European Neuropsychopharmacology - Articles in Press

Antipsychotic medication and prefrontal cortex activation: A review of neuroimaging findings - Corrected Proof

2012-02-03

Abstract: Decreased prefrontal activation (hypofrontality) in schizophrenia is thought to underlie negative symptoms and cognitive impairments, and may contribute to poor social outcome. Hypofrontality does not always improve during treatment with antipsychotics. We hypothesized that antipsychotics, which share antagonism at dopamine receptors, with a relatively low dopamine receptor affinity and high serotonin receptor affinity may have a sparing effect on prefrontal function compared to strong dopamine receptor antagonists.We systematically investigated the relation between serotonin and dopamine antagonism of antipsychotics and prefrontal functioning by reviewing neuroimaging studies.The weight of the evidence was consistent with our hypothesis that antipsychotics with low dopaminergic receptor affinity and moderate to high serotonergic affinity were associated with higher activation of the prefrontal cortex. However, clozapine, a weak dopamine and strong serotonin antagonist, was associated with decrease in prefrontal activation.Future studies should further elucidate the link between prefrontal activation and negative symptoms using prospective designs and advanced neuroimaging techniques, which may ultimately benefit the development of treatments for disabling negative symptoms.

Changes in trend of antipsychotics prescription in patients treated with cholinesterase inhibitors after warnings from Italian Medicines Agency. Results from the EPIFARM-Elderly Project - Corrected Proof

2012-02-02

Abstract: The objective of the study was to assess the trend of antipsychotic prescription in elderly patients taking cholinesterase inhibitors (ChEIs) from 2002 to 2008 and the changes subsequent to two main official warnings issued by the Italian Medicines Agency to restrict their use. Elderly patients aged 65–94years who received at least one prescription of ChEIs between 1 January 2002 and 31 December 2008 were selected. We used data on prescriptions from the Lombardy Region Drug Administrative Database (Italy). The first prescription of one ChEI was used as the index day to calculate the prescription of an antipsychotic. The prescription of atypical antipsychotics in patients exposed to ChEIs declined from 21.0% in 2002 to 14.6% in 2008 (OR 0.92; 95%CI:0.90, 0.94; p<0.001), while the prescribing prevalence of typicals slightly increased (OR 1.08; 95%CI:1.03, 1.13; p=0.001). In relation to the two warnings, the prevalence of patients who received a prescription of antipsychotics was significantly lower in 2005 than 2004 (23.1% vs. 28.0%; OR 0.79; 95%CI:0.73–0.86; p<0.001) and in 2007 than 2006 (19.4% vs. 23.0%; OR 0.79; 95%CI:0.73–0.86; p<0.001). After the first safety warning the prevalence of prescriptions for risperidone and olanzapine dropped significantly, and there was a significant increase for quetiapine. Haloperidol prescriptions increased, especially after the second warning. Despite regulatory warnings issued to discourage the use of antipsychotics, they are still frequently prescribed to patients taking ChEIs. Awaiting further studies to clarify their therapeutic role, physicians should prescribe antipsychotics very cautiously and only after careful risk–benefit assessment.

A link between oxytocin and serotonin in humans: Supporting evidence from peripheral markers - Corrected Proof

2012-02-02

Abstract: Pharmacological studies indicate a functional interaction between the serotonergic and oxytocinergic systems. In particular, some selective serotonin (5-HT) reuptake inhibitors, such as citalopram and fluvoxamine, seem to exert part of their antidepressant effects through oxytocin (OT) release. Further, the administration of fenfluramine, a serotonergic agonist, to healthy subjects increases plasma OT levels. Interestingly, immunocytochemical and double-immunofluorescent techniques revealed a high degree of overlap between 5-HT transporter (SERT)-labeled fibers and OT-containing cells in the paraventricular and supraoptic nuclei of primate hypothalamus. These findings suggest that the influence of 5-HT on OT system might be mediated by SERT. In this study, we explored the possible existence of a link between OT and SERT in human subjects, by means of two peripheral markers, the platelet SERT, as measured by [3H]-paroxetine ([3H]-Par) binding, and plasma OT levels. As far as [3H]-Par binding parameters are concerned, the Bmax (mean±SD, fmol/mg protein) was 1155+130 and the Kd (mean±SD, nM) was 1.31±0.61. The OT plasma levels (mean±SD, pg/ml) were 1.14±1.07. A significant and positive correlation was found between plasma OT levels and Kd values (correlation coefficient: r: 0.466, p=.038). This result represents the first evidence of an interaction between OT and SERT, as measured by [3H]-Par binding, at peripheral levels in humans. Given the several activities mediated by both OT and 5-HT, such a relationship might provide new perspectives and insights into psychiatric disorders and/or social relationship disturbances, as well as novel treatment strategies overcoming and/or integrating the serotonergic paradigm.

Characterization of the neuropsychological phenotype of glycine N-methyltransferase−/− mice and evaluation of its responses to clozapine and sarcosine treatments - Corrected Proof

2012-01-24

Abstract: Glycine N-methyltransferase (GNMT) affects cellular methylation capacity through regulating the ratio between S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The product of its enzymatic reaction—sarcosine has antipsychotic effect in patients with schizophrenia. In this study, through RT-PCR and immunohistochemical staining, we demonstrated that GNMT expressed in various neurons located in the cerebral cortex, hippocampus, substantia nigra and cerebellum. Compared to the wild-type mice, Gnmt−/− mice had significantly lower level of sarcosine in the cerebral cortex. Real-time PCR identified genes involved in the methionine metabolism (Dnmt1 and Dnmt3a), ErbB (Nrg1 and ErbB4) and mTOR (Akt2, S6, S6k1 and S6k2) signaling pathways were dysregulated significantly in the cortex of Gnmt−/− mice. Acoustic startle reflex test demonstrated that Gnmt−/− mice had significantly lower level of prepulse inhibition and the deficit was ameliorated through clozapine or sarcosine treatment. Furthermore, liver-specific-human-GNMT transgenic with Gnmt−/− (Tg-GNMT/Gnmt−/−) mice were used to rule out that the phenotype was due to abnormal liver function. In summary, the neuropsychological abnormalities found in Gnmt−/− mice may represent an endophenotype of schizophrenia. GNMT plays an important role in maintaining normal physiological function of brain and Tg-GNMT/Gnmt−/− mice are useful models for development of therapeutics for patients with schizophrenia.

Perinatal effects on in vivo measures of human brain serotonin synthesis in adulthood: A 27-year longitudinal study - Corrected Proof

2012-01-19

Abstract: There is an increasing evidence that prenatal and early postnatal stressors have life long impacts on physical and mental health problems. Animal studies have shown that this could include enduring changes to brain serotonin neurotransmission. In the present study, we tested whether perinatal adversity in humans has a long-term impact on brain serotonin neurotransmission in adulthood. Twenty-six healthy males, recruited from a 27-year longitudinal study, underwent a positron emission tomography scan with the tracer alpha-[11C]methyl-l-tryptophan (11C-AMT), as an index of serotonin synthesis capacity. The trapping constant is taken as a proxy for the regional 5-HT synthesis.Birth complications, especially a delivery where the fetus showed signs of physiological distress, predicted lower 11C-AMT trapping in the hippocampus and medial orbitofrontal cortex. Lower 11C-AMT trapping in the medial orbitofrontal cortex was also predicted by maternal smoking and lower birth weight. There were no effects of childhood or recent adversity. This is the first human study reporting associations between perinatal adversity and adult 11C-AMT trapping in the hippocampus and medial orbitofrontal cortex. The associations suggest that limbic serotonin pathways may be particularly vulnerable to environmental challenges during the period when they undergo the most prominent neurodevelopmental changes. In combination with other risk factors, perinatal stressors may contribute to increased vulnerability for psychiatric disorders in which serotonin plays a major role.

Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor - Corrected Proof

2012-01-16

Abstract: Homer proteins are associated with both dopaminergic and glutamatergic function. In addition, these proteins are implicated in many signal transduction pathways that are also putative targets of the mood stabilizers lithium and valproate (VPA). This study investigated the effect of in vivo chronic administration of therapeutically-relevant doses of lithium and VPA on the expression of the inducible (Homer1a and ania-3) and constitutive (Homer1b/c) isoforms of the Homer1 gene in rat brain, and of two other Homer-related genes: Inositol 1,4,5 trisphosphate receptor (IP3R) and Shank. Homer1b/c was significantly decreased in cortex by VPA, and in striatal and accumbal subregions by both lithium and VPA. Both mood stabilizers reduced Homer1b/c expression in the dorsolateral caudate-putamen, while only VPA decreased gene expression in all other striatal subregions. Shank and IP3R were downregulated by both mood stabilizers in the cortex. Neither chronic lithium nor VPA affected Homer immediate-early genes. These results suggest that lithium and VPA similarly modulate the expression of structural postsynaptic genes with topographic specificity in cortical and subcortical regions. Thus, Homer may represent an additional molecular substrate for mood stabilizers, and a potential link with dopaminergic function.

Differential effects of ADORA2A gene variations in pre-attentive visual sensory memory subprocesses - Corrected Proof

Christian Beste, Ann-Kathrin Stock, Vanessa Ness, Jörg T. Epplen, Larissa Arning — 2012-01-13

Abstract: The ADORA2A gene encodes the adenosine A2A receptor that is highly expressed in the striatum where it plays a role in modulating glutamatergic and dopaminergic transmission. Glutamatergic signaling has been suggested to play a pivotal role in cognitive functions related to the pre-attentive processing of external stimuli. Yet, the precise molecular mechanism of these processes is poorly understood. Therefore, we aimed to investigate whether ADORA2A gene variation has modulating effects on visual pre-attentive sensory memory processing. Studying two polymorphisms, rs5751876 and rs2298383, in 199 healthy control subjects who performed a partial-report paradigm, we find that ADORA2A variation is associated with differences in the efficiency of pre-attentive sensory memory sub-processes. We show that especially the initial visual availability of stimulus information is rendered more efficiently in the homozygous rare genotype groups. Processes related to the transfer of information into working memory and the duration of visual sensory (iconic) memory are compromised in the homozygous rare genotype groups. Our results show a differential genotype-dependent modulation of pre-attentive sensory memory sub-processes. Hence, we assume that this modulation may be due to differential effects of increased adenosine A2A receptor signaling on glutamatergic transmission and striatal medium spiny neuron (MSN) interaction.

Age, sex and NK1 receptors in the human brain — A positron emission tomography study with [11C]GR205171 - Corrected Proof

2012-01-06

Abstract: The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n=9) and women (n=9) matched for age varying between 20 and 50years using the highly specific NK1 receptor antagonist [11C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence.

Predictors of medium and long-term outcome following capsulotomy for obsessive–compulsive disorder: One site may not fit all - Corrected Proof

Christian Rück, K. Johan Larsson, David Mataix-Cols — 2012-01-03

Abstract: Patients with treatment-refractory obsessive–compulsive disorder (OCD) are sometimes considered for surgical interventions. The identification of reliable predictors of outcome following such interventions would be of great clinical importance, as it would lead to stricter selection of suitable patients, thus avoiding unnecessary surgery and improving the overall response rate. We analyzed data from 24 severe treatment-resistant patients who underwent capsulotomy for OCD and were carefully followed-up one year after the surgery and at long term (mean 10.8years after surgery). The Yale-Brown Obsessive Compulsive Scale Symptom Checklist was administered to assess the lifetime presence of the most common symptom types. We applied an algorithm to calculate the patients' scores on 4 well-established symptom dimensions: Contamination/cleaning, forbidden thoughts, symmetry/order and hoarding. Multiple regression models were employed to examine whether scores on certain symptom dimensions were predictive of long-term outcome. The presence and number of lifetime symptoms in the symmetry/order domain were associated with greater severity of OCD, depression and anxiety, as well as greater impairment in various functional domains like work, social and family life at both one-year and long-term follow-ups. These results remained consistently significant after controlling for preoperative psychopathology, scores on other OCD symptom dimensions, sex, age, age of onset, duration of follow-up, type of surgical procedure, number of operations and lesion volume. The results could have implications for existing ablative and deep brain stimulation protocols and challenge our current conceptualization of OCD as a unitary diagnostic entity with a single neurobiological substrate.Graphical abstract:

A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD) - Corrected Proof

David S. Baldwin, Henrik Loft, Marianne Dragheim — 2012-01-03

Abstract: The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n=766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10mg Lu AA21004, placebo, or 60mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n=145) of −1.7 (Lu AA21004 5mg, n=155) and −1.5 points (Lu AA21004 10mg, n=151) were not statistically significant; nor were those for Lu AA21004 2.5mg (−1.4 points, n=155) or duloxetine (−2.0 points, n=149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5mg, 5mg and 10mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Lu AA21004 (2.5, 5 and 10mg) was well tolerated.

The acute effects of d-amphetamine and d-methamphetamine on ERP components in humans - Corrected Proof

B. Silber, R. Croft, D.A. Camfield, L.A. Downey, K. Papafotiou, C. Stough — 2012-01-03

Abstract: While a number of behavioural studies have been conducted to investigate the acute effects of amphetamines on tasks of attention and information processing, there is currently a scarcity of research concerning their electrophysiological effects in healthy adults. It is also unclear as to whether amphetamines exert effects on stimulus evaluation or response selection. In two studies, independent groups of twenty healthy illicit stimulant users aged between 21 and 32years were administered 0.42mg/kg d-amphetamine versus placebo, and 0.42mg/kg d-methamphetamine versus placebo respectively, and completed an auditory oddball task on two separate testing days. A 62-channel EEG was recorded during the completion of the task, and the effects of amphetamines on N200 and P300 ERP components were analysed. d-amphetamine significantly decreased reaction time, improved accuracy, and reduced the latency of the P300 component relative to placebo, while having no effect on the N200 component. d-methamphetamine had no effect on reaction time, accuracy or the P300 component, but reduced the amplitude of the N200 component, relative to placebo. It was concluded that there is tentative support to suggest that d-amphetamine at a dose of 0.42mg/kg may enhance speed of information processing while d-methamphetamine at a dose of 0.42mg/kg may reflect changes to stimulus evaluation.

Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism - Corrected Proof

2012-01-03

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long-term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3–CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT2 serotonin receptors and postsynaptic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA-dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP-dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synapses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals.

The melanin-concentrating hormone (MCH) system in an animal model of depression-like behavior - Corrected Proof

M.J. García-Fuster, G.S. Parks, S.M. Clinton, S.J. Watson, H. Akil, O. Civelli — 2012-01-03

Abstract: Selective breeding for divergence in locomotion in a novel environment (bHR, bred High-Responder; bLR, bred Low-Responder) correlates with stress-reactivity, spontaneous anxiety-like behaviors and predicts vulnerability in a rodent model of depression. Identifying genetic factors that may account for such vulnerability are key determinants not only for the illness outcome but also for the development of better-tailored treatment options. Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits some of the hallmarks of a regulator of affective states. The aim of this study was to ascertain the role of the MCH system in depression-like behaviors in bHR vs. bLR rats. bLR rats showed a 44% increase in hypothalamic pMCH mRNA and a 14% decrease in hippocampal CA1 MCH1R mRNA when compared to bHR rats. Interestingly, the amount of time that rats spent immobile in the FST (depressive-like behavior) correlated positively with the amount of hypothalamic pMCH mRNA and negatively with that of hippocampal CA1 MCH1R. The results indicate that the bLR–bHR is a useful rat model to investigate individual basal genetic differences that participate in the monitoring of emotional responsiveness (i.e., depression- and anxiety-like behaviors). They also point to the MCH system (i.e., chronically higher pMCH expression and consequently receptor down-regulation) as a candidate biomarker for the severity of depressive-like behavior. The data indicate that MCH1R participates in the modulation of depression-like behavior through a process that involves the CA1 region of the hippocampus, supporting the possible use of MCH1R antagonists in the treatment of depression.

Mapping serotonergic dysfunction in MDMA (ecstasy) users using pharmacological MRI - Corrected Proof

2012-01-03

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to induce loss of brain serotonin (5-HT) neurons. The purpose of this study was to determine the usefulness of pharmacological magnetic resonance imaging (phMRI) in assessing 5-HT dysfunction by examining the hemodynamic response evoked by infusion with the selective 5-HT reuptake inhibitor citalopram. We studied the effects of MDMA on brain hemodynamics using arterial spin labeling (ASL) based phMRI following a citalopram challenge (7.5mg/kg, i.v.), combined with [123I]β-CIT SPECT imaging in ten male MDMA users and seven healthy non-users. Single photon emission computed tomography (SPECT) imaging was used to assess the availability of 5-HT transporters (SERT). Imaging results were compared with the results of behavioral measures and mood changes following drug administration, in both groups (using the Beck Depression Inventory, Barratt Impulsiveness Scale and a visual analog scale). Reductions in SERT binding were observed in the occipital cortex of MDMA users. In line with this, citalopram induced decreases in cerebral blood flow (CBF) in the occipital cortex of MDMA users. ASL based phMRI also detected a CBF decrease in the thalamus of MDMA users. In concordance with imaging findings, behavioral measures differed significantly between MDMA users and controls. MDMA users had higher impulsivity scores and felt more uncomfortable after citalopram infusion, compared with control subjects. Our findings indicate that phMRI is very well suited for in-vivo assessment of 5-HT dysfunction.

Physiological and affective reactivity to a 35% CO2 inhalation challenge in individuals differing in the 5-HTTLPR genotype and trait neuroticism - Corrected Proof

Ellen Verschoor, C. Rob Markus — 2012-01-03

Abstract: The inhalation of 35% carbon dioxide (CO2) results in an acute stress response in healthy individuals and may accordingly provide a good paradigm to examine potential vulnerability factors for stress reactivity and stress-related psychopathology. It has been proposed that CO2 reactivity is moderated by genetic (5-HTTLPR) and personality (neuroticism) factors, yet no experimental study has investigated their effects on CO2 reactivity simultaneously. The current study examined the singular and interactive effects of the 5-HTTLPR genotype and neuroticism in predicting the affective and physiological response to a 35% CO2 challenge in a healthy sample of male and female students. From a large group of 771 students, 48 carriers of the low/low expressing allele (S/S, S/Lg, Lg/Lg) and 48 carriers of the high/high expressing allele (La/La) with the lowest and the highest neuroticism scores (77 females, 19 males; mean age±SD: 20.6±2years) were selected and underwent a 35% CO2 inhalation. Visual analogue scales for anxiety and discomfort and the Panic Symptom List were used to assess affective symptomatology, while salivary samples and heart rate were assessed to establish the physiological response. A typical pattern of responses to CO2 was observed, characterised by increases in anxiogenic symptoms and physical panic symptomatology and a reduction in heart rate; however, no effect on salivary cortisol concentration was observed. Additionally, the CO2 reactivity did not differ between groups divided by the 5-HTTLPR genotype or neuroticism. Findings of the current study do not support a role for singular or interactive effects of the 5-HTTLPR genotype and trait neuroticism on affective and physiological reactivity to a 35% CO2 inhalation procedure.

Head to head comparisons as an alternative to placebo-controlled trials - Corrected Proof

Eduard Vieta, Nuria Cruz — 2011-12-28

Abstract: Head to head trials have been proposed as an alternative to the ethical and methodological concerns related to placebo-controlled trials. While those studies may be particularly informative from the clinical and cost-effectiveness point-of-view, avoiding placebo poses several regulatory concerns: for superiority designs, the choice of the trial population, outcomes, dose and escalation of the comparator, as well as the comparator itself may be an issue; for non-inferiority studies, issues related to uncertain assay sensitivity and exposure of large samples to potentially ineffective or unsafe drugs make them inappropriate, in the absence of a previous positive superiority trial, for regulatory purposes. The inclusion of active comparators in regulatory trials should not be seen as an alternative, but as a useful complement to the information that can be obtained from placebo-controlled studies.

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment - Corrected Proof

2011-12-12

Abstract: The preferential dopamine D3-agonist pramipexole (4.25±0.38mg/day) or placebo were added for up to 12weeks to ongoing antipsychotic treatment for 24 adult patients with DSM-IV schizophrenia or schizoaffective disorder. Pramipexole was generally well-tolerated (82% trial-completion), and yielded greater decreases in PANSS-total scores (drug/placebo=2.1; p=0.04), with similar decreases in PANSS positive and negative scores and 6.7-fold greater reduction of serum prolactin concentrations compared to placebo. There were no differences in ratings of mood, cognition or extrapyramidal symptoms, all of which were low at intake.

Early gene mapping after deep brain stimulation in a rat model of tardive dyskinesia: Comparison with transient local inactivation - Corrected Proof

Meaghan C. Creed, Clement Hamani, José N. Nobrega — 2011-12-12

Abstract: Deep brain stimulation (DBS) has been extensively used in Parkinson's disease and is also currently being investigated in tardive dyskinesia (TD), a movement disorder induced by chronic treatment with antipsychotic drugs such as haloperidol (HAL). In rodents, vacuous chewing movements (VCMs) following chronic HAL administration are suggested to model orofacial dyskinesias in TD. We show that 60min of DBS (100μA, 90μs, 130Hz) applied to the entopeduncular (EPN) or subthalamic (STN) nuclei significantly decreases HAL-induced VCMs. Using zif268 as a neural activity marker, we found that in HAL-treated animals EPN stimulation increased zif268 mRNA levels in the globus pallidus (+65%) and substantia nigra compacta (+62%) and reticulata (+76%), while decreasing levels in the motor cortex and throughout the thalamus. In contrast, after STN DBS zif268 levels in HAL-treated animals decreased in all basal ganglia structures, thalamus and motor cortex (range: 29% in the ventrolateral caudate-putamen to 100% in the EPN). Local tissue inactivation by muscimol injections into the STN or EPN also reduced VCMs, but to a lesser degree than DBS. When applied to the EPN muscimol decreased zif268 levels in substantia nigra (−29%), whereas STN infusions did not result in significant zif268 changes in any brain area. These results confirm the effectiveness of DBS in reducing VCMs and suggest that tissue inactivation does not fully account for DBS effects in this preparation. The divergent effects of STN vs. EPN manipulations on HAL-induced zif268 changes suggest that similar behavioral outcomes of DBS in these two areas may involve different neuroanatomical mechanisms.

Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain - Corrected Proof

Ramez Ghanbari, Mostafa El Mansari, Pierre Blier — 2011-12-12

Abstract: Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT2C, 5-HT2A receptors and α1- and α2-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10mg/kg/day) for 2 or 14days. Administration of trazodone for 2 and 14days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT2C receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14days enhanced the tonic activation of postsynaptic α2-adrenoceptors, as indicated by the disinhibitory effect of the α2-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT1A receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT2A agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT2A receptors. The enhancement in α2-adrenergic transmission by trazodone, and its 5-HT2A and 5-HT2C receptor antagonism may contribute to its therapeutic action in major depression.

Imaging trait anxiety in high anxiety F344 rats: Focus on the dorsomedial prefrontal cortex - Corrected Proof

2011-12-08

Abstract: Functional magnetic resonance imaging (fMRI) has become an important method in clinical psychiatry research whereas there are still only few comparable preclinical investigations. Herein, we report that fMRI in rats can provide key information regarding brain areas underlying anxiety behavior. Perfusion as surrogate for neuronal activity was measured by means of arterial spin labeling-based fMRI in various brain areas of high anxiety F344 rats and control Sprague–Dawley rats. In one of these areas, the dorsomedial prefrontal cortex (dmPFC), c-Fos labeling was compared between these two strains with immunolabeling. The effects of a neurotoxic ibotenic acid lesion of the dmPFC in F344 rats were examined in a social approach–avoidance anxiety procedure and fMRI. Regional brain activity of high anxiety F344 rats was different in selective cortical and subcortical areas as compared to that of low anxiety Sprague–Dawley rats; the largest difference (i.e. hyperactivity) was measured in the dmPFC. Independently, c-Fos labeling confirmed that F344 rats show increased dmPFC activity. The functional role was confirmed by neurotoxic lesion of the dmPFC that reversed the high anxiety-like behavior and partially normalized the brain activity pattern of F344 rats. The current findings may have translational value as increased activity is reported in an equivalent cortical area in patients with social anxiety, suggesting that pharmacological or functional inhibition of activity in this brain area should be explored to alleviate social anxiety in patients.

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy - Corrected Proof

Stefano Porcelli, Chiara Fabbri, Alessandro Serretti — 2011-12-05

Abstract: In the last decade the serotonin transporter gene promoter polymorphism (5-HTTLPR) was likely the most studied genetic variant as predictor of antidepressant response. Nevertheless results are not consistent across studies and previous meta-analysis, since various factors seem to modulate its effect on antidepressant response.With the aim of clarifying this issue, we systematically reviewed literature, selecting 33 studies for an exploratory analysis without any a priori hypothesis. Then we analyzed separately 19 studies performed on Caucasians and 11 on Asians. We tested two phenotypes – remission and response rates – and three genotype comparisons – ll versus ls/ss, ss versus ll/ls and ll versus ss – using the Cochrane review manager. Evaluations were performed separately for SSRIs and mixed/other drugs. Possible clinical modulators were investigated.In the exploratory analysis, we found an association between l allele and l/l genotype and remission. When the analysis was split for ethnic group, in Caucasians we found an association between l allele and both response (OR=1.58, C.I. 1.16–2.16, p=0.004), and remission (OR=1.53, C.I. 1.14–2.04, p=0.004) in the SSRI group. Only a marginal association between l allele and remission (OR=1.41, C.I. 1.02–1.95, p=0.04) survived pooling together mixed antidepressant treatments. In Asians, a small effect of 5-HTTLPR on remission for mixed antidepressants was detected (OR=2.10, C.I. 1.15–3.84, p=0.02). Gender, age and age at onset modulated the association in Caucasians. Gender, age and depression severity at baseline modulated the association in Asians.In conclusion, in Caucasians 5-HTTLPR may be a predictor of antidepressant response and remission, while in Asians it does not appear to play a major role.Graphical abstract:

A validation of cognitive biomarkers for the early identification of cognitive enhancing agents in schizotypy: A three-center double-blind placebo-controlled study - Corrected Proof

2011-12-05

Abstract: A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.

Hematological clozapine monitoring with a point-of-care device: A randomized cross-over trial - Corrected Proof

2011-12-02

Abstract: Clozapine remains the drug of choice for patients with treatment-resistant schizophrenia, who show a response rate of about 50% despite their unresponsiveness to other antipsychotics. Although treatment with clozapine can lead to considerable savings on bed days, the drug is underutilized for several reasons, perhaps most importantly because of the mandatory hematological monitoring. The Chempaq Express Blood Counter (Chempaq XBC) is a point-of-care device providing counts of white blood cells (WBC) and granulocytes based on a capillary blood sampling. A randomized cross-over trial design was used comparing capillary blood sampling using a point-of-care device with traditional venous blood sampling. Patients were randomized to two sequences starting with either capillary or venous blood sampling followed by a repeated sequence. Primary outcome was measured on a 10-cm visual analog scale. Eighty-five patients were included in the test. Eight (9.4%) dropped out before completion. Patients indicated that they found capillary blood monitoring less painful than venous sampling (VAS ratings: 0.55cm 25–75 percentiles: 0.1–1.4cm vs. 1.75cm 25–75 percentiles: 0.7–2.6, p<0.001). They also felt less inconvenienced by the point-of-care method than the traditional blood sampling, which involved traveling to the laboratory clinical (0.3cm 25–75 percentiles: 0.05–0.7 vs. 2.3cm 25–75 percentiles: 0.75–4.5, p<0.001). For hematological monitoring of clozapine patients a point-of-care device based on capillary blood sampling is better tolerated than traditional venous blood sampling.

Effects of poloxamer 407-induced hyperlipidemia on the pharmacokinetics of carbamazepine and its 10,11-epoxide metabolite in rats: Impact of decreased expression of both CYP3A1/2 and microsomal epoxide hydrolase - Corrected Proof

2011-12-02

Abstract: The pharmacokinetics of carbamazepine (CBZ) and its active 10,11-epoxide metabolite (CBZ-E) were evaluated after intravenous and oral administration of 5mg/kg CBZ to rats with hyperlipidemia induced by poloxamer 407 (HL rats) and controls. The total area under the plasma concentration–time curve (AUC) of CBZ in HL rats after intravenous administration was significantly greater than that in controls due to their slower non-renal clearance (CLNR). This was due to slower hepatic CLint for metabolism of CBZ to CBZ-E in HL rats via CYP3A1/2. This result was consistent with a previous study indicating reduced hepatic CYP3A1/2 expression in HL rats. Interestingly, the AUC of CBZ-E was also increased in HL rats, while AUCCBZ-E/AUCCBZ ratios remained unchanged. These results suggested that further metabolism of CBZ-E to the inactive metabolite trans-10,11-dihydoxyl-10,11-dihydro-CBZ (CBZ-D) via microsomal epoxide hydrolase (mEH) was also slowed in HL rats. The significantly reduced hepatic mRNA level and expression of mEH protein in HL rats compared to controls confirmed the above hypothesis. Similar pharmacokinetic changes were observed in HL rats after oral administration of CBZ. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Caution is required regarding pharmacotherapy in the hyperlipidemic state in cases where drugs that are metabolized principally by CYP3A1/2 or mEH and have a narrow therapeutic range are in use.

Severe and anxious depression: Combining definitions of clinical sub-types to identify patients differentially responsive to selective serotonin reuptake inhibitors - Corrected Proof

George I. Papakostas, Hua Fan, Enrico Tedeschini — 2011-11-18

Abstract: Patients with severe major depressive disorder are more likely than those with mild/moderate depression to experience the relative benefits of antidepressant therapy versus placebo. Several studies have, unexpectedly, failed to show a similar antidepressant–placebo discrepancy between patients with versus without anxious depression, although patients with anxious depression are more likely to meet criteria for severe depression than those without. The aim of this study was to confirm the absence of treatment moderating effects for anxious depression in a general clinical trial population, and to examine for the presence of treatment moderating effects in severe depression. Patient-level outcome data from all randomized, double-blind, placebo-controlled trials involving the use of the selective serotonin reuptake inhibitor escitalopram for adults with major depressive disorder sponsored by H. Lundbeck A/S or Forest Laboratories were pooled. Studies focusing on patients with a specific axis-I or -III co-morbidity were excluded. Data from five trials were pooled. Anxious depression was not found to serve as a treatment moderator for selective serotonin reuptake inhibitor therapy versus placebo. However, when patients with severe depression were analyzed separately, anxious depression significantly influenced the relative degree of symptom reduction with selective serotonin reuptake inhibitors versus placebo (p=0.0094). In fact, the numbers needed to treat for remission for these two sub-types were the largest and smallest reported to date from analyses of large datasets of antidepressants (22 for severe anxious versus 4 for severe non-anxious depression). Subdividing patients with severe major depressive disorder into those with versus without anxious depression results in the characterization of sub-types that are particularly “responsive” (severe non-anxious) and “unresponsive” (severe anxious) to selective serotonin reuptake inhibitor therapy (relative to placebo). These findings are preliminary, of yet undetermined clinical relevance, and warrant replication and further exploration.

Placebo effect in child and adolescent psychiatric trials - Corrected Proof

2011-10-28

Abstract: Much literature has been written in the field of child psychiatry regarding the placebo as a tool to test drug efficacy in clinical trials, but quite little regarding the placebo effect itself or its clinical use in child psychiatry. In this article, we aim to critically review the literature regarding the placebo effect in children and adolescents with mental disorders, focusing especially on factors influencing the placebo effect and how they may influence the interpretation of clinical trials. The placebo effect seems to be more marked in children than adults, and particularly in children and adolescents with depression, although it is pervasive across ages and is present in non-psychiatric conditions as well. The use of a placebo in clinical trials as a comparator with drugs that have moderate efficacy at most makes it difficult to obtain positive results, and much effort is needed to design very high quality clinical trials that may overcome the limitations of using a placebo. In addition, the placebo effect across ages and clinical conditions must be tested directly (compared with no treatment whenever possible), in order to characterise which placebos work for what and to determine their use in clinical settings.

VEGF regulates antidepressant effects of lamotrigine - Corrected Proof

Rongju Sun, Nanxin Li, Tanshi Li — 2011-10-28

Abstract: The anticonvulsant drug lamotrigine has been shown to produce strong antidepressant effects in the treatment of bipolar disorder patients. Our previous studies have demonstrated that brain derived neurotrophic factor (BDNF) signaling plays an important role in regulating its behavioral actions in several rodent models of depression. The current study extends earlier work on BDNF and explores the role of another important neurotrophin vascular endothelial growth factor (VEGF) in regulating the antidepressant actions of lamotrigine. The results showed that chronic administration of 30mg/kg lamotrigine (14days) normalized the down-regulated frontal and hippocampal VEGF protein expression as well as the behavioral deficits induced by chronic unpredictable stress. In addition, pharmacological inhibition of VEGF signaling by infusion of SU5416, a selective Flk-1 receptor inhibitor, blocks the antidepressant effects of lamotrigine in all behavioral paradigms. Taken together, this study provides further evidence that VEGF is also an essential regulator for the antidepressant effects of lamotrigine.

Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder - Corrected Proof

2011-10-17

Abstract: Over one half of bipolar patients have been reported to be more prone to either depressive or manic relapses. This study aimed to define profiles of drugs used for maintenance treatment of bipolar disorder (BD) by the means of Polarity Index.Polarity Index is a new metric indicating the relative antimanic versus antidepressive preventive efficacy of drugs. Polarity Index was retrieved by calculating Number Needed to Treat (NNT) for prevention of depression and NNT for prevention of mania ratio, as emerging from the results of randomized placebo-controlled trials. Included trials were randomized and double blind, with a minimal duration of 24weeks, assessing effectiveness of a mood stabilizer or antipsychotic drug alone or in combination with a mood stabilizing agent versus a placebo comparator in BD maintenance treatment.Polarity Index value above 1.0 indicates a relative greater antimanic prophylactic efficacy, number below 1.0 a relative greater antidepressive efficacy. The polarity index for the drugs used in maintenance therapy for bipolar disorder was 12.09 for risperidone, 4.38 for aripiprazole, 3.91 for ziprasidone, 2.98 for olanzapine, 1.39 for lithium, 1.14 for quetiapine, and 0.40 for lamotrigine. Polarity index of valproate and oxcarbazepine may not be reliable due to the failure of their maintenance trials.The polarity index provides a measure of how much antidepressant versus antimanic a drug is in bipolar disorder prophylaxis, and may guide the choice of maintenance therapy in bipolar patients.

Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels - Corrected Proof

Katrina Weston-Green, Xu-Feng Huang, Jiamei Lian, Chao Deng — 2011-10-10

Abstract: The second generation antipsychotic drug (SGA) olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Cholinergic muscarinic M3 receptors (M3R) are expressed on pancreatic β-cells and in the brain where they influence insulin secretion and may regulate other metabolic hormones via vagal innervation of the gastrointestinal tract. Olanzapine's M3R antagonism is an important risk factor for its diabetogenic liability. However, the effects of olanzapine on central M3Rs are unknown. Rats were treated with 0.25, 0.5, 1.0 or 2.0mg olanzapine/kg or vehicle (3×/day, 14-days). M3R binding densities in the hypothalamic arcuate (Arc) and ventromedial nuclei (VMH), and dorsal vagal complex (DVC) of the brainstem were investigated using [3H]4-DAMP plus pirenzepine and AF-DX116. M3R binding correlations to body weight, food intake, insulin, ghrelin and cholecystokinin (CCK) were analyzed. Olanzapine increased M3R binding density in the Arc, VMH and DVC, body weight, food intake, circulating plasma ghrelin and CCK levels, and decreased plasma insulin and glucose. M3R negatively correlated to insulin, and positively correlated to ghrelin, CCK, food intake and body weight. Increased M3R density is a compensatory up-regulation in response to olanzapine's M3R antagonism. Olanzapine acts on M3R in regions of the brain that control food intake and insulin secretion. Olanzapine's M3R blockade in the brain may inhibit the acetylcholine pathway for insulin secretion. These findings support a role for M3Rs in the modulation of insulin, ghrelin and CCK via the vagus nerve and provide a mechanism for olanzapine's diabetogenic and weight gain liability.

Alteration in RGS2 expression level is associated with changes in haloperidol induced extrapyramidal features in a mutant mouse model - Corrected Proof

2011-10-10

Abstract: Antipsychotic induced Parkinsonism (AIP) is a common adverse effect of antipsychotic drug treatment among schizophrenia patients. Two previous studies showed association of the rs4606 SNP in the 3′ untranslated region of the regulator of G protein signaling 2 gene (RGS2) with susceptibility to AIP. Since rs4606 reportedly influences expression of RGS2, we applied a translational approach and studied the effect of chronic (24days) exposure to haloperidol on AIP-like features in mice carrying a mutation that causes lower Rgs2 gene expression. Haloperidol and vehicle treated male mice heterozygous (HET) or homozygous (HOM) for the mutation, or wild type (WT), were evaluated for open field locomotion, catalepsy duration, pole test performance and rota-rod latency to fall. We showed that in haloperidol treated mice lower Rgs2 expression is associated with better performance on the open field, catalepsy and rota-rod tests but not the pole test. Results were most consistent for the 0.2mg/kg/d haloperidol dose. These observations support the possible involvement of RGS2 in mechanisms underlying susceptibility to AIP.

Neuropathological abnormalities of astrocytes, GABAergic neurons, and pyramidal neurons in the dorsolateral prefrontal cortices of patients with major depressive disorder - Corrected Proof

Dong Hoon Oh, Hyeon Son, Sejin Hwang, Seok Hyeon Kim — 2011-10-03

Abstract: Human post-mortem brain studies have revealed reduced density and size of neurons and glial cells in the dorsolateral prefrontal cortex (dlPFC) in major depressive disorder (MDD). However, the basis of these cytoarchitectural abnormalities and the relationship between them are not understood. We hypothesized that the reduced density of GABAergic neurons and glial cells was associated with altered glutamate neurotransmission in the dlPFC. In order to test this hypothesis, we examined a specific marker type (i.e., calretinin, CR: as a marker of GABAergic neurons) and also attempted to identify the neuropathological markers that correlate with the density of CR-immunoreactive (IR) GABAergic neurons in the dlPFC, using the Stanley Neuropathology Consortium Integrative Database (SNCID, http://sncid.stanleyresearch.org/), which is a web-based tool used to integrate Stanley Medical Research Institute (SMRI) data sets. We found that the density of CR-IR GABAergic neurons was significantly lower in layer I of the dlPFC of MDD patients (n=15) than in that of unaffected controls (n=15) (p=0.021). CR-IR GABAergic neuronal changes were positively correlated with changes in several markers for glial cells and pyramidal neurons in the dlPFC of all SNC subjects (n=60). We also found that the glutamate changes negatively correlated with glial fibrillary acidic protein (GFAP) expression levels and CR-IR GABAergic neuronal density in the prefrontal cortex of all SNC subjects (P<0.05). These findings yield some insight into the mechanism by which increased glutamatergic neurotransmission leads to excitotoxic damage both in neurons and glial cells in the dlPFC of MDD patients.

Perinatal phencyclidine treatment alters neuregulin 1/erbB4 expression and activation in later life - Corrected Proof

Teresa Marie du Bois, Kelly Anne Newell, Xu-Feng Huang — 2011-10-03

Abstract: Schizophrenia is a complex and devastating mental disorder of unknown etiology. Hypofunction of N-methyl-d-aspartate (NMDA) receptors are implicated in the disorder, since phencyclidine (PCP) and other NMDA receptor antagonists mimic schizophrenia-like symptoms in humans and animals so well. Moreover, genetic linkage and post mortem studies strongly suggest a role for altered neuregulin 1 (Nrg1)/erbB4 signaling in schizophrenia pathology. This study investigated the relationship between the NMDA receptor and Nrg1 signaling pathways using the perinatal PCP animal model. Rats (n=5/group) were treated with PCP (10mg/kg) or saline on postnatal days (PN) 7, 9 and 11 and were sacrificed on PN12, 5weeks and 20weeks for biochemical analyses. Western blotting was used to determine total and phosphorylated levels of proteins involved in NMDA receptor/Nrg1 signaling in the prefrontal cortex and hippocampus. In the cortex, PCP treatment altered Nrg1/erbB4 expression levels throughout development, including decreased Nrg1 and erbB4 at PN12 (−25–30%; p<0.05); increased erbB4 and p-erbB4 (+18–27%; p<0.01) at 5weeks; and decreased erbB4 and p-erbB4 (−16–18%; p<0.05) along with increased Nrg1 (+33%; p<0.01) at 20weeks. In the hippocampus, levels of Nrg1/erbB4 were largely unaffected apart from a significant decrease in p-erbB4 at 20weeks (−13%; p<0.001); however NMDA receptor subunits and PSD-95 showed increases at PN12 and 5weeks (+20–32%; p<0.05), and decreases at 20weeks (−22–29%; p<0.05). This study shows that NMDA receptor antagonism early in development can have long term effects on Nrg1/erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia.

The effects of oxytocin and its analog, carbetocin, on genetic deficits in sensorimotor gating - Corrected Proof

David Feifel, Paul D. Shilling, Annabelle M. Belcher — 2011-10-03

Abstract: Converging evidence from preclinical and clinical studies suggest that oxytocin has therapeutic potential for schizophrenia and other neuropsychiatric disorders. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating, an important brain function involved in filtering environmental information. We previously demonstrated that systemically administered oxytocin reversed psychostimulant-induced PPI deficits in rats suggesting that oxytocin can produce antipsychotic-like central effects. That finding was supported by a recent trial in humans, which found that intranasal oxytocin reduced symptoms of schizophrenia. The goal of this study was to extend this line of investigation by testing the effects of oxytocin, and a structural analog of oxytocin, carbetocin, on non-pharmacological deficits in PPI. In experiment 1, Brown Norway (BN) rats, a rat strain that has naturally low PPI, were given either saline or one of three doses of oxytocin (0.04–1.0mg/kg, sc). In experiment 2, BN rats were given either saline, one of three doses of carbetocin (0.04–1.0mg/kg) or oxytocin (1mg/kg). PPI and acoustic startle response (ASR) of rats were tested. Oxytocin significantly increased PPI (P<0.01) and decreased ASR levels (P<0.01) in BN rats in a dose-dependent fashion. In contrast, carbetocin had no effect on PPI levels or ASR. The facilitation of BN PPI by oxytocin is similar to what we have previously observed with clozapine and thus further supports oxytocin having antipsychotic properties. In contrast to oxytocin, our data do not support the use of carbetocin as an antipsychotic drug.

The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder — A European Multicenter Study - Corrected Proof

2011-09-23

Abstract: Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts.Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D≤17 and remission as HAM-D≤7 after 4weeks of treatment with antidepressants at adequate dose. Genotyping was performed for seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene.With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes.In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further.

The CC genotype of transforming growth factor-β1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression - Corrected Proof

2011-09-19

Abstract: Transforming growth factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against β-amyloid-induced neurodegeneration. Recently, a specific impairment of the TGF-β1 signaling pathway has been demonstrated in Alzheimer's disease (AD) brain. TGF-β1 is also involved in the pathogenesis of depressive disorders, which may occur in 30–40% of AD patients. The TGF-β1 gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T/C) and +25 (G/C), which are known to influence the level of expression of TGF-β1.We investigated TGF-β1 +10 (T/C) and +25 (G/C) SNPs and allele frequencies in 131 sporadic AD patients and in 135 healthy age- and sex-matched controls. Genotypes of the TGF-β1 SNPs at codon +10 (T/C) and +25 (G/C) did not differ between AD patients and controls, whereas the allele frequencies of codon +10 polymorphism showed a significant difference (P=0.0306). We also found a different distribution of the +10 (C/C) phenotype (continuity-corrected χ2 test with one degree of freedom=4.460, P=0.0347) between late onset AD (LOAD) patients and controls (P=0.0126), but not between early onset AD (EOAD) patients and controls. In addition, the presence of the C/C genotype increased the risk of LOAD regardless of the status of apolipoprotein E4 (odds ratio [OR]=2.34; 95% CI=1.19–4.59). Compared to patients bearing the T/T and C/T polymorphisms, LOAD TGF-β1 C/C carriers also showed >5-fold risk to develop depressive symptoms independently of a history of depression (OR=5.50; 95% CI=1.33–22.69). An association was also found between the TGF-β1 C/C genotype and the severity of depressive symptoms (HAM-D17≥14) (P<0.05). These results suggest that the CC genotype of the TGF-β1 gene increases the risk to develop LOAD and is also associated with depressive symptoms in AD.

New insights on the consequences of biotransformation processes on the distribution and pharmacodynamic profiles of some neuropsychotropic drugs - Corrected Proof

2011-09-15

Abstract: The metabolic processes frequently trigger highly complex pharmacokinetic (PK) and pharmacodynamic (PD) characteristics for the coexisting entities, parent drug and its active or inactive metabolites. The interpretation of both individual and cumulative profiles, frequently used in the therapeutic drug monitoring procedures, must take into consideration the biological coherence of the changes of the molecular descriptors characterizing the metabolites versus the parent drugs, and further qualitative and quantitative consequences on permeability processes across highly specialized biological barriers (e.g. blood–brain barrier [BBB]). This paper analyzes the correlation of molecular descriptor differences and the PK/PD consequences for three representative psychotropic drugs (risperidone, clozapine and tramadol) and their active metabolites, underlying the safety and efficacy concerns of using the products of metabolic processes as potential new drugs. The minimal structural changes are correlated with the predicted or experimental penetrability across the biological membranes, with a special emphasis on BBB penetration, as the limiting phase for the effect at central nervous system level. The PD characteristics related to the active metabolites are compared to the ones reported for the parent drugs, concerning mainly the affinity for cerebral receptors and the type of activity at a specific level. For the neuropsychotropic substances, with BBB penetrability as a sine qua non condition, the comparative analysis of PK/PD properties for the parent drug and its metabolites generates a complete and highly complex image of the consequences of their coexistence, since these entities must be conceived and analyzed not separately, but by inclusion of usually complementary properties generating a unique therapeutic profile.

Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo - Corrected Proof

Matthew J. Robson, Meenal Elliott, Michael J. Seminerio, Rae R. Matsumoto — 2011-09-13

Abstract: Ketamine is an NMDA antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small-scale human clinical trials. Ketamine also binds to σ receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of σ receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for σ1 and σ2 receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The σ receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of σ receptors in the antidepressant-like effects of ketamine. Ketamine bound to both σ1 and σ2 receptors with μM affinities. Additionally, ketamine potentiated NGF-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that σ receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine.

Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats - Corrected Proof

2011-09-02

Abstract: The novel triple monoamine inhibitor tesofensine blocks dopamine, serotonin and norepinephrine re-uptake and is a promising candidate for the treatment of obesity. Obesity is associated with lower striatal dopamine D2 receptor availability, which may be related to disturbed regulation of food intake. This study assesses the effects of chronic tesofensine treatment on food intake and body weight in association with changes in striatal dopamine D2/D3 receptor (D2/3R) availability of diet-induced obese (DIO) rats. Four groups of 15 DIO rats were randomized to one of the following treatments for 28days: 1. tesofensine (2.0mg/kg), 2. vehicle, 3. vehicle+restricted diet isocaloric to caloric intake of group 1, and 4. tesofensine (2.0mg/kg)+a treatment-free period of 28days. Caloric intake and weight gain decreased significantly more in the tesofensine-treated rats compared to vehicle-treated rats, which confirms previous findings. After treatment discontinuation, caloric intake and body weight gain gradually increased again. Tesofensine-treated rats showed significantly lower D2/3R availability in nucleus accumbens and dorsal striatum than both vehicle-treated rats and vehicle-treated rats on restricted isocaloric diet. No correlations were observed between food intake or body weight and D2/3R availability. Thus, chronic tesofensine treatment leads to decreased food intake and weight gain. However, this appears not to be directly related to the decreased striatal D2/3R availability, which is mainly a pharmacological effect.

Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring - Corrected Proof

Dominique Nouel, Melissa Burt, Ying Zhang, Louise Harvey, Patricia Boksa — 2011-09-02

Abstract: Epidemiological studies implicate prenatal infection as a risk factor for the development of schizophrenia and autism. Subjects with schizophrenia and autism are reported to exhibit reduced levels of glutamic acid decarboxylase 67 (GAD67), a marker for GABA neurons, in various brain regions. Reduced levels of reelin, a secretory glycoprotein present in a subpopulation of GABA neurons, have also been found in these disorders. To test if prenatal infection can cause abnormalities in GAD67 and reelin in the brains of offspring, this study used a rat model of prenatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), and assessed numbers of GAD67-immunoreactive (GAD67+) and reelin-immunoreactive (reelin+) neurons in the hippocampus of offspring. In offspring at postnatal day 14 (PD14), GAD67+ cell counts were reduced in the dentate gyrus of the prenatal LPS group compared to prenatal saline controls, while at PD28, GAD67+ cells counts were reduced in the prenatal LPS group in both the dentate gyrus and the CA1. There was a decrease in the number of reelin+ cells in the prenatal LPS offspring compared to controls in the dentate gyrus at PD14. However using Western blotting, no significant effects of prenatal LPS on levels of GAD67 or reelin protein were observed in various brain regions at PD14. These findings support the idea that prenatal infection can cause reductions in postnatal expression of GAD67 and reelin, and in this way, possibly contribute to the pathophysiology of schizophrenia or autism.

Efficacy of a targeted cognitive–behavioral treatment program for cannabis use disorders (CANDIS*) - Corrected Proof

2011-08-25

Abstract: Aims: To examine the efficacy, 3- and 6-month follow-up effects of a psychological treatment for older adolescents and adults with DSM-IV cannabis use disorders. The program was tailored to the needs of this patient population.Experimental procedures: A randomized controlled clinical trial of 122 patients aged 16 to 44years with DSM-IV cannabis dependence as the main substance use diagnosis was conducted. Patients were randomly assigned to either Active Treatment (AT, n=90) or a Delayed Treatment Control group (DTC, n=32). Treatment consisted of 10 sessions of therapy, detailed in a strictly enforced manual. Assessments were conducted at baseline, during each therapy session, at post treatment and at follow-up assessments at 3 and 6months.Results: The treatment retention rate was 88%. Abstinence was achieved in 49% of AT patients and in 13% of those in DTC (p<0.001; intend-to-treat (ITT) analysis). Further, AT patients improved significantly (p<=0.001) in the frequency of cannabis use per week, addiction severity, number of disability days, and overall level of psychopathology. Program effects were maintained over a 3-month- (abstinence rate: 51%) and 6-month follow-up (45%) period.Conclusion: The treatment program is effective in obtaining abstinence as well as reducing cannabis use and improves the associated social and mental health burden.