European Neuropsychopharmacology (v.20, #8)

Contents (OBC).

Exploring the brain network: A review on resting-state fMRI functional connectivity by Martijn P. van den Heuvel; Hilleke E. Hulshoff Pol (519-534).
Our brain is a network. It consists of spatially distributed, but functionally linked regions that continuously share information with each other. Interestingly, recent advances in the acquisition and analysis of functional neuroimaging data have catalyzed the exploration of functional connectivity in the human brain. Functional connectivity is defined as the temporal dependency of neuronal activation patterns of anatomically separated brain regions and in the past years an increasing body of neuroimaging studies has started to explore functional connectivity by measuring the level of co-activation of resting-state fMRI time-series between brain regions. These studies have revealed interesting new findings about the functional connections of specific brain regions and local networks, as well as important new insights in the overall organization of functional communication in the brain network. Here we present an overview of these new methods and discuss how they have led to new insights in core aspects of the human brain, providing an overview of these novel imaging techniques and their implication to neuroscience. We discuss the use of spontaneous resting-state fMRI in determining functional connectivity, discuss suggested origins of these signals, how functional connections tend to be related to structural connections in the brain network and how functional brain communication may form a key role in cognitive performance. Furthermore, we will discuss the upcoming field of examining functional connectivity patterns using graph theory, focusing on the overall organization of the functional brain network. Specifically, we will discuss the value of these new functional connectivity tools in examining believed connectivity diseases, like Alzheimer's disease, dementia, schizophrenia and multiple sclerosis.
Keywords: Anatomical connectivity; Complexity; Complex systems; DTI; Diffusion tensor imaging; fMRI; Functional brain networks; Functional connectivity; Graph analysis; Network; Network analysis; Resting-state fMRI; Resting-state connectivity; Review; White matter;

Meta-analysis of BDNF Val66Met polymorphism association with treatment response in patients with major depressive disorder by Yan-Feng Zou; Dong-Qing Ye; Xiao-Liang Feng; Hong Su; Fa-Ming Pan; Fang-Fang Liao (535-544).
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.
Keywords: Major depressive disorder; BDNF; Polymorphism; Treatment response; Meta-analysis;

Effect of hypertriglyceridemia on the pharmacokinetics and blood–brain barrier penetration of clozapine and norclozapine following administration to rats by Pavel Gershkovich; Olena Sivak; Aishwariya Sharma; Alasdair M. Barr; Ric Procyshyn; Kishor M. Wasan (545-552).
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.
Keywords: Schizophrenia; Antipsychotic agents; Hypertriglyceridemia; Blood–brain barrier; Lipoproteins; Pharmacokinetics;

Impaired off-line memory consolidation in depression by Martin Dresler; Michael Kluge; Lisa Genzel; Petra Schüssler; Axel Steiger (553-561).
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.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 30 years: 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 ≤ 30 yrs 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.
Keywords: Depression; Sleep; Memory;

An increased likelihood of receiving placebo in randomized clinical trials has been found to predict greater chances of trial success. However, patients who are less likely to receive active therapy (and more likely to receive placebo) may be at increased risk of attrition which, in turn, can limit the statistical power of a study. Therefore, in the present work, we sought to investigate the relationship between the probability of receiving placebo and the likelihood of prematurely discontinuing treatment. Medline/Pubmed publication databases were searched for RCT in MDD. A meta-regression established that the likelihood of receiving placebo did not predict either antidepressant discontinuation rates, placebo-discontinuation rates or the risk ratio of discontinuing antidepressants versus placebo. An increased likelihood of receiving placebo did not inflate discontinuation rates which did not influence the degree of antidepressant-placebo “separation”.
Keywords: Antidepressant; Placebo; Discontinuation; Major; Depressive; Disorder; Adults;

Increased voluntary ethanol consumption and c-Fos expression in selected brain areas induced by fear memory retrieval in ethanol withdrawn rats by María Eugenia Bertotto; Daniela Fernanda Bussolino; Víctor Alejandro Molina; Irene Delia Martijena (568-581).
Withdrawal from chronic ethanol administration facilitated the formation of contextual fear memory. The effect of fear memory retrieval on subsequent ethanol consumption, by employing a two-bottle free-choice procedure with either water or ethanol (2–8% v/v), was investigated in ethanol withdrawn rats. The effect of fear memory extinction with or without d-cycloserine (DCS, 5 mg/kg i.p.) on subsequent ethanol consumption was also evaluated. In addition, we examined c-Fos expression in different brain areas following the fear memory recall. The retrieval of such fear memory induced a significant increase in ethanol consumption in ethanol withdrawn but not in control animals. Regardless of DCS treatment, this increase was attenuated by extinction training. In ethanol withdrawn rats, context-dependent memory retrieval was accompanied by an increased c-Fos expression in the basolateral amygdala, ventrolateral periaqueductal gray, dentate gyrus and dorsomedial periaqueductal gray. Among these brain areas suggested to be implicated in the modulation of motivation and of emotional states, the basolateral amygdala has a crucial role in the emergence of negative affective state during ethanol withdrawal. These data suggest that retrieval of fear memory in ethanol withdrawn rats affected ethanol consumption and that amygdala may be involved in this effect.
Keywords: Ethanol withdrawal; Fear conditioning; Memory retrieval; c-Fos; Ethanol intake;

Partial D2/3 dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D2/3 receptor partial agonist and full 5-HT1A receptor agonist pardoprunox (SLV308; 7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED = 0.03 mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED = 0.03 mg/kg; po) and decreased motor disability (MED = 0.03 mg/kg; po). The effects of pardoprunox were reversed by the D2 antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED = 0.01 mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED = 0.3 mg/kg; po) and apomorphine-induced climbing (MED = 0.6 mg/kg; po) in rodents. Pardoprunox also induced 5-HT1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED = 0.3 mg/kg; po) and these were reversed by the 5-HT1A receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D2 receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT1A agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.
Keywords: Pardoprunox (SLV308); Dopamine D2/D3 partial agonist; 5-HT1A agonist; MPTP; Parkinson's;

Broken heart syndrome: Tako Tsubo cardiomyopathy associated with an overdose of the serotonin–norepinephrine reuptake inhibitor Venlafaxine by Marian Christoph; Bernd Ebner; Dirk Stolte; Karim Ibrahim; Steffen Kolschmann; Ruth H. Strasser; Steffen Schön (594-597).
To describe a case of Tako Tsubo cardiomyopathy [TTC] in a patient after an overdose of the serotonin–norepinephrine reuptake inhibitor [SNRI] Venlafaxine.We present a case study including clinical and laboratory data. Current relevant literature is reviewed and summarized in regard to Tako Tsubo syndrome and SNRI.A 43 year-old woman was admitted with acute angina pectoris after accidentally taking an overdose on Venlafaxine in order to treat major depression. Because of the ECG-T-wave-inversions in the precordial leads, the slightly increased Troponin/Creatine kinase levels and the apical systolic dysfunction of the left ventricle in echocardiogram a cardiac catheterization was performed. Coronary artery disease could be excluded by coronary angiography. The followed laevocardiography and cardiac MRI scan showed apical akinesis and basal hypercontractibility typical for apical ballooning (Tako Tsubo cardiomyopathy). Urine analysis revealed elevated normetanephrine level potentially caused by Venlafaxine. Six weeks after the first admission the echocardiogram showed a complete recovery to normal left ventricular function.To our knowledge this is the first reported case of an overdose of Venlafaxine (SNRI) associated Tako Tsubo cardiomyopathy.
Keywords: Serotonin–norepinephrine reuptake inhibitor; Venlafaxine; Tako Tsubo cardiomyopathy; Apical ballooning; Pathogenesis;