European Neuropsychopharmacology (v.24, #1)

Contents (OBC).

Stratified medicine for mental disorders by Gunter Schumann; Elisabeth B. Binder; Arne Holte; E. Ronald de Kloet; Ketil J. Oedegaard; Trevor W. Robbins; Tom R. Walker-Tilley; Istvan Bitter; Verity J. Brown; Jan Buitelaar; Roberto Ciccocioppo; Roshan Cools; Carles Escera; Wolfgang Fleischhacker; Herta Flor; Chris D. Frith; Andreas Heinz; Erik Johnsen; Clemens Kirschbaum; Torkel Klingberg; Klaus-Peter Lesch; Shon Lewis; Wolfgang Maier; Karl Mann; Jean-Luc Martinot; Andreas Meyer-Lindenberg; Christian P. Müller; Walter E. Müller; David J. Nutt; Antonio Persico; Giulio Perugi; Mathias Pessiglione; Ulrich W. Preuss; Jonathan P. Roiser; Paolo M. Rossini; Janusz K. Rybakowski; Carmen Sandi; Klaas E. Stephan; Juan Undurraga; Eduard Vieta; Nic van der Wee; Til Wykes; Josep Maria Haro; Hans Ulrich Wittchen (5-50).
There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder. The resulting increase in diagnostic precision and targeted treatments may provide a window of opportunity to address the large public health burden, and individual suffering associated with mental disorders.While mental health and mental disorders have significant representation in the “health, demographic change and wellbeing” challenge identified in Horizon 2020, the framework programme for research and innovation of the European Commission (2014–2020), and in national funding agencies, clear advice on a potential strategy for mental health research investment is needed. The development of such a strategy is supported by the EC-funded “Roadmap for Mental Health Research” (ROAMER) which will provide recommendations for a European mental health research strategy integrating the areas of biomedicine, psychology, public health well being, research integration and structuring, and stakeholder participation. Leading experts on biomedical research on mental disorders have provided an assessment of the state of the art in core psychopathological domains, including arousal and stress regulation, affect, cognition social processes, comorbidity and pharmacotherapy. They have identified major advances and promising methods and pointed out gaps to be addressed in order to achieve the promise of a stratified medicine for mental disorders.
Keywords: Mental disorder; Roadmap; Stratified medicine; Psychopathology; Neural processes; Treatment;

Cannabidiol as a potential treatment for psychosis by C.D. Schubart; I.E.C. Sommer; P. Fusar-Poli; L. de Witte; R.S. Kahn; M.P.M. Boks (51-64).
Although cannabis use is associated with an increased risk of developing psychosis, the cannabis constituent cannabidiol (CBD) may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD. In this targeted literature review we performed a search for English articles using Medline and EMBASE. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention. Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment.
Keywords: Cannabidiol; Schizophrenia; Psychosis; Treatment; Cannabis; Antipsychotics;

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis by H. Weber; D. Klamer; F. Freudenberg; S. Kittel-Schneider; O. Rivero; C.-J. Scholz; J. Volkert; J. Kopf; J. Heupel; S. Herterich; R. Adolfsson; A. Alttoa; A. Post; H. Grußendorf; A. Kramer; A. Gessner; B. Schmidt; S. Hempel; C.P. Jacob; J. Sanjuán; M.D. Moltó; K.-P. Lesch; C.M. Freitag; L. Kent; A. Reif (65-85).
NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein–protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1–NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.
Keywords: Glutamate; Nitric oxide; Association; Schizophrenia; Post-synapse; Prefrontal cortex;

5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option by Leonhard Lennertz; Michael Wagner; Hans Jörgen Grabe; Petra E. Franke; Vera Guttenthaler; Friederike Rampacher; Svenja Schulze-Rauschenbach; Andrea Vogeley; Jens Benninghoff; Stephan Ruhrmann; Ralf Pukrop; Joachim Klosterkötter; Peter Falkai; Wolfgang Maier; Rainald Mössner (86-94).
A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent–child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples. OCD patients scoring high for the washing subtype were significantly more likely to carry the c.256G-allele of the HTR3E variant rs7627615 (p=0.0001) as compared to OCD patients low for this symptom dimension. Visual organization was impaired in OCD patients and unaffected relatives as compared to healthy control subjects and carriers of the HTR3E c.256G/c.256G-genotype performed significantly worse (p=0.007). The case-control analyses revealed a nominal significant association of the HTR3D variant rs1000592 (p.H52R) with OCD (p=0.029) which was also evident after combination of the case-control and the trio-results (p=0.024). In male subjects, the variant rs6766410 (p.N163K) located in the HTR3C was significantly associated with OCD (p=0.007). The association findings of the HTR3C and the HTR3E remained significant after correction for the number of variants investigated. These findings indicate a role of common variants of the HTR3A-E genes in OCD and OCD-related phenotypes and further support the use of 5-HT3 receptor antagonists as novel treatment options. The HTR3E gene is a novel candidate gene impacting on the individual expression of OC symptoms and OCD-related cognitive dysfunction.
Keywords: Obsessive-compulsive disorder; HTR3A; HTR3B; HTR3C; HTR3D; HTR3E; 5-HT3; Serotonin; Symptom dimensions; Endophenotype; Visual memory; Visual organization;

Trends in use of antipsychotics in elderly patients with dementia: Impact of national safety warnings by Adeline Gallini; Sandrine Andrieu; Julie M. Donohue; Naïma Oumouhou; Maryse Lapeyre-Mestre; Virginie Gardette (95-104).
Based on evidence of an increased risk of death, drug agencies issued safety warnings about the use of second generation antipsychotics (SGAs) in the elderly with dementia. The French agency issued a warning in 2004. which was extended to all antipsychotics in 2008. Little is known about the impact of these warnings on use. We conducted a quasi-experimental study (interrupted time-series) in France, for 2003–2011, including subjects aged ≥65 with dementia and subjects aged ≥65 without dementia in the EGB database (1/97th representative random sample of claims from the main Health Insurance scheme). Outcomes were monthly rates of use of antipsychotics (by class and agent) and of five comparison drug classes (antidepressants, benzodiazepines, dermatologicals, antidiabetics, antiasthmatics). Trends were analyzed by joinpoint regression, impact of warnings by linear segmented regression. In patients with dementia (n=7169), there was a 40% reduction in antipsychotic use from 14.2% in 2003 to 10.2% in 2011. The reduction began before 2004 and was unaffected by the warnings. Use of first generation antipsychotics declined over the period, while use of SGAs increased and leveled off from 2007. Use of the five comparison drug classes increased on the period. In subjects without dementia (n=91,942), rates of overall antipsychotic use decreased from 2.3% in 2003 to 1.8% in 2011 with no effect of the warnings. Meanwhile, use of SGAs continuously increased from 0.37% to 0.64%. Antipsychotic use decreased in the elderly between 2003 and 2011, especially in dementia. The timing of the decrease, however, did not coincide with safety warnings.
Keywords: Drug utilization/trends; Elderly; Dementia; Alzheimer's disease; Antipsychotics;

Functional effects of chronic paroxetine versus placebo on the fear, stress and anxiety brain circuit in Social Anxiety Disorder: Initial validation of an imaging protocol for drug discovery by Mónica Giménez; Hector Ortiz; Carles Soriano-Mas; Marina López-Solà; Magí Farré; Joan Deus; Rocio Martín-Santos; Sofia Fernandes; Paolo Fina; Massimo Bani; Stefano Zancan; Jesús Pujol; Emilio Merlo-Pich (105-116).
Recent studies suggest that pharmacologic effects of anxiolytic agents can be mapped as functional changes in the fear, stress and anxiety brain circuit. In this work we investigated the effects of a standard treatment, paroxetine (20 mg/day), in subjects with Social Anxiety Disorder (SAD) versus placebo using different fMRI paradigms. The fMRI sessions, performed before and after the treatment, consisted of a public exposition of recorded performance task (PERPT), an emotional face processing task (EFPT) and a 6-min resting state followed by an off-scanner public speaking test. Paroxetine significantly improved the clinical conditions of SAD patients (n=17) vs. placebo (n=16) as measured with Clinical Global Inventory – Improvement (CGI-I) while no change was seen when using Liebowitz Social Anxiety Scale, as expected given the small size of the study population. Paroxetine reduced the activation of insula, thalamus and subgenual/anterior cingulate cortex (ACC) in PERPT. Resting-state fMRI assessment using Independent Component Analysis indicated that paroxetine reduced functional connectivity in insula, thalamus and ACC when compared with placebo. Both paradigms showed significant correlation with CGI-I in rostral prefrontal cortex. Conversely, paroxetine compared to placebo produced activation of right amygdala and bilateral insula and no effects in ACC when tested with EFPT. No treatment effects on distress scores were observed in the off-scanner Public Speaking Test. Overall this study supports the use of fMRI as sensitive approach to explore the neurobiological substrate of the effects of pharmacologic treatments and, in particular, of resting state fMRI given its simplicity and task independence.
Keywords: fMRI; Resting state; Social emotional stimuli; Public speaking test; Anxiety; Placebo; Randomized clinical trial;

The literature suggests that post-traumatic stress disorder (PTSD) is associated with increased mortality. However, to date, mortality rates amongst veterans diagnosed with post-traumatic stress disorder have not been reported for Israeli veterans, who bear a different profile than veterans from other countries. This study aims to evaluate age-adjusted mortality rates amongst Israeli Defense Forces veterans with and without PTSD diagnosis. The study was carried out in a paired sample design with 2457 male veterans with treated PTSD and 2457 matched male veterans without a PTSD diagnosis. Data on PTSD and non-PTSD veterans was collected from the Rehabilitation Division of the Israeli Ministry of Defense (MOD) and the Israeli Defense Forces' (IDF) special unit for treatment of combat stress reaction. Mortality data were collected from the Ministry of the Interior (MOI) computerized database. Comparison of mortality rates between PTSD and non-PTSD veterans was done using paired observations survival analysis by applying a proportional hazards regression model. Overall no statistically significant difference in mortality rates was found between veterans with treated PTSD and veterans without PTSD. These findings hold even when excluding veterans who died in battle and including non-PTSD veterans who died before their matched PTSD veteran was diagnosed. However, among pairs with similar military jobs PTSD group had significantly less mortality. The results of this large national cohort suggest that treated PTSD is not associated with increased mortality. We submit that the lack of this association represents the “net” pathophysiology of PTSD due to the unique characteristics of the sample.
Keywords: PTSD; Mortality; Veterans;

The aim of this post-hoc comparison is to compare efficacy and tolerability results from two generalized anxiety disorder (GAD) studies: a placebo-controlled, randomized controlled trial (RCT) and a study conducted in the clinical practice setting, and to evaluate the extent to which results from RCTs in GAD patients can be generalized to clinical practice. In the clinical practice study, GAD outpatients (n=578) were treated with 4 weeks of pregabalin 150–600 mg/day. In the double-blind placebo-controlled RCT, GAD outpatients (n=249) were randomized to 8 weeks of pregabalin (300–600 mg/day), or placebo (only the first 4 weeks are included in the current analysis). Efficacy measures included the Hospital Anxiety and Depression Scale – Anxiety and Depression subscales (HADS-A; HADS-D), a visual analogue anxiety scale (VAS-Anxiety), and the Medical Outcomes Study Sleep Problems Index (MOS-SPI). Baseline HADS-A and HADS-D scores were both higher in the clinical practice study vs. the RCT. In the RCT, treatment with pregabalin resulted in significantly greater Week 4 change vs. placebo in the HADS-A (−5.3 vs. −3.9; P<0.005), VAS-Anxiety (−24.0 vs. −13.3; P<0.02), MOS-SPI (−19.1 vs. −9.5; P<0.01), and HADS-D (−2.7 vs. −1.4; P<0.05). The magnitude of Week 4 improvement on pregabalin in the clinical practice study was numerically larger on the HADS-A (−5.9), VAS-Anxiety (−36.0), MOS-SPI (−22.7), and HADS-D (−5.1), despite use of lower doses. These results suggest that clinical practice patients with GAD may achieve comparable efficacy on lower doses of pregabalin than tested in RCTs, despite having comparable levels of anxiety symptom severity at baseline. The current exploratory comparison also suggests that results from RCTs in patients with GAD may not be directly generalizable to clinical practice.
Keywords: Randomized controlled trial; Generalized anxiety disorder; Hospital Anxiety and Depression Scale; Pregabalin;

Routine clinical assessment of cognitive functioning in schizophrenia, major depressive disorder, and bipolar disorder by Wael Belgaied; Jennifer Samp; Alexandre Vimont; Cécile Rémuzat; Samuel Aballéa; Emna El Hammi; Amna Kooli; Mondher Toumi; Kasem Akhras (133-141).
As more evidence points to the association of cognitive dysfunction with mental health disorders, the assessment of cognitive function in routine clinical care of these disorders is increasingly important. Despite this, it remains unknown how cognitive function is measured in routine clinical practice. The objective of this study was to assess psychiatrists' awareness of cognitive dysfunction in mental health disorders and their methods of cognitive assessment. An online survey was disseminated to psychiatrists in Europe, Asia, Australia and the United States. The survey asked about their perceptions of cognitive dysfunction in several mental health disorders, knowledge of cognitive assessment, method of cognitive assessment, and instruments used to measure cognitive function. Among the 61 respondents, most perceived that schizophrenia was associated with the greatest cognitive dysfunction. Many were unaware whether guidelines were available on cognitive assessment. In schizophrenia, 59% of psychiatrists reportedly used cognitive instruments, while the remainder relied solely on patient history interviews. The use of instruments to assess cognition in major depressive disorder (MDD) and bipolar disorder (BPD) was lower, 38% and 37% respectively. Of the reported instruments used, only a few were actually appropriate for use in the diseases of interest (12% in schizophrenia, 3% in MDD and 0% in BPD). Other instruments reported were clinical measures that did not assess cognition. These findings reveal some inconsistencies in psychiatrists' routine clinical evaluation of cognitive function. There appeared to be low use of true cognitive assessment instruments in clinical practice and confusion regarding what constituted a cognitive assessment instrument.
Keywords: Cognitive dysfunction; Schizophrenia; Major depressive disorder; Bipolar disorder; Cognitive instruments; Survey;

PTSD is a debilitating neuropsychiatric disorder and many patients do not respond sufficiently to current treatments. Neuropeptide Y (NPY) is suggested to provide resilience to the development of PTSD and co-morbid depression. Injections of NPY to the rodent brain are anxiolytic. Recently we showed that intranasal delivery of NPY to rats before or immediately after exposure to single prolonged stress (SPS) animal model of PTSD prevented development of many biochemical and behavioral symptoms of PTSD, indicating its prophylactic potential. Here, we investigated whether intranasal NPY might provide benefits once symptoms have already developed. One week after exposure to SPS stressors, animals were given intranasal NPY or vehicle and tested on elevated plus maze 2 h or 2 days later. The NPY treated rats had lower anxiety-like behavior than vehicle treated rats as indicated by more entries into open arms and fewer into closed arms, lower anxiety index, higher risk assessment and unprotected head dips and reduced grooming time. Their anxiety index was similar to that of unstressed controls. On most of these variables there was no effect of time interval and rats displayed similar overall changes 2 h or 2 days after the infusion. Moreover, intranasal NPY led to reduced depressive-like behavior, assessed by forced swim test. Thus, intranasal NPY reversed several behavioral impairments triggered by the traumatic stress of SPS and has potential for non-invasive PTSD therapeutic intervention.
Keywords: Anxiety; Depression; Intranasal; Neuropeptide Y; PTSD; Stress;

Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-HT depletion in rats: Evidence for direct 5-HT receptor modulation by Jesper Bornø Jensen; Kristian Gaarn du Jardin; Dekun Song; David Budac; Gennady Smagin; Connie Sanchez; Alan Lars Pehrson (148-159).
Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86 mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.
Keywords: Vortioxetine; Lu AA21004; Major depressive disorder; Cognitive impairment; Memory; 5-HT depletion;

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1 mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0 mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0 μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0 mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0 mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine′s effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.
Keywords: 5-HT depletion; Major depressive disorder; 5-HT1A receptor; 5-HT3 receptor; Cognitive dysfunction; Vortioxetine;

Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress by Jin-Fang Ge; Wen-Chao Gao; Wen-Ming Cheng; Wei-Li Lu; Jie Tang; Lei Peng; Ning Li; Fei-Hu Chen (172-180).
This study focused on the antidepressant potential of orcinol glucoside (OG) and its possible mechanisms of action. We established a depressed rat model using 3 consecutive weeks of chronic unpredictable mild stress (CUMS). The antidepressant-like effect of OG was revealed using the sucrose preference test, the open field test, the forced swimming test (FST), and the tail suspension test (TST). The activity of the hypothalamic–pituitary–adrenal (HPA) axis was evaluated by detecting the serum corticosterone (CORT) concentrations and mRNA expression of corticotrophin-releasing hormone (CRH) in the hypothalamus. The protein expression levels of brain-derived neurotrophic factor (BDNF) and total phosphorylated-ERK1/2 were detected by western blot. The results showed that OG treatment (1.5, 3, or 6 mg/kg) alleviated the depression-like behaviour of rats under CUMS, as indicated by the increased sucrose preference and the decreased immobility in both the FST and TST, although the rearing frequency in the open field test increased only in the group that received the lowest dose (1.5 mg/kg OG). Rats that received OG treatment exhibited reduced serum CORT levels and CRH mRNA expression in the hypothalamus, suggesting that the hyperactivity of the HPA axis in CUMS rats was reversed by OG treatment. Moreover, OG treatment upregulated the protein levels of BDNF and phosphorylated-ERK1/2 in the hippocampus, even above control levels. Our findings suggest that OG improved depressive behaviour in CUMS rats by downregulating HPA axis hyperactivity and increasing BDNF expression and ERK1/2 phosphorylation in the hippocampus.
Keywords: Orcinol glucoside; Antidepressant; Hypothalamic–pituitary–adrenal (HPA) axis; Brain-derived neurotrophic factor (BDNF); Extracellular signal-regulated kinase (ERK);