European Neuropsychopharmacology (v.23, #3)

Contents (OBC).

Antidepressants act directly on astrocytes: Evidences and functional consequences by Boldizsár Czéh; Barbara Di Benedetto (171-185).
Post-mortem histopathological studies report on reduced glial cell numbers in various frontolimbic areas of depressed patients implying that glial loss together with abnormal functioning could contribute to the pathophysiology of mood disorders. Astrocytes are regarded as the most abundant cell type in the brain and known for their housekeeping functions, but as recent developments suggest, they are also dynamic regulators of synaptogenesis, synaptic strength and stability and they control adult hippocampal neurogenesis. The primary aim of this review was to summarize the abundant experimental evidences demonstrating that antidepressant therapies have profound effect on astrocytes. Antidepressants modify astroglial physiology, morphology and by affecting gliogenesis they probably even regulate glial cell numbers. Antidepressants affect intracellular signaling pathways and gene expression of astrocytes, as well as the expression of receptors and the release of various trophic factors. We also assess the potential functional consequences of these changes on glutamate and glucose homeostasis and on synaptic communication between the neurons. We propose here a hypothesis that antidepressant treatment not only affects neurons, but also activates astrocytes, triggering them to carry out specific functions that result in the reactivation of cortical plasticity and can lead to the readjustment of abnormal neuronal networks. We argue here that these astrocyte specific changes are likely to contribute to the therapeutic effectiveness of the currently available antidepressant treatments and the better understanding of these cellular and molecular processes could help us to identify novel targets for the development of antidepressant drugs.
Keywords: Astroglia; Reactive astrocyte; Tripartite synapse; Trophic factor; Plasticity; Mood disorder;

Resting-state functional connectivity abnormalities in limbic and salience networks in social anxiety disorder without comorbidity by J. Nienke Pannekoek; Ilya M. Veer; Marie-José van Tol; Steven J.A. van der Werff; Liliana R. Demenescu; André Aleman; Dick J. Veltman; Frans G. Zitman; Serge A.R.B. Rombouts; Nic J.A. van der Wee (186-195).
The neurobiology of social anxiety disorder (SAD) is not yet fully understood. Structural and functional neuroimaging studies in SAD have identified abnormalities in various brain areas, particularly the amygdala and elements of the salience network. This study is the first to examine resting-state functional brain connectivity in a drug-naive sample of SAD patients without psychiatric comorbidity and healthy controls, using seed regions of interest in bilateral amygdala, in bilateral dorsal anterior cingulate cortex for the salience network, and in bilateral posterior cingulate cortex for the default mode network. Twelve drug-naive SAD patients and pair-wise matched healthy controls, all drawn from the Netherlands Study of Depression and Anxiety sample, underwent resting-state fMRI. Group differences were assessed with voxel-wise gray matter density as nuisance regressor. All results were cluster corrected for multiple comparisons (Z>2.3, p<.05). Relative to control subjects, drug-naive SAD patients demonstrated increased negative right amygdala connectivity with the left middle temporal gyrus, left supramarginal gyrus and left lateral occipital cortex. In the salience network patients showed increased positive bilateral dorsal anterior cingulate connectivity with the left precuneus and left lateral occipital cortex. Default mode network connectivity was not different between groups. These data demonstrate that drug-naive SAD patients without comorbidity show differences in functional connectivity of the amygdala, and of areas involved in self-awareness, some of which have not been implicated in SAD before.
Keywords: Resting-state functional connectivity; Social anxiety disorder; Amygdala; Anterior cingulate cortex; Salience network; Default mode network;

Persistent negative symptoms in first episode patients with schizophrenia: Results from the European First Episode Schizophrenia Trial by Silvana Galderisi; Armida Mucci; Istvan Bitter; Jan Libiger; Paola Bucci; W. Wolfgang Fleischhacker; René S. Kahn; for the EUFEST Study Group (196-204).
Negative symptoms that do not improve following antipsychotic treatment represent a challenge for development of effective treatments. Few studies have been carried out so far, especially in first-episode schizophrenia patients, to clarify prevalence, correlates and impact of persistent negative symptoms (PNS) on short- and long-term outcome of the disease.All patients from EUFEST study for whom both baseline and 12-month assessments were available were included (N=345). PNS were defined as the presence of at least one negative symptom of moderate or higher severity, not confounded by depression or parkinsonism, at baseline and after 1 year of treatment. Patients with PNS were compared to those with at least one negative symptom of moderate or higher severity at the baseline, not persisting after 1 year, on demographic, clinical, neurocognitive, global functioning and quality of life measures.PNS not confounded by depression or parkinsonism were present in 6.7% of the sample. The symptom that more often persisted was blunted affect. Patients with PNS differed from those without PNS for a longer duration of untreated psychosis (DUP) and a more frequent discontinuation of study treatment; they also had a poorer psychopathological outcome and a worse global functioning after 1 year of treatment.The presence of PNS was associated to poorer improvement of all psychopathological dimensions and worse global functioning after 1 year of treatment. The longer DUP in subjects with PNS suggests that programs aimed at shortening DUP might reduce the prevalence of PNS and improve prognosis of schizophrenia.
Keywords: Duration of untreated psychosis; Quality of life; Global functioning; Cognitive functioning; Remission;

Prediabetic increase in hemoglobin A1c compared with impaired fasting glucose in patients receiving antipsychotic drugs by Peter Manu; Christoph U. Correll; Martien Wampers; Ruud van Winkel; Weiping Yu; Alex J. Mitchell; Marc De Hert (205-211).
In 2010, the American Diabetes Association recommended that individuals with hemoglobin A1c 5.7–6.4% be classified as prediabetic even in the absence of impaired fasting glucose (IFG).To compare the clinical and metabolic characteristics of patients receiving antipsychotic drugs who have normal glucose tolerance (NGT), hemoglobin A1c 5.7–6.4% or IFG (fasting glucose 100–125 mg/dL).Body mass index, waist circumference, fasting glucose, insulin, lipids, hemoglobin A1c, and insulin resistance assessed with the homeostatic model (HOMA-IR) were measured in a consecutive cohort of adult psychiatric inpatients with NGT (N=423), hemoglobin A1c 5.7–6.4% (N=130), IFG (N=52) and IFG plus hemoglobin A1c 5.7–6.4% (n=39).The hemoglobin A1c 5.7–6.4% group had lower fasting insulin levels (9.8±5.6 vs. 15.5±11.4 μU/mL, p<0.0001) and HOMA-IR (2.1±1.2 vs. 4.1±3.1, p<0.0001) than the IFG group, but were metabolically similar to those with NGT. The hemoglobin A1c 5.7–6.4% was the predominant prediabetic pattern in patients treated with antipsychotics other than clozapine or olanzapine. Patients with hemoglobin A1c 5.7–6.4% and those with IFG were statistically similar in age (40.1±13.6 vs. 39.7±10.3 years), body mass index (26.0±4.8 vs. 26.3±4.9) and waist circumference 93.1±13.9 vs. 98.1±12.1 cm for males and 92.5±13.5 vs. 90.7±15.8 cm for females.The hemoglobin A1c in the 5.7–6.4% range is common in euglycemic patients receiving antipsychotic drugs and this prediabetic pattern has metabolic and pharmacological features that differentiates it from IFG.
Keywords: Prediabetes; Hemoglobin A1c; Impaired fasting glucose; Antipsychotic drugs;

Chronic use of benzodiazepines and latent cognitive decline in the elderly: Results from the Three-city study by Thibault Mura; Cécile Proust-Lima; Tasnime Akbaraly; Hélène Amieva; Christophe Tzourio; Hugues Chevassus; Marie-Christine Picot; Hélène Jacqumin-Gadda; Claudine Berr (212-223).
We aimed to examine whether long-term use of benzodiazepines is associated with an accelerated decline of cognitive performances by using a statistical model specifically adapted to multivariate longitudinal bounded quantitative outcomes. The data came from the “Three-city” study, a French population based study. All the subjects were 65 years old or older at inclusion and had been followed-up for 7 years. The use of benzodiazepines and cognitive functioning were assessed at each examination phase (baseline, 2, 4 and 7 years). Cognitive decline was analyzed using a nonlinear multivariate mixed model with a latent process. This model makes it possible to assess change over time of the latent cognitive process underlying several neuropsychological tests: Mini Mental Status Examination, Isaacs Set test, Benton Visual Retention Test, and Trail Making Test (A and B), and to describe and account for their metrological properties. Analyses were adjusted for age, center, gender, education, socio-professional status, depression, insomnia, high blood pressure, hypercholesterolemia, alcohol, tobacco consumption and physical activity. Nine hundred and sixty nine subjects who reported taking benzodiazepines for 2, 4 or 7 consecutive years were compared to 4226 subjects who were non-benzodiazepine users. Chronic use of benzodiazepine was significantly associated with a lower latent cognitive level (β=−1.79 SE=0.25 p=<0.001), but no association was found between chronic use and an acceleration of cognitive decline, neither on the latent cognitive process (β×time=0.010 SE=0.04 p=0.81), nor on specific neuropsychological tests. Our results suggest that chronic benzodiazepine use is associated with poorer cognitive performance but not with accelerated cognitive decline with age.
Keywords: Cognitive decline; Cognitive impairment; Benzodiazepines; Latent process; Longitudinal study;

Finite mixture regression model analysis on antipsychotics induced weight gain: Investigation of the role of the serotonergic genes by Behdin Nowrouzi; Renan P. Souza; Clement Zai; Takahiro Shinkai; Marcellino Monda; Jeffrey Lieberman; Jan Volvaka; Herbert Y. Meltzer; James L. Kennedy; Vincenzo De Luca (224-228).
Antipsychotics-induced weight gain is a complex phenomenon with a relevant underlying genetic basis. Polymorphisms of serotonin receptors and related proteins were genotyped in 139 schizophrenia patients and incorporated as covariates in a mixture regression model of weight gain in combination with clinical covariates. The HTR1D rs6300 polymorphism was showing a slight significance conferring risk for obesity (heavy weight gain group) under additive model. After correcting for multiple testing all the genetic predictors were non-significant, however the clinical predictors were associated with the risk of heavy weight gain. These findings suggest a role of ethnicity and olanzapine in increasing the risk for obesity in the heavy weight gain group and haloperidol protecting against heavy weight gain. The mixture regression model appears to be a useful strategy to highlight different weight gain subgroups that are affected differently by clinical and genetic predictors.
Keywords: Schizophrenia; Antipsychotics; Weight gain; Genetics; Serotonin; FMM;

Chronic effects of corticosterone on GIRK1-3 subunits and 5-HT1A receptor expression in rat brain and their reversal by concurrent fluoxetine treatment by Laura Saenz del Burgo; Roser Cortés; Guadalupe Mengod; Mario Montaña; Gontzal García del Caño; Joan Sallés (229-239).
Dysregulation of the serotonergic system and abnormalities of the hypothalamic–pituitary–adrenal axis have been demonstrated in major depression. Animal studies indicate that 5-HT1A receptor expression may be reduced by long-term administration of corticosterone. However, similar studies on the regulation of GIRK channels, one of the most important effectors of the neuronal 5-HT1A receptor, are limited. In order to address these issues, slow-release corticosterone pellets were implanted subcutaneously to adrenal intact male rats (200 mg pellets, 35 days release). Starting on day 15, animals were treated for 21 days with fluoxetine (5 mg/kg/day, i.p.), or vehicle. Using in situ hybridization histochemistry and receptor autoradiography, we found that chronic corticosterone treatment was accompanied by a significant decrease on the mRNAs coding for mineralocorticoid receptors in hippocampal areas. Under these conditions, 5-HT1A receptor mRNA expression decreased in dorsal raphe nucleus and dentate gyrus. However, 5-HT1A receptor levels, as measured by [3H]-8-OH-DPAT binding, diminished significantly only in dentate gyrus. It is noteworthy that chronic treatment with fluoxetine reversed the alterations on 5-HT1A receptor mRNA levels only in dorsal raphe. Finally, chronic corticosterone treatment produced an increase on the mRNA coding for the GIRK2 subunit in several hypothalamic and thalamic areas, which was reversed by fluoxetine. Measurements of cell density and volume of the granular layer of the dentate gyrus did not reveal significant changes after corticosterone or corticosterone plus fluoxetine treatments. These data are relevant for a better understanding of the differential regulation of pre- and postsynaptic 5-HT1A receptors by corticosterone flattened rhythm.
Keywords: Mineralocorticoid receptor; Glucocorticoid receptor; Corticosterone flattened rhythm; Depression; [3H]-8-OH-DPAT binding; Hippocampus;

Operant behavior to obtain palatable food modifies ERK activity in the brain reward circuit by Thomas Guegan; Laura Cutando; Giuseppe Gangarossa; Emanuela Santini; Gilberto Fisone; Albert Martinez; Emmanuel Valjent; Rafael Maldonado; Miquel Martin (240-252).
Food palatability produces behavioral modifications that resemble those induced by drugs of abuse. Palatability-induced behavioral changes require both, the activation of the endogenous cannabinoid system, and changes in structural plasticity in neurons of the brain reward pathway. The ERK intracellular pathway is activated by CB1 receptors (CB1-R) and plays a crucial role in neuroplasticity. We investigated the activation of the ERK signaling cascade in the mesocorticolimbic system induced by operant training to obtain highly palatable isocaloric food and the involvement of the CB1-R in these responses. Using immunofluorescence techniques, we analyzed changes in ERK intracellular pathway activation in the mesocorticolimbic system of wild-type and CB1 knockout mice (CB1−/−) trained on an operant paradigm to obtain standard, highly caloric or highly palatable isocaloric food. Operant training for highly palatable isocaloric food, but not for standard or highly caloric food, produced a robust activation of the ERK signaling cascade in the same brain areas where this training modified structural plasticity. These changes induced by the operant training were absent in CB1−/−. We can conclude that the activation of the ERK pathway is associated to the neuroplasticity induced by operant training for highly palatable isocaloric food and might be involved in CB1-R mediated alterations in behavior and structural plasticity.
Keywords: CB1 cannabinoid receptor; ERK-intracellular pathway; Food-seeking; Mesocorticolimbic; Neuroplasticity; Palatability; Immunofluorescence;

Allosteric modulators are emerging as new therapeutics for the treatment of psychiatric illnesses, such as schizophrenia. Conventional antipsychotic drugs are typically dopamine D2 receptor antagonists that compete with endogenous dopamine at the orthosteric site, and block excessive dopamine neurotransmission in the brain. However, they are unable to treat all symptoms of schizophrenia and often cause adverse motor and metabolic side effects. The binding profile of allosteric modulators differs, as they interact with their receptor at a novel binding site and their activity is determined by physiological signaling. In collaboration, our laboratories have synthesized and evaluated over 185 compounds for their allosteric modulatory activity at the dopamine D2 receptor. Of these compounds, PAOPA is among the most potent allosteric modulators, and has been shown to be effective in treating the MK-801 induced preclinical animal model of schizophrenia. The objective of this study was to evaluate PAOPA's ability to prevent and reverse behavioral abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia. Amphetamine sensitized rats were given PAOPA during sensitization and following sensitization to determine whether PAOPA is able to prevent and reverse behavioral abnormalities. Furthermore, changes in post-mortem dopamine levels were measured by high performance liquid chromatography in various brain regions. The results presented demonstrate that PAOPA is able to prevent and reverse behavioral and biochemical abnormalities in an amphetamine-sensitized animal model of schizophrenia.
Keywords: PAOPA; Allosteric regulation; Dopamine D2 receptor; Schizophrenia; Amphetamine; Animal models;