinical Response to Quetiapine in Children and Adolescents with Psychotic and Mood Disorders.

Pharmacopsychiatry 2017 Nov 23;50(6):248-255. Epub 2017 May 23.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Centre for Mental Health,Würzburg, Germany.

In child and adolescent psychiatry, therapeutic drug monitoring (TDM) is strongly recommended. However, therapeutic ranges (TR) are defined only for adults. The objectives of this naturalistic study were to assess the relationships between serum quetiapine concentration, daily dose, and clinical outcomes as well as the determinants of pharmacokinetic variability. Furthermore, it was elucidated whether the recommended TR for adult patients with psychotic disorders is valid for children and adolescents. TDM was performed in 180 pediatric patients treated with quetiapine. Psychopathological changes were assessed by the Clinical Global Impression - Improvement scale (CGI-I). Adverse drug reactions (ADRs) were assessed by using a short form of the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale. A weak positive linear relationship between daily dose (mean 349.9±248.9 mg/day) and serum concentration of quetiapine (r=0.496, p<0.001) was found (mean age 15.6±1.9 years, 45.6% male, 31.1% monotherapy), but no relationship between serum concentration and clinical outcome was found. Dose variation accounted for only 12.5% (r=0.125) of the variability of serum concentrations. No effects by gender, age, body weight, smoking habits, and co-medication were found. The majority of patients with psychotic (67.8%) and mood disorders (74.5%) showed a serum concentration below the suggested lower limit (100 ng/mL) of the TR for adults. There are several limitations of this study because of the naturalistic design, and our results should therefore be interpreted with caution. Notwithstanding, our data suggest that the lower limit of the TR for quetiapine is lower than the limit in adult patients.
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http://dx.doi.org/10.1055/s-0043-109695DOI Listing
November 2017

Perception in attention deficit hyperactivity disorder.

Atten Defic Hyperact Disord 2018 Mar 11;10(1):21-47. Epub 2017 Apr 11.

Department of Clinical and Developmental Neuropsychology, Faculty of Behavioural and Social Sciences, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands.

A large body of research demonstrated that individuals with attention deficit hyperactivity disorder (ADHD) suffer from various neuropsychological deficits. In contrast, less is known and only divergent evidence exists on perceptual functions of individuals with ADHD. This is problematic as neuropsychological and perceptual functions are closely interrelated and are often difficult to disentangle in behavioral assessments. This study presents the conduct and results of a systematic literature review on perceptual functions in children and adults with ADHD. This review considers studies using psychophysical methods (objective measurements) and self- and informant reports (subjective measurements). Results indicate that individuals with ADHD have altered perceptual functions in various domains as compared to typically developing individuals. Increased perceptual functions in individuals with ADHD were found with regard to olfactory detection thresholds, whereas reduced perceptual functions were evident for aspects of visual and speech perception. Moreover, individuals with ADHD were found to experience discomfort to sensory stimuli at a lower level than typically developing individuals. Alterations of perceptual functions in individuals with ADHD were shown to be moderated by various factors, such as pharmacological treatment, cognitive functions, and symptom severity. We conclude by giving implications for daily life functioning and clinical practice.
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http://dx.doi.org/10.1007/s12402-017-0230-0DOI Listing
March 2018

Therapeutic Drug Monitoring in Children and Adolescents Under Pharmacotherapy With Olanzapine in Daily Clinical Practice.

Ther Drug Monit 2017 06;39(3):273-281

*Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Centre for Mental Health, Würzburg, Germany; †Clinics of City Cologne GmbH, Child and Adolescent Psychiatry and Psychotherapy, Cologne, Germany; ‡Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Ulm, Ulm, Germany; §Hemera Private Hospital for Mental Health-Adolescents and Young Adults, Bad Kissingen, Germany; ¶DRK, Clinic of Child and Adolescent Psychiatry, Psychotherapy/Psychosomatics, Bad Neuenahr, Germany; and ‖Laboratory for Therapeutic Drug Monitoring, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Centre for Mental Health, Würzburg, Germany.

Background: The relationship between daily dose, serum concentrations, and clinical outcomes of olanzapine as well as the influencing factors thereof in children and adolescents treated for different psychiatric disorders were investigated in daily clinical practice. In addition, it was examined whether the current recommended therapeutic range (TR) for adult patients with psychotic disorders is valid for minors.

Methods: The Competence Network for Therapeutic Drug Monitoring (www.tdm-kjp.com) routinely collects demographic and clinical outcome data as well as serum concentrations of children and adolescents treated with psychotropics. The therapeutic effect is documented using the Clinical Global Impression Scale subscale for Global Improvement. Adverse drug reactions (ADRs) are assessed using the Udvalg for Kliniske Undersogelser-Side Effect Rating Scale.

Results: One hundred fifteen patients (mean age = 15.9 years; range = 10.4-18.8 years; 40.9% male) were included. The majority (72.1%) was cotreated with other psychotropic drugs. A positive medium linear relationship (r = 0.619; P < 0.001) between olanzapine dose (mean = 11.64 mg/d) and serum concentration (mean = 35.65 ng/mL) was found with a marked interindividual variability of serum concentrations. Neither relationship between olanzapine serum concentration and treatment response (clinical benefit documented in 80%) nor ADRs (documented in 53.3%, in 7.5% judged as severe) was detected. Most of the patients with psychotic and eating disorders (68.8% and 71.8%, respectively) had an olanzapine serum concentration within the TR suggested for adults.

Conclusions: There are several limitations of this study because of the naturalistic design, and our results should therefore be interpreted with caution. As most of the patients showed a clinical benefit under olanzapine concentrations within the TR for adults and only a minority had severe ADRs, it is reasonable to conclude a similar TR for children, adolescents, and adults.
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http://dx.doi.org/10.1097/FTD.0000000000000398DOI Listing
June 2017

No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease in nine ADHD candidate SNPs.

Atten Defic Hyperact Disord 2017 Jun 7;9(2):121-127. Epub 2017 Feb 7.

Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.
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http://dx.doi.org/10.1007/s12402-017-0219-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233883PMC
June 2017
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