European Neuropsychopharmacology (v.27, #3)

Contents (OBC).

Dried Blood Spot sampling in psychiatry: Perspectives for improving therapeutic drug monitoring by Lisa C. Martial; Rob E. Aarnoutse; Martina Mulder; Arnt Schellekens; Roger J.M. Brüggemann; David M. Burger; Aart H. Schene; Albert Batalla (205-216).
Assessment of drug concentrations is indicated to guide dosing of a selected number of drugs used in psychiatry. Conventionally this is done by vena puncture. Novel sampling strategies such as dried blood spot (DBS) sampling have been developed for various drugs, including antipsychotics, antidepressants and mood-stabilizers. DBS sampling is typically performed by means of a finger prick. This method allows for remote sampling, which means that patients are not required to travel to a health care facility. The number of DBS assays for drugs used in psychiatry has increased over the last decade and includes antidepressants (tricyclic and serotonin and/or norepinephrine reuptake inhibitors), mood stabilizers and first- and second-generation antipsychotics. Available assays often comply with analytical validation criteria but are seldom used in routine clinical care. Little attention has been paid to the clinical validation and implementation processes of home sampling. Ideally, not only medicines but also clinical chemistry parameters should be measured within the same sample. This article reflects on the position of DBS remote sampling in psychiatry and provides insight in the requisites of making such a sampling tool successful.
Keywords: TDM; Dried blood spot; Finger prick; Antipsychotics; Mood stabilizers; Antidepressants;

We evaluated the most current evidence regarding the benefits and harms of atypical antipsychotics in adults with dementia.In June 2016, following a protocol developed a priori, we systematically searched several databases for published and unpublished data from randomized controlled trials (RCT), observational studies, and meta-analyses; conducted direct meta-analyses using a random effects model; and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group.One high-quality meta-analysis and published and unpublished data from 8 RCTs and 12 large observational studies met inclusion criteria. When compared with placebo, aripiprazole, risperidone, and olanzapine but not quetiapine result in modest (standardized mean difference <0.5 standard deviations) improvement in neuropsychiatric symptoms. Aripiprazole, risperidone, quetiapine, and olanzapine are associated with increased odds of acute myocardial infraction, and risperidone and olanzapine are associated with increased odds of hip fracture. Observational studies suggest no differences in all-cause mortality between atypical antipsychotics.Observational studies suggest that atypical antipsychotics are associated with lower risk of all-cause mortality and extrapyramidal symptoms but higher risk of stroke when compared with conventional antipsychotics.To manage agitation in adults with progressive dementia, clinicians may recommend atypical antipsychotics with continuous monitoring of behavioral symptoms, informing patients and their families or caregivers of the significant risk of adverse effects and baseline risk of acute myocardial infraction and bone fractures.
Keywords: Evidence-based medicine; Quality of evidence; Atypical antipsychotics; Aripiprazole; Risperidone; Olanzapine; Quetiapine;

Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects by Patrick Vizeli; Yasmin Schmid; Katharina Prestin; Henriette E. Meyer zu Schwabedissen; Matthias E. Liechti (232-238).
In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.
Keywords: 3,4-Methylenedioxymethamphetamine; 3,4-Methylenedioxyamphetamine; Pharmacokinetics; CYP1A2; CYP2C19; CYP2B6;

Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors by Renata Basso Cupertino; Jaqueline Bohrer Schuch; Cibele Edom Bandeira; Bruna Santos da Silva; Diego Luiz Rovaris; Djenifer B. Kappel; Verônica Contini; Angélica Salatino-Oliveira; Eduardo Schneider Vitola; Rafael Gomes Karam; Mara Helena Hutz; Luis Augusto Rohde; Eugenio Horacio Grevet; Claiton Henrique Dotto Bau; Nina Roth Mota (239-247).
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.
Keywords: SNARE; Attention-Deficit/Hyperactivity Disorder; Synaptotagmin; ASPD; Antisocial Personality Disorder; Meta-analysis;

Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial by Andreas G. Franke; Patrik Gränsmark; Alexandra Agricola; Kai Schühle; Thilo Rommel; Alexandra Sebastian; Harald E. Balló; Stanislav Gorbulev; Christer Gerdes; Björn Frank; Christian Ruckes; Oliver Tüscher; Klaus Lieb (248-260).
Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess – a competitive mind game requiring highly complex cognitive skills – can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2×200 mg modafinil, 2×20 mg methylphenidate, and 2×200 mg caffeine or placebo in a 4×4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players’ strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.
Keywords: Cognitive enhancement; Chess; Stimulants; Methylphenidate; Modafinil; Caffeine;

Effects of amphetamine on pro-social ultrasonic communication in juvenile rats: Implications for mania models by K.-Alexander Engelhardt; Eberhard Fuchs; Rainer K.W. Schwarting; Markus Wöhr (261-273).
Communication is the act of information transfer between sender and receiver. In rats, vocal communication can be studied through ultrasonic vocalizations (USV). 50-kHz USV occur in appetitive situations, most notably juvenile play, likely expressing the sender׳s positive affective state. Such appetitive 50-kHz USV serve important pro-social communicative functions and elicit social exploratory and approach behavior in the receiver. Emission of 50-kHz USV can be induced pharmacologically by the administration of psychostimulant drugs, such as amphetamine. However, it is unknown whether amphetamine affects the pro-social communicative function of 50-kHz USV in the receiver. We therefore assessed dose-response effects of amphetamine (0.0 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.5 mg/kg, 5.0 mg/kg) on pro-social ultrasonic communication on both, sender and receiver, in juvenile rats. We found an inverted U-shaped effect of amphetamine on 50-kHz USV emission, with 50-kHz USV levels being strongly enhanced by moderate doses, yet less prominent effects were seen following the highest dose. Likewise, amphetamine exerted inverted U-shaped effects on social exploratory and approach behavior induced by playback of appetitive 50-kHz USV. Social approach was enhanced by moderate amphetamine doses, but completely abolished following the highest dose. Amphetamine further dose-dependently promoted the emission of 50-kHz USV following playback of appetitive 50-kHz USV, indicating more vigorous attempts to establish social proximity. Our results support an important role of dopamine in closing a perception-and-action-loop through linking mechanisms relevant for detection and production of social vocalizations. Moreover, our approach possibly provides a new means to study mania-like aberrant social interaction and communication in animal models for bipolar disorder.
Keywords: Ultrasonic vocalizations; Acoustic communication; Social behavior; Playback; Dopamine; Bipolar disorder;

Lithium reverses behavioral and axonal transport-related changes associated with ANK3 bipolar disorder gene disruption by Michael G. Gottschalk; Melanie P. Leussis; Tillmann Ruland; Klaudio Gjeluci; Tracey L. Petryshen; Sabine Bahn (274-288).
Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of Ank3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MSE) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein-protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by Ank3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MSE or highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in Ank3+/− mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MSE followed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of Ank3+/− pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in Ank3+/− mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating Ank3-related psychiatric-related behavior.
Keywords: Bipolar disorder; Translational model; Proteomics; Protein interaction networks; Mass spectrometry;

Serious adverse events are poorly reported in clinical trials of second-generation antidepressants. Moreover some key opinion leaders (eg. in France) deliberately failed to warn against them. The gross distortions of antidepressants’ benefit:harm ratio in adolescents showed evidence that open science (ie access to de-identified individual patient data for re-analyses) is a mandatory prerequisite for a trustworthy science.
Keywords: Serious adverse events; Antidepressants; Clinical trials; Research integrity; Industry;

Benzodiazepine withdrawal syndrome induced by thiocolchicoside by Marion Lepelley; Michel Mallaret (291-292).