European Neuropsychopharmacology

Editorial Board

2012-06-01

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

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.

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

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.

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

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:

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment

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.

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

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.

VEGF regulates antidepressant effects of lamotrigine

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.

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

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.

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

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.

ECNP Calendar of Events

2012-06-01

European Neuropsychopharmacology

Editorial Board

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

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

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

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment

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

VEGF regulates antidepressant effects of lamotrigine

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

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

ECNP Calendar of Events

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