European Neuropsychopharmacology - Articles in Press

Does subtle disturbance of neuronal migration contribute to schizophrenia and other neurodevelopmental disorders? Potential genetic mechanisms with possible treatment implications - Corrected Proof

Stephen I. Deutsch, Jessica A. Burket, Elionora Katz — 2010-03-08

Abstract: Pathways associated with genes that regulate neuronal migration by influencing the function of microtubules in the developing fetal brain may be interfered with as part of the “first-hit” of schizophrenia. In the fully-developed brain, these same pathways that impact microtubule function mediate at least some aspects of experience-dependent plasticity, which may also be impaired in schizophrenia. Whereas severe presentations of “lissencephaly” are associated with mutations and deletions of DISC1, LIS1 and the gene for the very low-density lipoprotein receptor, genetic variations of these loci are good candidate schizophrenia genes. Importantly, in the fully-developed brain, there is a possibility that at least some of the consequences of these disturbed genetic pathways that adversely affect microtubule function may be “bypassed” or mitigated.

Drug attitude as predictor for effectiveness in first-episode schizophrenia: Results of an open randomized trial (EUFEST) - Corrected Proof

2010-03-04

Abstract: Effectiveness has become more and more important as a comprehensive outcome measure for (long-term) treatment in schizophrenia. Early predictors to identify patients at a high risk for not succeeding the initiated treatment would be very useful. Discontinuation of the initiated treatment was used as criterion for effectiveness and patients' drug attitude was shown to be predictive for non-adherence or discontinuation of long-term treatment in schizophrenia. Accordingly, the predictive validity of the Drug Attitude Inventory (DAI) for effectiveness should be evaluated. Based on a sub-sample of patients from the EUFEST study for whom DAI assessments were available significant predictors for effectiveness as measured by discontinuation of initiated treatment were identified based on a logistic and a Cox-regression analysis. A Receiver-Operating Characteristic- (ROC-) analysis was conducted for the DAI, prognostic / diagnostic parameters (sensitivity, specificity) were calculated and a cut-off value suggested. In a sample of 228 first-episode patients, the DAI score was the most powerful predictor for effectiveness (p<0.001) besides two other significant predictors (PANSS-positive score and sexual side effects). The ROC-analysis revealed an area under the curve of 0.64 (p<0.001). The suggested cut-off point of about 20 yielded a sensitivity of 70–75% and a specificity of 40–45%. Study results indicate that the Drug Attitude Inventory, filled in by patients early in treatment seems to be a valid predictor for effectiveness as measured by discontinuation of the initiated treatment. DAI scores could also serve as an (differential) indicator for the need of enhanced treatment monitoring. These findings have to be validated in other (first-episode) samples.

Impaired off-line memory consolidation in depression - Corrected Proof

Martin Dresler, Michael Kluge, Lisa Genzel, Petra Schüssler, Axel Steiger — 2010-03-03

Abstract: Sleep is critically involved in the consolidation of procedural memory. In major depression (MD) and during antidepressant pharmacotherapy, changes in sleep EEG are well documented. Here, we test if off-line motor memory consolidation is impaired in MD.A 50 medicated patients with an acute episode of MD, 50 normal controls and 12 patients with a remitted episode of MD were assessed using a sequential finger tapping task before and after a night of sleep. Although depressed patients and control subjects did not differ in practice-dependent learning, healthy subjects showed markedly overnight improvements in tapping performance of 18% while patients failed to show any improvement. This pattern became even more striking when the subjects were divided by an age threshold of 30years: In the 30+yrs group the healthy subjects showed 16% overnight increase in motor performance, whereas the patients showed −10% overnight decrease. In contrast, patients and controls in the ≤30yrs group showed virtually the same motor performance, as well as remitted patients and controls in the 30+yrs group. In addition, the younger controls showed stronger overnight improvements than the older controls. This pattern might be interpreted as a synergistic interaction between age and depression: Off-line motor memory consolidation is not affected in young patients, but severely impaired in older patients with an acute episode of MD. This impairment seems to recover after remission from depression.

Effects of chronic nicotine on food intake and anxiety-like behaviour in CB1 knockout mice - Corrected Proof

S.Andreea Bura, Aurelijus Burokas, Elena Martín-García, Rafael Maldonado — 2010-03-02

Abstract: We have evaluated the effects of chronic nicotine administration and withdrawal in food intake and preference, metabolic parameters and anxiety-like behaviour in CB1 knockout mice and wild-type littermates. Mutant mice showed lower levels of glucose, insulin and cholesterol after two weeks of high fat diet and reduced preference for saccharine solution when compared with wild-type mice. Nicotine reduced body weight and induced anxiogenic-like effects in wild-type, but not in CB1 knockout mice. Our results suggest a modulatory role of the endocannabinoid system on the effects induced by nicotine on metabolic parameters and anxiety-like responses.

Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder - Corrected Proof

2010-02-18

Abstract: The aim of our meta-analysis was to assess the association between BDNF Val66Met polymorphism and treatment response in patients with MDD. 8 studies that included data from 1115 subjects were identified. We tested two phenotypes: response rate and remission rate. OR was used as a measure of the effect of the association in a fixed/random effect model. Meta-analysis was performed for genotypes Met/Met versus Val/Val, Val/Met versus Val/Val, Met/Met versus Val/Met, Val/Met+Met/Met versus Val/Val, Met/Met versus Val/Val+Val/Met, and Met allele versus Val allele. When all groups were pooled, a significant association of Val/Met genotype and increased response rate was found in comparison to Val/Val in overall population (OR=1.66, 95%CI=1.07–2.57, P=0.02). In the subgroup analysis, similar result was shown in Asian population (OR=1.83, 95%CI=1.03–3.26, P=0.04), but not in Caucasian population. We didn't observe a significant association of BDNF Val66Met polymorphism with remission rate. This meta-analysis demonstrates the association between BDNF Val66Met polymorphism and treatment response in patients with MDD, and Val66Met heterozygous patients have a better response rate in comparison to Val/Val homozygote patients, especially in Asian population.

Effect of hypertriglyceridemia on the pharmacokinetics and blood–brain barrier penetration of clozapine and norclozapine following administration to rats - Corrected Proof

2010-02-17

Abstract: There is a long-term discussion in the literature concerning the possible link between the improved efficacy of clozapine treatment and elevated plasma triglyceride levels, but no mechanistic studies have been performed to date. The aim of this work was to investigate whether the postprandial hypertriglyceridemia affects the pharmacokinetics and brain distribution of clozapine and norclozapine. Experimental hypertriglyceridemia in rats was induced by oral administration of peanut oil and the pharmacokinetic parameters and brain penetration of clozapine and norclozapine following administration of clozapine were compared to normotriglyceridemic control animals. Moderately increased clearance of clozapine was found in hypertriglyceridemic animals compared to control group. No changes were found in penetration of compounds across the blood–brain barrier (BBB). Taken together, the results do not support the hypothesis that hypertriglyceridemia improves the effect of clozapine by altered pharmacokinetics of clozapine and norclozapine and their increased penetration across the BBB.

Outcomes of 1014 naturalistically treated inpatients with major depressive episode - Corrected Proof

2010-01-25

Abstract: Due to strict exclusion criteria the generalizability of randomized controlled trials appears to be limited. Therefore, outcomes of naturalistically treated depressive inpatients with respect to depression mean scores, response and remission rates were evaluated. This was a multicenter trial, conducted in 12 psychiatric hospitals in Germany with a follow-up period of 4years. Patients were assessed biweekly from admission to discharge with diverse psychopathological rating scales. All patients (n=1014) met DSM-IV criteria for major depressive episode. Results are presented only for the acute inpatient treatment period. Mean inpatient treatment duration was 53.6±47.5days. Reduction on depression scales was evident as soon as week 2 and remained significant. Mean HAMD-17 total score decreased from 22.3 to 8.8. A total of 68.9% were classified as responders (≥50% reduction of the initial HAMD-17 score), whereas 51.9% achieved remission (HAMD-17 total score≤7). Of those who ultimately achieved response more than 40% did so within the first 2weeks. An individualized naturalistic inpatient treatment approach appears to be beneficial in terms of effectiveness.

Antidepressants in healthy subjects: What are the psychotropic/psychological effects? - Corrected Proof

2010-01-18

Abstract: A wide debate is ongoing regarding whether antidepressant effects should be considered a general property of these agents or whether they exclusively belong to the context of target symptoms. The aim of the present review is to summarize findings on antidepressant influences on healthy volunteers, focusing on changes in psychological and cognitive functions. Differences have been detected between acute and chronic treatments. Acute treatment has been found to lead to positive bias in emotion processing and facilitation in negative emotion recognition. Chronic treatments have been found to stabilise some changes induced by acute treatment, such as increased social behaviours. Regarding antidepressant modulation of affective symptomatology contrasting results have been reported suggesting that the link between action on cognitive processes and mood may be not direct. In fact, meta-analyzing data on mood and anxiety symptoms no difference was detected between subjects receiving placebo and SSRIs. However, meta-analyzing data on negative affects, a significant decrease was detected in subjects receiving SSRIs in comparison with subjects receiving placebo. In summary, antidepressants seem to exert a detectable influence also in healthy subjects.

No interactions between genetic polymorphisms and stressful life events on outcome of antidepressant treatment - Corrected Proof

2009-12-18

Abstract: Genetic polymorphisms seem to influence the response on antidepressant treatment and moderate the impact of stress on depression. The present study aimed to assess, whether allelic variants and stressful life events interact on the clinical outcome of depression. In a sample of 290 systematically recruited patients diagnosed with a single depressive episode according to ICD-10, we assessed the outcome of antidepressant treatment and the presence of stressful life events in a 6-month period preceding onset of depression by means of structured interviews. Further, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophan hydroxylase, and the serotonin receptors 1A, 2A, and 2C. We found no evidence that the effects of the genetic polymorphisms on treatment outcome were dependent on stressful life events experienced by the individual prior to onset of depression.

Region- and phase-dependent effects of 5-HT1A and 5-HT2C receptor activation on adult neurogenesis - Corrected Proof

Amélie Soumier, Mounira Banasr, Lydia Kerkerian-Le Goff, Annie Daszuta — 2009-12-18

Abstract: Adult neurogenesis and serotoninergic transmission are associated to mood disorders and their treatments. The present study focused on the effects of chronic activation of 5-HT1A and 5-HT2C receptors on newborn cell survival in the dentate gyrus (DG) and olfactory bulb (OB), and examined whether potential neurogenic zones as the prefrontal cortex (PFC) and striatum (ST) are reactive to these treatments. Administration of 8-OH-DPAT, but not RO600,175 increases neurogenesis and survival of late differentiating cells (15–21days) in the DG. Both 8-OH-DPAT and RO600,175 increase neurogenesis in the OB, but only 8-OH-DPAT affected cell survival, inducing a parallel decrease in the number of BrdU cells in the OB and increase in the SVZ, which suggests an impaired migration. In the PFC and ST, 8-OH-DPAT and R0600,175 increase gliogenesis (NG2-labeled cells). This study provides new insights on the serotonergic regulation of critical phases of neurogenesis helpful to understand the neurogenic and gliogenic effects of antidepressant treatments in different brain regions.

Chromosomal mapping of excessive physical activity in mice in response to a restricted feeding schedule - Corrected Proof

C. Gelegen, E. Pjetri, I.C. Campbell, D.A. Collier, H. Oppelaar, M.J.H. Kas — 2009-11-09

Abstract: Excessive physical activity plays an important role in the progression of anorexia nervosa (AN) by accelerating weight loss during dietary restriction. To search for mechanisms underlying this trait, a panel of mouse chromosome substitution strains derived from C57BL/6J and A/J strains was exposed to a scheduled feeding paradigm and to voluntary running wheel (RW) access. Here, we showed that A/J chromosomes 4, 12 and 13 contribute to the development of a disrupted RW activity in response to daily restricted feeding. This pattern is characterized by intense RW activity during the habitual rest phase and leads to accelerated body weight loss. Regions on mouse chromosomes 4, 12 and 13 display homology with regions on human chromosomes linked with anxiety and obsessionality in AN cohorts. Therefore, our data open new roads for interspecies genetic studies of AN and for unraveling novel mechanisms and potential effective treatment strategies for these neurobehavioral traits.

Differential gene expression in a rat model of depression based on persistent differences in exploratory activity - Corrected Proof

Aet Alttoa, Kadri Kõiv, Timothy A. Hinsley, Andrew Brass, Jaanus Harro — 2009-10-26

Abstract: Affective disorders are often accompanied by changes in motivation and anxiety. We investigated the genome-wide gene expression patterns in an animal model of depression that separates Wistar rats belonging into clusters of persistently high anxiety/low motivation to explore and low anxiety/high motivation to explore (low explorers and high explorers, LE and HE, respectively), in three brain regions previously implicated in mood disorders (raphe, hippocampus and the frontal cortex). Several serotonin-, GABA-, and glutamatergic genes were differentially expressed in LE- and HE-rats. The analysis of Gene Ontology biological process terms associated with the differentially regulated genes identified a significant overrepresentation of genes involved in the neuron development, morphogenesis, and differentiation; the most enriched pathways from the Kyoto Encyclopedia of Genes and Genomes were the Wnt signalling, MAPK signalling, long-term potentiation, and long-term depression pathways. These findings corroborate some expression data from other models of depression, and suggest additional targets.

Neuropeptide Y (NPY) gene: Impact on emotional processing and treatment response in anxious depression - Corrected Proof

2009-10-26

Abstract: Neuropeptide Y (NPY) has been found to play a role in the pathomechanism of both anxiety and depression. Thus, NPY is a promising candidate in the investigation of the clinical phenotype of “anxious depression”.Five NPY gene variants were investigated for an influence on antidepressant treatment response in a sample of 256 patients with depression. Additionally, NPY gene impact on amygdala activation during facial emotion processing was analyzed in a subsample of 35 depressed patients.Particularly in anxious depression, the less active NPY rs16147 −399C allele conferred slow response after 2weeks and failure to achieve remission after four weeks of treatment. The rs16147 C allele was further associated with stronger bilateral amygdala activation in response to threatening faces in an allele-dose fashion.The present results point towards a possible influence of functional NPY gene variation on antidepressant treatment response in anxious depression, potentially conveyed by altered emotional processing.