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Psychiatry Service

Madrid, Spain
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Gudelsky G.,University of Cincinnati | Ahlbrand R.,Psychiatry Service | Ahlbrand R.,University of Cincinnati | Bronson S.L.,University of Cincinnati | And 4 more authors.
Neuroscience Letters | Year: 2011

The NMDA glutamate hypofunction model of schizophrenia is based in part upon acute effects of NMDA receptor blockade in humans and rodents. Several laboratories have reported glutamate system abnormalities following prenatal exposure to immune challenge, a known environmental risk factor for schizophrenia. Here we report indices of NMDA glutamate receptor hypofunction following prenatal immune activation, as well as the effects of treatment during periadolescence with the atypical antipsychotic medications risperidone and paliperidone. Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or saline on gestational day 14. Male offspring were treated orally via drinking water with vehicle, risperidone (0.01. mg/kg/day), or paliperidone (0.01. mg/kg/day) between postnatal days 35 and 56 (periadolescence) and extracellular glutamate levels in the prefrontal cortex were determined by microdialysis at PD 56. Consistent with decreased NMDA receptor function, MK-801-induced increases in extracellular glutamate concentration were markedly blunted following prenatal immune activation. Further suggesting NMDA receptor hypofunction, prefrontal cortex basal extracellular glutamate was significantly elevated (p<. 0.05) in offspring of poly I:C treated dams. Pretreatment with low dose paliperidone or risperidone (0.01. mg/kg/day postnatal days 35-56) normalized prefrontal cortical basal extracellular glutamate (p<. 0.05 vs. poly I:C vehicle-treatment). Pretreatment with paliperidone and risperidone also prevented the acute MK-801-induced increase in extracellular glutamate. These observations demonstrate decreased NMDA receptor function and elevated extracellular glutamate, two key features of the NMDA glutamate receptor hypofunction model of schizophrenia, during periadolescence following prenatal immune activation. Treatment with the atypical antipsychotic medications paliperidone and risperidone normalized basal extracellular glutamate. Demonstration of glutamatergic abnormalities consistent with the NMDA glutamate receptor hypofunction model of schizophrenia as an early developmental consequence of prenatal immune action provides a model to identify novel early interventions targeting glutamatergic systems which play an important role in both positive and negative symptoms of schizophrenia. © 2011.

Isom A.M.,University of Cincinnati | Gudelsky G.A.,University of Cincinnati | Benoit S.C.,University of Cincinnati | Richtand N.M.,Psychiatry Service | Richtand N.M.,University of Cincinnati
Medical Hypotheses | Year: 2013

We hypothesize the interaction between antipsychotic medications and regulation of extracellular glutamate which has gone largely unnoticed in the medical community has significant clinical importance. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate because they exert antagonist effects on dopamine D2 and serotonin 5HT1A receptors. In contrast, serotonin 5HT2A receptor antagonists inhibit glutamate release. Glutamate is potentially excitotoxic through effects on ionotropic receptor channels and may exert synergistic effects with other neurotoxic pathways. In contrast to typical antipsychotic drugs, pharmacological properties of atypical antipsychotic medications at dopamine D2, serotonin 5HT1A and 5HT2A receptors limit extracellular glutamate and may theoretically be neuroprotective in certain clinical settings. In this review we discuss three common clinical settings in which typical antipsychotic medications may potentiate neurotoxicity by elevating extracellular glutamate. The most common clinical setting, hypoglycemia during combined use of antipsychotic medications and insulin, presents a theoretical risk for 35 million diabetic patients worldwide using antipsychotic medications. Antipsychotic medication treatment during hypoxic episodes in the intensive care unit and following traumatic brain injury are two other common clinical settings in which this interaction poses theoretical risk. Further study is needed to test hypothesized risk mechanisms, and determine clinical and epidemiological consequences of these exposures. © 2012.

Roenker N.L.,University of Cincinnati | Gudelsky G.A.,University of Cincinnati | Ahlbrand R.,Psychiatry Service | Ahlbrand R.,University of Cincinnati | And 4 more authors.
Neuropharmacology | Year: 2012

Systemic administration of NMDA receptor antagonists elevates extracellular glutamate within prefrontal cortex. The cognitive and behavioral effects of NMDA receptor blockade have direct relevance to symptoms of schizophrenia, and recent studies demonstrate an important role for nitric oxide and GABA B receptors in mediating the effects of NMDA receptor blockade on these behaviors. We sought to extend those observations by directly measuring the effects of nitric oxide and GABAB receptor mechanisms on MK-801-induced glutamate release in the prefrontal cortex. Systemic MK-801 injection (0.3 mg/kg) to male Sprague-Dawley rats significantly increased extracellular glutamate levels in prefrontal cortex, as determined by microdialysis. This effect was blocked by pre-treatment with the nitric oxide synthase inhibitor l-NAME (60 mg/kg). Reverse dialysis of the nitric oxide donor SNAP (0.5-5 mM) directly into prefrontal cortex mimicked the effect of systemic MK-801, dose-dependently elevating cortical extracellular glutamate. The effect of MK-801 was also blocked by systemic treatment with the GABAB receptor agonist baclofen (5 mg/kg). In combination, these data suggest increased nitric oxide formation is necessary for NMDA antagonist-induced elevations of extracellular glutamate in the prefrontal cortex. Additionally, the data suggest GABAB receptor activation can modulate the NMDA antagonist-induced increase in cortical glutamate release. © 2012 Elsevier Ltd. All rights reserved.

Verdura Vizcaino E.J.,Psychiatry Service | Fernandez-Navarro P.,National Center for Epidemiology Carlos Institute of Health | Fernandez-Navarro P.,CIBER ISCIII | Petry N.,University of Connecticut Health Center | And 2 more authors.
Addiction | Year: 2014

Aims: To examine differences between early-onset versus later-onset pathological gamblers in socio-demographic characteristics, rates of Axis I and II disorders, preferred type of gambling and rates of treatment-seeking in a large nationally representative survey of adults in the United States. Design: Data were collected from face-to-face interviews using the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV version IV (AUDADIS-IV). Setting and Measurement: The study drew on data from the United States' National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Participants: All individuals with a DSM-IV diagnosis of pathological gambling (PG). To be consistent with prior studies, age of onset of PG was dichotomized as 25 years and younger (early-onset) versus 26 years and older (later-onset). Findings: Individuals with early-onset PG were more likely than individuals with later-onset PG to be male [odds ratio (OR)=2.86; 95% confidence interval (CI)=1.20, 6.82], never married (OR=3.51; 95% CI=1.39, 8.84), to have income below US$70000 (OR=0.09; 95% CI=0.01, 0.61), to belong to younger cohorts (OR=0.93; 95% CI=0.89, 0.97) and to have a cluster B personality disorder (OR=4.11; 95% CI=1.77, 9.55), but less likely to have a mood disorder (OR=0.42; 95% CI=0.19, 0.94). There were no differences between individuals with early- and later-onset PG regarding rates of treatment-seeking (OR=0.71; 95% CI=0.20, 2.43) or preferred type of gambling (OR=2.00; 95% CI=0.55, 7.3). All results remained significant after adjusting for age, sex and race, except the difference in the prevalence for mood disorders, which was no longer significant. Conclusions: Individuals with early-onset versus later-onset pathological gambling differ in several socio-demographic and clinical characteristics, but not in their preferred types of game. Individuals from more recent cohorts appear to be at significantly increased risk for developing early-onset pathological gambling. © 2013 Society for the Study of Addiction.

Carli V.,University of Molise | Carli V.,Karolinska Institutet | Mandelli L.,University of Bologna | Zaninotto L.,University of Bologna | And 6 more authors.
European Psychiatry | Year: 2011

Genetic aspects may influence the effect of early adverse events on psychological well being in adulthood. In particular, a common polymorphism within the serotonin transporter gene (5-HTTLPR short/long) has been associated to the risk for stress-induced psychopathology. In the present study we investigated the role of childhood traumas and 5-HTTLPR on measures of psychological resilience and depression in a sample of individuals at a high risk for psychological distress (763 male prisoners). The 5-HTTLPR genotype did not influence resilience and depressive severity. However, a significant interaction was observed between 5-HTTLPR and childhood traumas on both resilience and depressive severity. In particular, among subjects exposed to severe childhood trauma only, the long-allele was associated to lower resilience scores and increased current depressive severity as compared to short/short homozygous. Sex specific effects, difference in type and duration of stressors and the specific composition of the sample may explain discrepancy with many studies reporting the short-allele as a vulnerability factor for reactivity to stress. We here speculated that in males the long-allele may confer lower resilience and therefore higher vulnerability for depressive symptoms in subjects exposed to early stress and currently living in stressful environments. © 2011 Elsevier Masson SAS.

Lertxundi U.,Pharmacy Service | Hernandez R.,Internal Medicine Service | Medrano J.,Psychiatry Service | Domingo-Echaburu S.,Pharmacy Service | And 2 more authors.
Seizure | Year: 2013

Purpose: Almost all antipsychotics have been associated with a risk of epileptic seizure provocation. Among the first-generation antipsychotics (FGA) chlorpromazine appears to be associated with the greatest risk of seizures among the second-generation antipsychotics (SGA) clozapine is thought to be most likely to cause convulsions. This information is largely based on studies that are not sufficiently controlled. Besides, information about the seizure risk associated with newer antipsychotics is scarce. Method: The Pharmacovigilance Unit of the Basque Country (network of centers of the Spanish Pharmacovigilance System, SEFV) provided reporting data for adverse reactions (AR) from the whole SEFV to estimate the reporting odds ratio (ROR) for antipsychotics and seizures ("convulsions" as Single MedDra Query). Data was obtained from SEFV database from 1984 to the June 2011. Results: The total number of convulsions reported for SGA was 169 (total reported AR 3.204). The number of convulsions reported for FGA was 35 (total reported AR 2.051). 94 convulsions were reported in association with clozapine (total AR 1.052). The ROR for SGA versus FGA was 3.2 (CI 95%: 2.21-4.63). The ROR for SGA excluding clozapine versus FGA was 2.08 (CI 95%: 1.39-3.12). Conclusion: Our results show that SGA may pose a higher risk of seizures than FGA, mainly, but not only due to clozapine. This is line with recent studies suggesting that some SGA carried a higher average risk of electroencephalographic abnormalities than many FGA. Nonetheless, It is well known that spontaneous reports do not allow strong inferences about adverse drug effects, because differences in reporting fractions by time, drug or type of event are difficult or even impossible to distinguish from differences in the occurrence rates of adverse events. Still, we consider that the possibility of SGA carrying a higher risk of seizure induction than FGA warrants further research. © 2012 British Epilepsy Association.

Bongiovanni R.,Psychiatry Service | Leonard S.,University of Colorado at Denver | Jaskiw G.E.,Psychiatry Service | Jaskiw G.E.,Case Western Reserve University
Schizophrenia Research | Year: 2013

Background: Schizophrenia is associated with altered tyrosine transport across plasma membranes. This is typically demonstrated by measuring the uptake of radiolabeled tyrosine in cultured human fibroblasts. Our primary goal was to determine whether tyrosine uptake could be characterized using unlabeled tyrosine. A secondary goal was to assess the effect of antipsychotic drugs added during the incubation. Method: Epithelium-derived fibroblast cultures were generated from patients with schizophrenia (n=6) and age-matched controls (n=6). Cells between cycles 8-12 were exposed to an amino acid free medium for 60. min and then for 1. min to media containing tyrosine (0.008-1.0. mM). Amino acid levels were measured and Michaelis-Menten parameters determined. Uptake of tyrosine (0.5. mM) was also measured in control cells after antipsychotic drugs were introduced during the depletion or uptake phases. Results: Tyrosine uptake was sodium-independent. The maximal transport velocity (Vmax) was significantly lower in patients with schizophrenia than in controls (p<0.01). The transporter affinity (Km) did not differ between the groups. Tyrosine uptake was differentially affected (p<0.001) by inclusion of 10-4M haloperidol, chlorpromazine or clozapine during different periods of incubation. Conclusion: Dysregulated tyrosine kinetics in schizophrenia can be readily studied without the use of radiolabeled tracers. The data also indicate that tyrosine uptake may be subject to complex pharmacological effects. © 2013.

Carli V.,University of Molise | Carli V.,Karolinska Institutet | Roy A.,Psychiatry Service | Bevilacqua L.,U.S. National Institutes of Health | And 3 more authors.
Psychiatry Research | Year: 2011

Insomnia has been associated with suicidality. Prisoners have an increased risk of both insomnia and suicidal behaviour. Therefore, it was decided to examine for a relationship between insomnia and suicidal behaviour in a large group of 1420 prisoners. Prisoners had a semi-structured psychiatric interview, which included the Hamilton Depression Rating Scale (HDRS), and completed the Childhood Trauma Questionnaire, Eysenck Personality Questionnaire, Spielberg Anger Expression Inventory and Connor-Davidson Resilience Scale. It was found that 568 (61.2%) of the prisoners scored in the insomnia cluster of the HDRS and that 183 (12.8%) had attempted suicide. Regression analyses showed that insomnia was significantly and independently associated with a lifetime history of attempting suicide. Insomnia was also significantly related to actual suicidality. After controlling for confounders, axis 1 psychiatric disorder, childhood trauma, neuroticism, low resilience, and anger were significantly associated with insomnia in male prisoners. These data suggest the possibility of a relationship between insomnia and suicidality in prisoners. Assessing insomnia may be helpful when evaluating the risk of suicidality in prisoners. © 2009 Elsevier Ltd.

Sarchiapone M.,University of Molise | Mandelli L.,University of Molise | Mandelli L.,University of Bologna | Iosue M.,University of Molise | And 2 more authors.
International Journal of Environmental Research and Public Health | Year: 2011

Background: Restricting access to common means of suicide, such as firearms, toxic gas, pesticides and other, has been shown to be effective in reducing rates of death in suicide. In the present review we aimed to summarize the empirical and clinical literature on controlling the access to means of suicide. Methods: This review made use of both MEDLINE, ISI Web of Science and the Cochrane library databases, identifying all English articles with the keywords "suicide means", "suicide method", "suicide prediction" or "suicide prevention" and other relevant keywords. Results: A number of factors may influence an individual's decision regarding method in a suicide act, but there is substantial support that easy access influences the choice of method. In many countries, restrictions of access to common means of suicide has lead to lower overall suicide rates, particularly regarding suicide by firearms in USA, detoxification of domestic and motor vehicle gas in England and other countries, toxic pesticides in rural areas, barriers at jumping sites and hanging, by introducing "safe rooms" in prisons and hospitals. Moreover, decline in prescription of barbiturates and tricyclic antidepressants (TCAs), as well as limitation of drugs pack size for paracetamol and salicylate has reduced suicides by overdose, while increased prescription of SSRIs seems to have lowered suicidal rates. Conclusions: Restriction to means of suicide may be particularly effective in contexts where the method is popular, highly lethal, widely available, and/or not easily substituted by other similar methods. However, since there is some risk of means substitution, restriction of access should be implemented in conjunction with other suicide prevention strategies. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

Solomon R.,New York University | Kirwin P.,Psychiatry Service | Kirwin P.,Yale University | Van Ness P.H.,Yale University | And 3 more authors.
Journal of the American Geriatrics Society | Year: 2010

OBJECTIVES: To examine subjective ratings of quality of life (QoL) in older adults with advanced illness. DESIGN: Observational cohort study with interviews at least every 4 months for up to 2 years conducted between December 1999 and December 2002. SETTING: Participants' homes. PARTICIPANTS: One hundred eighty-five community-dwelling individuals aged 60 and older with advanced cancer, heart failure, or chronic obstructive pulmonary disease. MEASUREMENTS: Participants were asked how they would rate their overall QoL. RESULTS: Of participants who died, 46% reported good or best possible QoL at their final interview, 21% reported improvement in QoL from their penultimate to final interview, and 39% reported no change. Forty-nine percent of participants reported two or more changes in the direction of their QoL trajectories (e.g., QoL improved then declined). As measured over time in a multivariable longitudinal regression analysis, greater activity of daily living disability (adjusted odds ratio (AOR)=0.85, 95% confidence interval (CI)=0.75-0.95) and depressed mood (AOR=0.42, 95%CI=0.27-0.66) were associated with poorer QoL, whereas better self-rated health (AOR=4.79, 95% CI=2.99-7.69) and having grown closer to one's church (AOR=1.99, 95% CI=1.17-3.39) were associated with better QoL. CONCLUSION: Although declining QoL is not an inevitable consequence of advancing illness, individuals' ratings of QoL are highly variable over time, suggesting that temporary factors may influence subjective QoL. Functional status, depression, and connection to one's religious community are shared determinants of QoL. © 2010, Copyright the Authors. Journal compilation © 2010, The American Geriatrics Society.

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