Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model.

There is a link between depression, cardiovascular events and inflammation. We have explored this connection through endothelial dysfunction, using in vivo and in vitro approaches. We evaluated circulating biomarkers of endothelial dysfunction in patients with major depression at their diagnosis (MD-0) and during antidepressant treatment with the selective serotonin reuptake inhibitor escitalopram, for 8 and 24 weeks (MD-8 and MD-24). Results were always compared with matched healthy controls (CON). We measured in vivo circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in blood samples, and assessed plasma levels of soluble von Willebrand factor (VWF) and vascular cell adhesion molecule-1 (VCAM-1). CEC counts, soluble VWF and VCAM-1 were statistically elevated in MD-0 (P<0.01 versus CON) and gradually decreased during treatment. Conversely, EPC levels were lower in MD-0, tending to increase throughout treatment. In vitro studies were performed in human endothelial cells cultured in the presence of sera from each study group. Elevated expression of the inflammation marker intercellular adhesion molecule-1 and oxidative stress, with lower presence of endothelial nitric oxide synthase and higher reactive oxygen species production, were found in cells exposed to MD-0 sera (P<0.05 versus CON). These results were normalized in cells exposed to MD-24 sera. Thrombogenicity of extracellular matrices generated by these cells, measured as expression of VWF, tissue factor and platelet reactivity, showed non-significant differences. We provide a model of cultured endothelial cells reproducing endothelial dysfunction in naive patients with major depression, demonstrating endothelial damage and inflammation at diagnosis, and recovering with selective serotonin reuptake inhibitor treatment for 24 weeks.

Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins.

Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.

Polymorphic variation in the epigenetic gene DNMT3B modulates the environmental impact on cognitive ability: a twin study.

BACKGROUND: Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors. METHODS: Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance. RESULTS: MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs. CONCLUSIONS: Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity.

Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes.

OBJECTIVE: To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene. METHOD: Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. RESULTS: Childhood abuse showed a significant main effect on both positive (ß = 0.09; SE = 0.04; P = 0.047) and negative PEs (ß = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (ß = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. CONCLUSION: Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis.

Childhood adversity and psychosis: examining whether the association is due to genetic confounding using a monozygotic twin differences approach.

PURPOSE: To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. METHOD: Childhood adversity and psychotic experiences were assessed in an ongoing sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. RESULTS: In the whole sample, childhood adversity was significantly associated with positive (ß=45; SE=0.16; P=0.008) and negative psychotic experiences (ß=0.77; SE=0.18; P<0.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (ß=71; SE=0.29; P=0.016) and negative psychotic experiences (ß=98; SE=0.38; P=0.014) in a subsample of 85 MZ twin pairs. CONCLUSIONS: Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that this association is not due to genetic confounding.

Mild cognitive impairment: a risk indicator of later dementia, or a preclinical phase of the disease?

OBJECTIVES: The proposals for classifying the transitional range between normal, ageing-associated cognitive dysfunctions and those suggestive of evolution towards dementia do not clarify whether the profiles are risk indicators of later cognitive impairment or represent preclinical phases of dementia. METHODS: Retrospective study of the baseline neuropsychological performance of ten subjects with subjective complaints of memory loss which evolved to dementia within 2 years and who meet clinical and neurological diagnosis for Probable Alzheimer's Disease (Progression group). They were compared with 34 normal subjects (Normative group), 33 patients with subjective complaints of memory who in 2 year did not evolve towards dementia and presented a stable profile (Stable group), and 47 Alzheimer's patients (Alzheimer group). A broad neuropsychological battery was administered to assess a range of cognitive functions. RESULTS: The Progression group presented a globally poor baseline neuropsychological performance, except in Working Memory, with clear deficits in Episodic Memory and Visual Memory. In the logistic regression analysis, Delayed Verbal Memory was significant as prognostic value for 80 . 5% of cases. CONCLUSION: Deficit on Episodic and Visual Memory at least 1.5 SD below T = 50 are preclinical manifestations of dementia in subjects with complain of memory loss. The use of broad neuropsychological batteries and the quantitative assessment of deficits is essential to identify and predict the risk of dementia.

A 6-month prospective, observational, naturalistic, uncontrolled study to evaluate the effectiveness and tolerability of oral ziprasidone in patients with schizophrenia.

This multicenter, uncontrolled, naturalistic study evaluated the effectiveness and tolerability of 6 months of treatment with ziprasidone in 1266 patients with a diagnosis of schizophrenia. The percentage of responders (at least 30% reduction in PANSS total score) in the primary analysis sample (n=1022) was 47.3% (95% CI 44.2-50.4) at the end of the study. Patients showed a significant and clinically relevant reduction in the PANSS total, positive, negative and general psychopathology subscales scores (effect size of 1.60, 1.83, 0.62 and 1.40 respectively). Overall, 453 (35.8%) patients withdrew from the study; 9.3% withdrew owing to adverse events. Ziprasidone doses greater than 120 mg/day were associated with a lower risk of discontinuation for any cause (OR 0.46, 95% CI 0.33-0.65) Ziprasidone was well tolerated. Most common side effects were: insomnia, somnolence and nervousness. The effectiveness and tolerability of ziprasidone in clinical practice are consistent to those previously shown in the more restricted and homogeneous populations of clinical trials.

Impaired response inhibition in obsessive compulsive disorder.

OBJECTIVE: The present study investigates different three inhibitory control functions in patients with obsessive-compulsive disorder (OCD). Selective motor response inhibition was tested in a GO/NO-GO paradigm, the inhibition of a triggered motor response in a STOP paradigm and the ability to inhibit cognitive interference in a motor STROOP paradigm. METHODS: 27 patients who met DSM-IV criteria for OCD and 25 age, handedness and IQ-matched healthy control subjects were tested in the GO/NO-GO, STOP and motor STROOP tasks. RESULTS: OCD patients performed significantly worse than controls in the selective inhibition of their motor responses (GO/NO-GO) and in the inhibition of cognitive interference (STROOP), and also showed worse performance in suppressing previously triggered motor responses (STOP). CONCLUSION: Patients with OCD are impaired in motor and cognitive inhibitory mechanisms. The findings are consistent with psychobiological and neuropsychological models of OCD suggesting impairment of frontostriatal circuitries that mediate functions of inhibitory control.

Subtyping obsessive-compulsive disorder: clinical and immunological findings in child and adult onset.

It has been suggested that certain kinds of childhood OCD with specific clinical, biological and immunological characteristics may form a subgroup of OCD. We study the presence of these characteristics in child onset OCD and propose that the disorder be considered as a subtype of adult OCD. Forty adult patients with OCD were divided in two groups according to time of disease onset: 18 early onset and 21 late. Both sets were compared with a control group of 14 psychiatric patients. Child onset OCD was associated with higher mean ASLO titers, higher frequencies of history of tic disorders and tonsillitis in childhood and compulsive symptoms. No differences were found in D8/17 antibody titers or in other autoimmune parameters. The findings suggest that child onset OCD can be considered as a subgroup of adult OCD, although more specific biological markers are needed to identify it.

Patient-rated emotional and physical functioning among hematologic cancer patients during hospitalization for stem-cell transplantation.

In this 3-year prospective inpatient study, 220 patients received stem-cell transplantation (SCT) for hematologic cancer at a single institution. The objective of the study is to provide data on patient-rated emotional (depression and anxiety) and physical (overall physical status, energy level, and systemic symptomatology) functioning during hospitalization for SCT and to compare whether these differ between autologous and allogeneic SCT. Patients were assessed at hospital admission (T1), day of SCT (T2), and 7 days (T3) and 14 days (T4) after SCT, yielding a total of 852 evaluations. For the overall sample, anxiety was highest at T1 and decreased afterwards; a marked worsening in physical health status variables corresponded with a sharp increase in depression from T1 to T3, and was followed by an improvement in physical health and a reduction of depression. Compared to allogeneic SCT, a better physical outcome for autologous SCT was demonstrated by the significant group effect for systemic symptomatology and by the significant group x time interaction for overall physical status and energy level; there were no significant differences in depression or anxiety between SCT groups. These findings have implications for treatment decision making, coping with the transplantation process, and improving prevention and treatment strategies.

No brain perfusion impairment at long-term follow-up in elderly patients treated with electroconvulsive therapy for major depression.

No functional neuroimaging study has previously assessed the long-term effects of electroconvulsive therapy (ECT) on brain perfusion. In this study, long-term follow-up brain perfusion in elderly patients treated with ECT for severe unipolar major depression was assessed. In 14 elderly major depressed patients who were ECT remitters, 22 elderly major depressed patients who were pharmacological treatment remitters and 25 age- and sex-matched healthy controls, a medication-free brain 9mTc-HMPAO-SPECT was performed after a minimum period of 12 months of euthymia and, in the case of the ECT remitters, at least 12 months after the last ECT session. Brain perfusion ratios in major depressed patients administered ECT were similar to those in major depressed patients receiving pharmacological treatment and in control subjects. This result suggests that elderly patients given ECT for severe unipolar major depression do not suffer brain perfusion abnormalities at long-term follow-up. Our study adds new evidence in favor of the safety of the ECT, particularly in elderly subjects.

Gilles de la Tourette y la enfermedad de los tics convulsivos / Gilles de la Tourette and the convulsive tic illness

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[The 5-HT1A receptors: from molecular biology to neuropsychiatric symptoms]. / Receptores 5-HT1A: de la biología molecular a la clínica neuropsiquiátrica.

Among the multiple serotonin receptors identified to date, the 5-hydroxytryptamine (5-HT)1A subtype is among the best known because selective ligands have been available for more than 15 years. Radioactive derivatives of these ligands make it possible to demonstrate the presence of 5-HT1A binding sites mainly in the limbic areas and in the raphe nuclei in the brain, where they correspond to post-synaptic receptors and pre-synaptic autoreceptors respectively. On stimulation of 5-HT1A autoreceptors, they regulate serotonin release in the distal regions of the neuron by inhibitory firing activity. In this way, they help to maintain the serotonin in the terminal regions at physiological levels, which favors correct neuronal functioning. This review article summarizes key data on localization, study technique, molecular biology, signal transduction, differential functional properties of pre-synaptic versus post-synaptic 5-HT1A receptors, and behavioral effects and clinical correlates of their activation, especially cognitive and emotional responses. Mention is made about the role of these receptors in the neurogenesis process of certain brain areas and of the possible clinical and therapeutic implications of these processes.

Receptores 5-HT1A: de la biología molecular a la clínica neuropsiquiátrica / The 5-HT1A receptors: from molecular biology to neuropsychiatric symptoms

De entre los múltiples receptores de serotonina identificados hasta el momento, el subtipo 5-HT1A es uno de los más conocidos, en parte porque desde hace más de 15 años se ha dispuesto de ligandos selectivos para su estudio. Utilizando derivados radioactivos de estos ligandos se ha podido demostrar la presencia de receptores 5-HT1A principalmente en áreas límbicas, donde actúan como receptores postsinápticos y en los núcleos del rafe cerebrales, donde actúan como autorreceptores presinápticos. Estos últimos, al ser estimulados, regulan la liberación de serotonina en las regiones distales de la neurona mediante la atenuación de su disparo. De esta forma ayudan a mantener la serotonina en las regiones terminales en niveles fisiológicos, lo cual favorece el correcto funcionamiento neuronal. En este artículo se revisa el conocimiento actual sobre los receptores 5-HT1A en lo referente a su localización, métodos para su investigación, estructura molecular, mecanismos de transducción receptorial, diferencias funcionales entre los receptores 5-HT1A pre y postsinápticos e implicaciones funcionales, especialmente en lo que concierne a respuestas cognitivas y emocionales. Se hace mención al papel de estos receptores en los procesos de neurogénesis de ciertas áreas cerebrales y a las posibles implicaciones clínicas y terapéuticas de dichos procesos. (AU)

Residual cognitive impairment in late-life depression after a 12-month period follow-up.

OBJECTIVES: This study investigated cognitive impairment in late-life depression in a follow-up design. The main objective was to assess the most important cognitive domains implicated in late-life depression, in patients who underwent pharmacological treatment, in the acute phase and twelve months after. METHODS: Neuropsychological and clinical data were used from the baseline of patients and controls, to determine the cognitive impairment in the acute phase. Patients repeated the neuropsychological assessment at twelve months. RESULTS: There were significant differences between patients and controls at baseline. But in the patients there was no change over twelve months. There were no differences between remitted and non-remitted patients on neuropsychological scores. CONCLUSIONS: The cognitive impairment seen in the elderly depressed patients seems to be a trait characteristic of this mental disease, even when the depressive episode has remitted.

Residual symptoms in elderly major depression remitters.

OBJECTIVE: To assess residual symptoms in severe geriatric major depression in remission, and to determine baseline clinical and sociodemographic predictors of residual symptoms in remitters. METHOD: A total of 108 elderly patients with unipolar major depression were evaluated and treated naturalistically for 9 months so as to record the predictors of residual symptoms in remitters. In order to reduce the likelihood of confusing residual symptoms with normal effects of age, 30 control subjects were also monitored. RESULTS: Seventy-nine patients (73.1%) were considered remitters and 82.3% of remitters showed residual symptoms. Medical burden, chronic stress and subjective social support were the only variables which predicted the severity of residual symptoms in remitters. CONCLUSION: Residual symptoms in elderly patients with major depression in remission should not only be attributed exclusively to intrinsic factors of the illness or the age of the individual patient, but also to external factors.

[Treatment of bipolar II disorder with lamotrigine]. / Tratamiento del trastorno bipolar II con lamotrigina.

INTRODUCTION: This study analyzes the effectiveness and safety of lamotrigine in the treatment of bipolar II disorder. Patients and methods. Seventeen patients with DSM-IV bipolar II disorder with a history of poor response to lithium or other mood-stabilizers gave their consent to be treated with lamotrigine. Th ey we re followed-up for 6 months and assessed with the Young Mania Scale (YMRS), Hamilton Depression Rating Scale (HDRS-17) and the modified version of the Global Clinic Impresion Scale for Bipolar Disorder ( CG I-BP-M). RESULTS: Twelve patients completed the study. Three patients dropped out due to side effects (two because of mild rash, which vanished after treatment was discontinued and one because of vomiting) and two due to lack of efficacy. The mean dose of lamotrigine for patients completing the study was 202.1 64.4 mg/day. There was a significant improvement in HDRS-17 scores (p= 0.004) and the depressive (p=0.002) and overall (p= 0.002) subscales of the CGI-BP-M. CONCLUSIONS: This study confirms previous findings concerning the antidepressant profile of lamotrigine and its potential effectiveness in bipolar II disorder.

Tratamiento del trastorno bipolar II con lamotrigina / Treatment of bipolar II disorder with lamotrigine

Introducción. Se analiza la efectividad y seguridad de la lamotrigina en el tratamiento de pacientes bipolares de tipo II.Pacientes y métodos. Un total de 17 pacientes con trastorno bipolar II según criterios DSM-IV con antecedentes de respuesta insuficiente al tratamiento con litio u otros eutimizantes dieron su consentimiento para recibir lamotrigina para el tratamiento de su enfermedad.La respuesta se evaluó con la Escala de Manía de Young (YMRS), Escala de Hamilton para la Depresión (HDRS-17) y la versión modificada de la Escala de Impresión Clínica Global para el Trastorno Bipolar (CGI-BP-M) a lo largo de 6 meses.Resultados. Completaron los 6 meses de seguimiento 12 pacientes. Hubo tres abandonos por efectos secundarios (dos por exantema de escasa gravedad que desapareció al interrumpir el tratamiento y uno por vómitos) y dos por falta de eficacia. La dosis media de lamotrigina de los pacientes que completaron el estudio fue de 202,1ñ 64,4 mg/día.Se produjo una mejoría significativa en las escalas HDRS-17 (p =0,004) y las subescalas de depresión (p= 0,002) y general (p=0,002) de la CGI-BP-M.Conclusiones. Este estudio confirma los hallazgos de estudios previos respecto al perfil predominantemente antidepresivo de la lamotrigina y su potencial terapéutico en el trastorno bipolar II (AU)