Atomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark.

We investigated wide-ranging clinical outcomes in atomoxetine users in association with PGx variability.

We analyzed 6,798 individuals (55% children) with a first prescription for atomoxetine identified from the Danish population-based iPSYCH case-cohort study linking biobank information with Danish registers. Individuals were categorized based on their single-nucleotide-polymorphism-based CYP2D6 genotype into normal (NM), intermediate (IM), and poor metabolizer (PM). Clinical outcomes included treatment switching, discontinuation, psychiatric inpatient-, outpatient-, and emergency contact, suicide attempt/self-harm, sleep problem, and depression. Individuals’ CYP2D6-status could change due to drug-drug-interactions of weak, intermediate, or strong-CYP2D6 inhibitors (phenoconversion), which we accounted for by time-varying phenotype assessment. Incidence rate ratios (IRR) were estimated using Poisson regression analyses and adjusted for a wide range of potential confounders and covariates.

Over two-thirds of the individuals had a hospital diagnosis of ADHD at the first atomoxetine prescription. The distribution of CYP2D6 phenotypes was similar in children and adults. IM/PM children had a significantly higher risk of a sleeping problem compared with NM children (IRR 1.25, 95% CI 1.01-1.54). Compared with NM adults, those with IM/PM had a higher risk of switching (1.15, 95% CI 0.98-1.35).

This is the first study showing the potential impact of PGx variability on clinical outcomes of atomoxetine users in a population-based setting, highlighting the utility of PGx testing.

No significant relationships.

Studies on the impact of stalking on victims suggest that stalking may have serious psychosocial consequences. Using data from the Mannheim stalking study (Dressing, Kuehner & Gass, 2005) the present report analyses gender differences with regard to various mental health indicators and potential mediator effects of stalking victimization. Furthermore, we were interested in whether the impact of stalking on mental health was comparable for men and women.

The study included a postal survey of 675 community residents on the experience of intruding harassment and on mental health indicators.

In the Patient Health Questionnaire (PHQ-D) women scored higher on most of the subscales. Furthermore, more women fulfilled criteria for at least one threshold or sub-threshold mental disorder syndrome according to DSM-IV, and more women than men used psychotropic medication. However, identified associations were completely mediated by the higher prevalence of stalking victims in women. In contrast, the associations of stalking victimization with poor mental health, psychosocial functioning, and use of medication were largely comparable across gender.

Our study indicates clear associations between stalking victimization and impaired mental health, quantified at diagnostic levels in the general population. Furthermore, the experience of being a stalking victim seems to act as a substantial mediator of the associations between gender and mental health outcomes in the community.

NMDA receptor antagonists as ketamine represent fast-acting alternatives to monoaminergic-based antidepressants. Major drawbacks of these drugs are psychosis-like states and cortical neurotoxicity, effects correlating with potent activation of the cingulated and retrosplenial cortex. The molecular mechanisms underlying these side-effects have not been deciphered yet.

We aimed to determine potential molecular components of the NMDA receptor implicated in their psychotomimetic action and investigated whether subunit-specific NMDA receptor antagonists also induce similar neurotoxic changes as ketamine.

To investigate deleterious effects of NMDA receptor antagonists, we used brain mapping with the immediate early gene c-Fos. We analyzed the expression pattern of c-Fos in brain areas responsible for deleterious adverse events, after treatment with ketamine and the NR2B subunit-specific antagonist Ro 25-6981, both in wild-type and knockout mice, lacking either the entire NR2A subunit (NR2A ko mice) or its intracellular C-terminus (NR2A deltaC mice).

In contrast to ketamine (10mg/kg), Ro 25-6981, even at high dosages (50mg/kg) does not induce any c-Fos expression in the cingulated and retrosplenial cortex of wildtype mice. However, Ro 65-2981 evokes, both in NR2A ko mice and NR2A deltaC mice, strong c-Fos expression in these areas.

Our data indicate that blockade of both NR2A and NR2B subunits is necessary to induce deleterious effects specific for ketamine. Deletion of the C-terminus of the NR2A subunit is sufficient to disinhibit, together with pharmacological NR2B blockade, neuronal networks associated with psychosis. Therefore, NR2B antagonists may represent safer alternatives to ketamine as potential antidepressants.

The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-Methyl-D-aspartate (NMDA)-receptors (NR). Several therapeutic strategies address NR function and effects of antipsychotic agents on NR expression have been described.

The partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract behavioural effects of NR antagonists, but effects of APZ on NR expression have not been investigated.

To evaluate effects of APZ on NR mRNA and protein expression

We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kg body weight. Expression of the NR subunits NR1, NR2A, NR2B, NR2C and NR2D was assessed by semiquantitative radioactive in situ-hybridization, and in parallel receptor binding using 3H-MK-801 receptor autoradiography.

Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months) and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses and time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40 mg-group and after 4 months in the 10 mg-group.

The effects of APZ converge in enhanced NMDA-receptor expression and a shift of subunit-composition towards adult-type receptors. Our results confirm regulatory connections between dopaminergic, serotonergic and glutamatergic neurotransmission with relevance for cognitive and negative symptoms of schizophrenia.

Research on the effectiveness of different intervention strategies for stalking victims is scarce.

To present the “Mannheim Pilot Project on Stalking” that aims at linking-up different local activities for stalking victims.

An information centre at the prevention directorate of the police station and a cognitive group therapy for stalking victims were established.

Data of this research project are outlined.

Requirements of stalkees are better complied with. Group therapy reduces stress and enables victims to cope with their problems more adequately.

More research on the effects of different interventions strategies is needed.

The glutamate system is implicated both in mood disorders and schizophrenia. Mice lacking metabotropic mGlu5 receptors (mGluR5 KO) display schizophrenia-like abnormalities. Additionally, mGluR5 antagonists represent promising alternative anxiolytics/antidepressants. However, the underlying age-specific molecular/cellular mechanisms are only partially understood.

We aimed at identifying molecular alterations associated with a genetically induced mGluR5 deletion, which results in a schizophrenia-like phenotype. Additionally, we investigated age-specific effects of mGluR5 antagonists on emotional behaviour and c-fos activation.

For analysis of mRNA and protein levels we performed Real-time RT-PCR and Western blot investigations of brains from mGluR5 KO and wild-type mice. Additionally we used classical behavioral tests for determining anxiety- and depression-like changes triggered by the mGluR5 antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP). Finally, we used profiling of c-Fos expression, as marker of neuronal activity, induced by MPEP from postnatal day 16 (P16) to adulthood (P90).

We found reduced expression levels of reelin, GAD65, GAD67, parvalbumin, as well as NMDA and AMPA receptor subunits in mGluR5 KO mice, especially in the prefrontal cortex (PFC). We measured age-specific alterations in emotional behaviour of mGluR5 KO mice, with marked increase of anxiety during aging. There was a remarkably conserved activation of the paraventricular nucleus of the hypothalamus, implicated in stress regulation, by MPEP at all investigated ages, whereas the extended amygdala was specifically activated in adulthood only.

Our animal data provide new insights into the potential role of mGluR5 in neurochemical and behavioural changes associated with schizophrenia and mood disorders during the lifespan.

The authors have not supplied their declaration of competing interest.

Cardiovascular (CV) co-morbidity is one of the major modifiable risk factors driving the excess mortality in individuals with schizophrenia or bipolar disorder. Population-based studies in this area are sparse.

We used Danish population registers to calculate incidence rate ratios (IRRs) for CV drug use, and mortality rate ratios comparing subjects with schizophrenia or bipolar disorder with subjects with no prior psychiatric hospitalization.

IRRs for CV prescriptions were significantly decreased in patients with schizophrenia or bipolar disorder compared with the general population. Among persons without previous myocardial infarction (MI) or cerebrovascular disease, persons with schizophrenia or bipolar disorder had an up to 6- and 15-fold increased mortality from all causes or unnatural causes, respectively, compared with the general population, being most pronounced among those without CV treatment (16-fold increase). Among those with previous MI or cerebrovascular disease, excess all-cause and unnatural death was lower (up to 3-fold and 7-fold increased, respectively), but was similar in CV-treated and -untreated persons.

The present study shows an apparent under-prescription of most CV drugs among patients with schizophrenia or bipolar disorder compared with the general population in Denmark. The excess of mortality by unnatural deaths in the untreated group suggests that the association between CV treatment and mortality may be confounded by severity of illness. However, our results also suggest that treatment of CV risk factors is neglected in these patients.

Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis.

In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes.

Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity.

This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.