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Background Clinical staging model for depression helps to better define the clinical situation of patients. The objectives of this study are: to correlate the Hetrick’s staging model of depression with the severity of depression, associated disability, and resistance to treatment in the established disease stages and to test the modification introduced by our group consisting in the introduction of a substage for recurrence from a previous episode that was stabilized with a complete remission. Methods A Cross-sectional study with 133 adult subjects having a current and primary diagnosis of Depressive disorder was developed. Patients were classified according to the model and assessed with: 17-item Hamilton Depression Scale (HAM-D), Clinical Global Impression (CGI); Global Assessment of Function (GAF); Maudsley Staging Method for treatment resistance (MSM) and Sheeham Disability Schedule (SDS). Results The variable that best contributes to the differentiation between clinical stages, in established Depression, is resistance to treatment evaluated by the MSM. Correlations between MSM and the clinical stages were statistically significant between most pairs of stages. Finally, we showed preliminary data in order to prove that a differential sub-stage for recurrent depression with and without inter-episodic remission in the current heuristic models could be a possible stage for better define depression staging model. Conclusions Resistance to treatment should be included in the definition of clinical stages in established depression. Despite the difficulty of establishing a valid model for the staging of depression, it can certainly add great value to diagnosis, therapeutic interventions and clinical research.

The objective of the study was to examine the cognitive profile of Spanish patients with a first episode of schizophrenia (FESz) and to compare that to the profile of patients with a chronic schizophrenia (CSz) and non-psychiatric (NP) control subjects. The study included 106 FESz, 293 CSz, and 210 NP, assessed with the Spanish version of the MATRICS Consensus Cognitive Battery (MCCB). The MCCB cognitive profile in a Spanish sample of FESz was similar to the cognitive profile of CSz with some discrepancies in select domains. The scores of both patient samples were about 1-2 SD below the scores of non-psychiatric control subjects.

There is increasing focus on use of resting-state functional connectivity (RSFC) analyses to subtype depression and to predict treatment response. To date, identification of RSFC patterns associated with response to electroconvulsive therapy (ECT) remain limited, and focused on interactions between dorsal prefrontal and regions of the limbic or default-mode networks. Deficits in visual processing are reported in depression, however, RSFC with or within the visual network have not been explored in recent models of depression. Here, we support prior studies showing in a sample of 18 patients with depression that connectivity between dorsal prefrontal and regions of the limbic and default-mode networks serves as a significant predictor. In addition, however, we demonstrate that including visual connectivity measures greatly increases predictive power of the RSFC algorithm (>80% accuracy of remission). These exploratory results encourage further investigation into visual dysfunction in depression, and use of RSFC algorithms incorporating the visual network in prediction of response to both ECT and transcranial magnetic stimulation (TMS), offering a new framework for the development of RSFC-guided TMS interventions in depression.

The ankyrin repeat and kinase domain containing 1 (ANKK1) TaqIA polymorphism has been extensively studied as a marker of the gene for dopamine receptor D2 (DRD2) in addictions and other dopamine-associated traits. In vitro mRNA and protein studies have shown a potential connection between ANKK1 and the dopaminergic system functioning. Here, we have investigated whether Ankk1 expression in the brain is regulated by treatment with dopaminergic agonists. We used quantitative RT-PCR of total brain and Western blots of specific brain areas to study Ankk1 in murine brain after dopaminergic treatments. We found that Ankk1 mRNA was upregulated after activation of D1R-like dopamine receptors with SKF38393 (2.660 ± 1.035-fold; t: 4.066, df: 11, P = 0.002) and apomorphine (2.043 ± 0.595-fold; t: 3.782, df: 8, P = 0.005). The D2R-like agonist quinelorane has no effect upon Ankk1 mRNA (1.004 ± 0.580-fold; t: 0.015, df: 10, P = 0.9885). In contrast, mice treatment with the D2R-like agonists 7-OH-DPAT and aripiprazole caused a significant Ankk1 mRNA downregulation (0.606 ± 0.057-fold; t: 2.786, df: 10, P = 0.02 and 0.588 ± 0.130-fold; t: 2.394, df: 11, P = 0.036, respectively). With respect the Ankk1 proteins profile, no effects were found after SKF38393 (t: 0.54, df: 2, P = 0.643) and Quinelorane (t: 0.286, df: 8, P = 0.782) treatments. In contrast, the D2R-like agonist 7-OH-DPAT (±) caused a significant increment of Ankk1 in the striatum (t: 2.718, df: 7; P = 0.03) when compared to the prefrontal cortex. The activation of D1R-like and D2-R-like leads to opposite transcriptional regulation of Ankk1 by specific pathways.

It has been suggested that data on positive and negative psychotic symptoms in patients with schizophrenia as assessed using different scales may be combined. For the first time, we assessed correlations between the positive syndrome subscale of the Positive and Negative Syndrome Scale (PANSS-P) and the Scale for the Assessment of Positive Symptoms (SAPS), and between the negative syndrome subscale of the Positive and Negative Syndrome Scale (PANSS-N) and the Scale for the Assessment of Negative Symptoms (SANS) in patients with bipolar disorder. We also aimed to confirm these correlations in patients with schizophrenia. This cross-sectional study was conducted with a group of 94 patients (40 diagnosed with bipolar disorder, 54 with schizophrenia). Assessments were carried out using the PANSS, SAPS and SANS. Large significant correlations were found between the PANSS-P and SAPS, and between the PANSS-N and SANS, in both the bipolar disorder group and the schizophrenia group. These results confirm previous findings regarding correlations between these scales in schizophrenia, and support the hypothesis that similar correlations exist in bipolar disorder. Therefore, our data support the potential usefulness in collaborative research of combining results from different scales for the assessment of psychotic symptoms in patients with bipolar disorder.

Inflammatory and immune processes have been implicated in the etiopathology of schizophrenia. We demonstrate the existence of immune function alteration, assessed by serum cytokine's levels, not only in schizophrenia patients but also in their unaffected first-degree relatives. This finding may provide a new data for considering cytokines as schizophrenic disease biomarkers. © 2012 Elsevier Ireland Ltd.

The study aims to identify psychopathologic variables in cannabis-induced psychosis and recent-onset primary psychoses using the Symptom Checklist-90-R and the Psychiatric Research Interview for Substance and Mental Disorders. A sample of 181 subjects with psychotic symptoms and cannabis use referred to the psychiatry inpatient units of 3 university general hospitals were assessed. The final sample included 50 subjects with a diagnosis of cannabis-induced psychotic disorder (CIPD) and 104 subjects with primary psychotic disorders. Using receiver operating characteristic curves, the most efficient psychopathologic variables for classifying CIPD were interpersonal sensitivity, “depression,” phobic anxiety, and Scale to Assess Unawareness of Mental Disorders subscales. The area under the receiver operating characteristic curve of the model including depression and “misattribution” scores was 96.78% (95% confidence interval, 94.43-99.13). Depressive symptoms could be used to distinguish CIPD from other primary psychotic disorders. Clinical variables related to “neurotic” symptoms could be involved in the susceptibility to cannabis-induced psychosis.

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates.

Objective To evaluate the prevalence, clinical features, and comorbidities of restless legs syndrome (RLS) among psychogeriatric patients in an out-patient clinical setting. Methods Cross-sectional study of a sample of 100 non-demented psychogeriatric outpatients that were assessed for the presence of RLS using the Revised International Restless Legs Syndrome Study Group criteria and other support criteria. Medical and psychiatric illnesses, drug treatments, and other risk factors for RLS were documented. Results Prevalence of definite RLS in our sample was 11.11% with an additional prevalence of 10.10% of possible RLS. None of these patients had received a diagnosis of RLS previously. RLS was associated with major depressive disorder and with hypertension, but not with other previously described risk factors as female gender, some medical conditions, or psychoactive drug treatments. Conclusions RLS is a frequent condition in psychogeriatric patients, especially among those with depression, and is commonly underdiagnosed and undertreated. Clinicians should routinely ask for RLS symptoms when assessing their patients in their regular clinical practice. Copyright © 2011 John Wiley & Sons, Ltd.

A number of findings suggest that inflammation plays a role in the pathophysiology of schizophrenia. Taking into account a physiological balance between pro- and anti-inflammatory mediators, we measured the plasma levels of cyclooxygenase-derived mediators and other key pro- and anti-inflammatory transcription factors in peripheral blood mononuclear cells (PBMC). Forty healthy subjects and 46 treated chronic schizophrenic patients with an acutely exacerbated condition who met DSM-IV criteria were included. COX by-products prostaglandin E2 (PGE2) and 15d-prostaglandin J2 (15d-PGJ2) plasma levels were measured by EIA. Peroxisome proliferator-activated receptor gamma (PPARγ) as well as nuclear factor kappaB (NFκB) activity in nuclear extracts from PBMC and expression of its inhibitory subunit IκBα in cytosolic extracts were determined using ELISA-based kits. Schizophrenic patients showed higher plasma levels of pro-inflammatory PGE2 than age-matched controls (p=0.043). On the contrary, levels of anti-inflammatory 15-d-PGJ2 were lower (p=0.004), correlating with a lower expression of its nuclear target, PPARγ in nuclear extracts from PBMC (p=0.001). Although no changes in NFκB activity were observed between patients and healthy controls, the expression of its inhibitory protein IκBα was lower in the patients compared to the controls (p=0.027). These findings suggest that schizophrenia is associated with a systemic imbalance in the plasma levels of pro-inflammatory/anti-inflammatory prostaglandins in favor of the former. Furthermore, the expression and activity of anti-inflammatory PPARγ are diminished in PBMC, which indicates a state of inflammation and blunted anti-inflammatory counterbalancing mechanisms at systemic level in these patients.

Cognitive function in schizophrenia has been associated with different sociodemographic and clinical variables. Substance use disorder (SUD) history has also been associated with cognition in schizophrenia; however, contradictory results have been found regarding its influence on cognitive function. Our aim was to study the relationship between executive function and a) age, b) duration of illness, c) number of psychotic episodes, d) positive symptoms, and e) negative symptoms, in a sample of schizophrenic patients, and secondly to study whether these relationships persisted after stratification of the sample according to the presence or absence of SUD history. A final sample of 203 schizophrenic patients were evaluated for psychotic symptoms using the PANSS, and assessed using a neuropsychological battery to calculate a composite executive function score. Linear regression analyses were performed, with this executive score as the dependent variable, and age, duration of illness, number of psychotic episodes, positive PANSS score and negative PANSS score as independent variables. For the total sample, the regression model showed three variables to be significant predictors of the executive score: age (p=0.004), number of episodes (p=0.027), and PANSS negative score (p=0.003). However, once the sample was stratified, the regression model showed age (p=0.011) and number of episodes (p=0.011) to be predictor variables for the executive score in the group of schizophrenic patients with SUD history, while age (p=0.028) and PANSS negative score (p=0.006) were predictors in the group of schizophrenic patients without such history. These findings highlight the importance of considering SUD history in studies of cognitive function in schizophrenia.

Polymorphisms of DRD2 and ANKK1 have been associated with psychiatric syndromes where there is believed to be an underlying learning process deficit such as addiction, post-traumatic stress disorder and psychopathy. We investigated the effects of the DRD2 C957T and ANKK1 TaqIA single nucleotide polymorphism (SNP), which have been associated with psychopathic traits in alcoholic patients, on fear conditioning and aversive priming in healthy volunteers. We found that the DRD2 C957T SNP, but not the ANKK1 TaqIA SNP, was associated with both differential conditioning of the skin conductance response and the aversive priming effect. There were no differences between the genotype groups with respect to the extinction of the skin-conductance conditioned response. These results suggest that the C957T SNP could be related to learning differences associated with the risk of developing psychiatric disorders in individuals that are carriers of the C homozygous genotype. Our genetic data raise the possibility that the dopaminergic system functional variations determined by this SNP could affect fear learning.

Binge drinking is a common pattern of alcohol use in the US. However, no studies have evaluated the effectiveness of brief interventions targeting only binge drinkers.Randomized controlled clinical trial with a 12-month follow-up period conducted from March 1, 2003 to March 1, 2006 in Spain. Of a screened population of 15,325 patients seeking routine medical care from their primary care providers, patients who met inclusion criteria were randomized into an experimental group (n=371) or a control group (n=381). The primary outcome measures were the frequency of binge drinking episodes and weekly alcohol intake.There were no significant differences at baseline between groups in alcohol use and demographic variables. At the end of the 12-month follow-up period, there were significant reductions in binge-drinking status (52.2% vs 67.2%, P.001), number of episodes of binge drinking (1.14 vs 1.56, P.001), number of drinks weekly (19.2 vs 22.4, P.001), and frequency of excessive alcohol intake in 7 days (47.9% vs 66.6%, P.001).This study provided evidence that screening and brief counseling delivered by a primary care physician as part of regular health care significantly reduced binge drinking episodes in binge drinkers.

Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin-1 (IL-1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL-1 cluster on brain morphology in bipolar disorder. Genetic variability at IL-1B and IL-1RN genes was analyzed in 20 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole-brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A -511C/T polymorphism (rs16944) of IL-1B gene was associated with whole-brain GM deficits (P = 0.031) and left DLPFCGM deficits (P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL-1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.

Cognitive symptoms, considered in conjunction both with their regional brain and biomarkers as well as affective, attributional and neurodevelopmental components, demonstrate ever-increasing complexity to facilitate conceptualization yet, unavoidably, bedevil diagnosis in neuropsychiatry even before considerations of the enigmatic processes in memory, such as executive function and working memory, are drawn into the myriads of equations that await remedial interpretations. Prefrontal and limbic regions of the brain are involved in a diversity of expressions of cognition, normal or dysfunctional, at synaptic, intracellular and molecular levels that mobilize a concatenation of signaling entities. Serotoninergic neurotransission at prefrontal regions directs cognitive-affective entities that mediate decision-making and goal-directed behaviour. Clinical, non-clinical and basic studies challenge attempts to consolidate the multitude of evidence in order to obtain therapeutic notions to alleviate the disordered status of the diagnosed and yet-to-be diagnosed individuals. Locus of control, a concept of some utility in health-seeking procedures, is examined in three self-report studies from the perspective of a cognitive-emotional situation through observations of ordinary, 'healthy' young and middle-aged individuals, to assess the predictors of internal and external locus of control. A notion based on high level executive functioning in the dorsolateral prefrontal cortex (DLPFC) in individuals characterised by internal locus of control is contrasted with a hypofunctional executive DLPFC, characterising individuals that express an external locus of control, is discussed.

Aims.In a background of interest in staging models in psychiatry, we tested the validity of a simple staging model of cognitive impairment to predict incident dementia.Method.A large community sample of adults aged ≥55 years (N = 4803) was assessed in the baseline of a longitudinal, four-wave epidemiological enquiry. A two-phase assessment was implemented in each wave, and the instruments used included the Mini-Mental Status Examination (MMSE); the History and Aetiology Schedule and the Geriatric Mental State-AGECAT. For the standardised degree of cognitive impairment Perneczky et al's MMSE criteria were applied. A panel of psychiatrists diagnosed cases of dementia according to DSM-IV criteria, and cases and sub-cases of dementia were excluded for the follow-up waves. Competing risk regression models, adjusted by potential confounders, were used to test the hypothesised association between MMSE levels and dementia risk.Results.Out of the 4057 participants followed up, 607 (14.9%) were classified as ‘normal’ (no cognitive impairment), 2672 (65.8%) as ‘questionable’ cognitive impairment, 732 (18.0%) had ‘mild’ cognitive impairment, 38 (0.9%) had ‘moderate’ cognitive impairment and eight (0.2%) had ‘severe’ impairment.Cognitive impairment was associated with risk of dementia, the risk increasing in parallel with the level of impairment (hazard ratio: 2.72, 4.78 and 8.38 in the ‘questionable’, ‘mild’ and ‘moderate’ level of cognitive impairment, respectively).Conclusions.The documented gradient of increased risk of dementia associated with the severity level of cognitive impairment supports the validity of the simple staging model based on the MMSE assessment.

Background: Different neuropsychological studies have shown schizophrenic patients to have executive function deficits, as illustrated by their performance in neuropsychological tasks such as the Wisconsin Card Sorting Test (WCST); certain studies have described a relationship between these deficits and negative symptoms. Schizophrenic patients also exhibit a high lifetime prevalence (40–50%) of comorbid substance use disorders (SUDs). However, little attention has been paid to this comorbidity (dual diagnosis) in studies associating executive functions and negative symptoms. Sampling and Methods: Our objective is to investigate the relationship between performance in the WCST and psychopathology as measured by the Positive and Negative Syndrome Scale (PANSS) in a sample of 65 male schizophrenic patients with a history of SUDs (Sch SUD+) and in a sample of 48 male schizophrenic patients without such history (Sch SUD–). Results: In the Sch SUD– group, patients who completed 4 or more categories in the WCST (‘good performers’) obtained a mean score of 21.2 ± 8.8 on the negative subscale of the PANSS, compared with a mean score of 27.8 ± 8.6 in those who completed 3 or less (‘poor performers’); these differences were statistically significant (p = 0.015). In the Sch SUD+ group, however, no association was found between WCST performance and the PANSS negative subscale score. Conclusions: The presence of a history of comorbid SUDs should be taken into consideration in studies investigating executive functions and negative symptoms in schizophrenia.

ObjectivesA study of N-acetyl-aspartate (NAA) can provide data of interest about cortical alterations in psychotic illnesses. Although a decreased NAA level in the cerebral cortex is a replicated finding in chronic schizophrenia, the data are less consistent for bipolar disease. On the other hand, it is likely that NAA values in schizophrenia may differ in men and women.MethodsWe used proton magnetic resonance spectroscopy (1H MRS) to examine NAA levels in the prefrontal cortex in two groups of male patients, one with schizophrenia (n = 11) and the other with bipolar disorder (n = 13) of similar duration, and compared them to a sample of healthy control males (n = 10). Additionally, we compared the degree of structural deviations from normal volumes of gray matter (GM) and cerebrospinal fluid (CSF) in the dorsolateral prefrontal cortex.ResultsCompared to controls, schizophrenia and bipolar patients presented decreased NAA to creatine ratios, while only the schizophrenia group showed an increase in CSF in the dorsolateral prefrontal region. There were no differences in choline to creatine ratios among the groups.ConclusionsThese data suggest that the decrease in NAA in the prefrontal region may be similar in schizophrenia and bipolar disorder, at least in the chronic state. However, cortical CSF may be markedly increased in schizophrenia patients.

This study evaluated the effects of a putative activator of brain reward circuitry on outcomes in a 1-y prospective comprehensive outpatient clinical program. As part of the Gene Narcotic Attenuation Program, Haveos (Synaptamine)(TM) was administered for the treatment of substance use disorder. Seventy-six patients (45 males and 31 females; mean age, 33 y [standard deviation, 7.0]) who had been given a diagnosis of serious substance use disorder were recruited. After exclusion of 15 patients who dropped out before the end of the study, self-reported craving decreased from program entrance to 12 wk (visual analog scale whereby 0 represents no craving and 5, the strongest craving) for 61 compliant patients (mean decrease, 2.85, 95% confidence interval [CI], 2.65, 3.05); this improvement was significant (P

Objective In a background of revision of criteria for states of increased risk for progression to dementia, we compare the conversion rate to dementia and Alzheimer's disease (AD) of mild cognitive impairment (MCI) as diagnosed using DSM-5 (DSM-5-MCI) and Petersen's (P-MCI) criteria. Method A population representative cohort of 4057 dementia-free individuals 55+ years of age was followed up at 2.5 and 4.5 years in Zaragoza, Spain (ZARADEMP). Using the Geriatric Mental State- AGECAT for assessment, research psychiatrists diagnosed DSM-5-MCI and P-MCI following operationalized criteria. ‘Conversion rate’ (CR), ‘annual conversion rate’ (ACR), and incidence rate (IR) were calculated along with incidence rate ratio (IRR) to compare the performance of the intermediate cognitive definitions. Results At 4.5-year follow-up, in individuals aged 65+ years, ACRs for non-cases, P-MCI, and DSM-5-MCI were 0.8, 1.9 and 3.4, respectively, for global dementia. The IRRs were 2.9 and 5.3 for P-MCI and DSM5-MCI, respectively, being the non-cases the reference category. The corresponding values were slightly lower for AD. Conclusion Conversion rate to dementia and AD was higher using DSM-5-MCI criteria than using Petersen's criteria. However, prediction of the construct still has some way to go, as most MCI individuals did not convert at 4.5-year follow-up.

Gamma oscillations are key in coordinating brain activity and seem to be altered in schizophrenia. In previous work, we studied the spatial distribution of a noise power measure (scalp-recorded electroencephalographic activity unlocked to stimuli) and found higher magnitudes in the gamma band related to symptoms and cognition in schizophrenia. In the current study, we sought to replicate those findings and to study its specificity for schizophrenia in a completely independent sample. A principal component analysis (PCA) was used to determine the factorial structure of gamma noise power acquired with an electroencephalographic recording during an odd-ball P300 paradigm in the 250- to 550-ms window in 70 patients with schizophrenia (16 patients with first episode), 45 bipolar patients and 65 healthy controls. Clinical and cognitive correlates of the resulting factors were also assessed. Three factors arose from the PCA. The first displayed a midline-parietal distribution (roughly corresponding to the default mode network), the second was centro-temporal and the third anterior–frontal. Schizophrenia but not bipolar patients showed higher gamma noise power loadings in the first factor in comparison with controls. Scores for this factor were significantly and directly associated with positive and total symptoms in patients and inversely associated with global cognition in all participants. The results of this study replicate those of our previous publication and suggest an elevated midline-parietal gamma noise power specific to schizophrenia. The gamma noise power measure seems to be a useful tool for studying background oscillatory activity during performance of cognitive tasks.

Prior studies have shown deficits in social cognition and emotion perception in first-episode psychosis (FEP) and multi-episode schizophrenia (MES) patients. These studies compared patients at different stages of the illness with only a single control group which differed in age from at least one clinical group. The present study provides new evidence of a differential pattern of deficit in facial affect recognition in FEP and MES patients using a double age-matched control design. Compared to their controls, FEP patients only showed impaired recognition of fearful faces (p=.007). In contrast to this, the MES patients showed a more generalized deficit compared to their age-matched controls, with impaired recognition of angry, sad and fearful faces (ps

Previous studies have generally found a relationship between negative and cognitive symptoms in schizophrenia. The present study investigated the relationship between the 5 PANSS factors of a recent consensus model developed by NIMH researchers, and cognitive performance as assessed with the MATRICS Consensus Cognitive Battery (MCCB) in 80 patients with schizophrenia using correlation and regression analyses. The PANSS Cognitive factor showed a small to moderate significant association with MCCB Speed of processing, Working memory, Verbal learning, the Neurocognitive composite score, and the Overall composite score. Notably, however, no relationship was found between the PANSS Negative factor and any of the MCCB scores. The Positive, Excited and Depressed factors also did not show associations with the MCCB. These results highlight the need for refined assessment instruments and support the relative independence of cognition from other domains of psychopathology, including negative symptoms, in patients with schizophrenia.

OBJECTIVE: Despite the clinical observation that antipsychotics can produce negative symptoms, no previous controlled study, to our knowledge, has evaluated this action in healthy subjects. The present study assessed observer-rated and self-rated negative symptoms produced by conventional and second-generation antipsychotics in healthy volunteers. METHOD: The authors used a double-blind, placebo-controlled trial of single doses of haloperidol (5 mg) and risperidone (2.5 mg) in normal subjects. Thirty-two subjects were administered haloperidol, risperidone, and placebo in a random order. Motor variables and observer-rated negative symptoms were assessed after 3-4 hours and subjective negative symptoms and drowsiness after 24 hours. RESULTS: Neither of the active drugs caused significant motor extrapyramidal symptoms after administration. Haloperidol caused significantly more negative signs and symptoms than placebo on the Scale for the Assessment of Negative Symptoms (SANS) and two self-rated negative symptom scales: the Subjective Deficit Syndrome Scale total score and an analog scale that evaluates subjective negative symptoms. Risperidone caused significantly more negative signs and symptoms than placebo on the Brief Psychiatric Rating Scale (BPRS), the SANS, the Subjective Deficit Syndrome Scale total score, and the analog scale for subjective negative symptoms. After control for drowsiness, risperidone but not haloperidol produced more negative symptoms than placebo on the BPRS and the SANS. Significance was lost for the subjective negative symptoms with both drugs. CONCLUSIONS: Single doses of both haloperidol and risperidone produce negative symptoms in normal individuals. Drowsiness may be an important confounding factor in the assessment of negative symptoms in antipsychotic trials.

ObjectiveExcessive cortical cerebrospinal fluid (CSF) has been acknowledged as a possible marker of a gray matter loss. This excess in schizophrenia is found predominantly in the prefrontal and temporal regions. We hypothesized that the poorer global outcome and treatment response in males with schizophrenia are related to a greater cortical volume loss as compared to females.Subjects and methodsIn order to test this hypothesis we have used magnetic resonance imaging (MRI) to study the cortical (prefrontal, temporal, and hemispheric) CSF values in a group of 85 patients with schizophrenia, of whom 56 were males and 29, females. We calculated the residual values of CSF in the patients based on the data pertaining to 45 control subjects and linear regression, from which the normal effects of age and intracranial volume were discounted. These residual scores constitute a quantitative measurement of the excess of CSF due to the disease.ResultsMales, but not females, presented a trend-level significant excess of left prefrontal CSF. The prefrontal and temporal residual values were significantly associated with illness duration in males, but not in females.DiscussionThese results conform to the worse outcome and the higher severity of structural abnormalities generally found in schizophrenia in male subjects.ConclusionOur data support the hypothesis of accelerated prefrontal cortical loss in males, but not in females with schizophrenia.

Aims: To determine the clinically ascertained variables that are related to satisfactory response to naltrexone (NTX) treatment of alcohol dependence after detoxification. Methods: The use of intake and outcome variables were measured in a randomized 3-month open-controlled trial comparing the effects of naltrexone plus psychotherapy treatment versus psychotherapy treatment alone on the maintenance of abstinence in the final 28 days (n = 336, all male). Results: Predictors of a positive response to NTX treatment were family history of alcoholism (P = 0.010), early age at onset of drinking problems (P = 0.014) and comorbid use of other drugs of abuse (P < 0.001). Among the subjects not treated with NTX, the greater the number of predictor variables, the lower the final 28 days abstinence rates (P = 0.00003), but this was not the case in patients treated with NTX (P = 0.844). Conclusions: Patients with these features, suggesting biological vulnerability overall have poorer outcomes, but this can be reduced with NTX treatment. The type of alcoholism should be considered before deciding on the pharmacological strategy.

Aim: To specify the functional activity of cannabinoid CB 1 receptor in alcohol-preferring Fawn Hooded and alcohol nonpreferring Wistar rats under naive conditions. Method: Cannabinoid CB1 (WIN-55,212)-stimulated ( 35 S)-GTPs binding autoradiography, and cannabinoid CB 1 receptor gene expression were measured in rats of both strains that received only water. Results: Cannabinoid CB1 receptor stimulated ( 35 S)- GTPs binding was significantly lower in cingulate cortex (Cg), caudate-putamen (CPu), nucleus accumbens (Acc), ventromedial hypothalamic nucleus (VMN), amygdaloid area (AMG), fields (CA1, CA3) of the hippocampus and dentate gyrus (DG) in Fawn Hooded than in Wistar rats, whereas no differences were found either in substantia n igra pars reticulata (SNr) nor CA2 field of the hippocampus. In addition, cannabinoid CB 1 receptor gene expression was lower in Cg, CPu, VMN and CA3 field of the hippocampus in Fawn Hooded than in Wistar rats. Conclusions: We speculate that lower cannabinoid function appears to be related to greater vulnerability to alcohol consumption. Cannabinoid CB 1 receptor may represent a key target in the treatment of alcohol dependence.

Although a lower volume of prefrontal (PF) gray matter (GM) in patients with schizophrenia than in normal control subjects is a replicated finding, it is not yet clear whether this finding is present at the onset of illness. Clinical and imaging data suggest that the reduction in PF GM becomes apparent only some years following the onset of illness. To test this hypothesis, we used magnetic resonance imaging to study PF GM and sulcal cerebrospinal fluid (CSF) volumes in 81 schizophrenic patients. A Talairach-based tool was used for segmentation. Subjects included 44 healthy controls, 22 first-episode (FE), treatment-naïve patients with duration of illness of less than 1 year; 29 short-term chronic (SC) patients with durations of illness between 1.5 and 6 years; and 30 long-term chronic (LC) patients with duration of illness of more than 6 years. The data from healthy controls were used to calculate volume residuals in the patients, defined as deviations from the expected values given individual age and intracranial volume. The FE group did not show significant differences in GM or in CSF volumes compared with controls. However, both the SC and the LC patients showed the expected pattern of lower values for PF GM and an excess of PF sulcal CSF compared with controls. There were no significant differences between SC and LC patients in any of these measurements. There was a significant and inverse association between duration of illness and GM residuals. That association fit a nonlinear rather than a linear model, which was consistent with a decrease of GM volume during the first years following illness onset. No significant differences were found between those receiving atypical and typical antipsychotic drugs during the previous year.

This study aimed to examine the behavioural and neurochemical (cannabinoid CB1 receptor gene expression) changes induced by spontaneous cannabinoid withdrawal in mice. Tolerance was assessed by measuring rectal temperature and motor activity in the open-field test after CP-55, 940 administration. Cannabinoid withdrawal symptoms were determined by measuring motor activity and behavioural signs of abstinence. Cessation of CP-55, 940 treatment in tolerant mice induced a spontaneous time-dependent behavioural withdrawal syndrome consisting of marked increases (140%) in motor activity, number of rearings (170%), decreases in grooming (57%), wet dog shakes (73%) and rubbing behaviours (74%) on day 1, progressively reaching values similar to vehicle-treated mice on day 3. Interestingly, this spontaneous cannabinoid withdrawal resulted in CB1 gene expression upregulation (20–30%) in caudate-putamen, ventromedial hypothalamic nucleus, central amygdaloid nucleus and CA1, whereas in the CA3 field of hippocampus, a significant decrease (15–20%) was detected. Taken together, the results of this study suggest that cessation of CP-55, 940 administration in tolerant mice produces a behavioural cannabinoid withdrawal syndrome and a selective and differential responsiveness in CB1 receptor gene expression in several brain regions of the mice. These findings further suggest a time and regional differential role for cannabinoid receptors in short- and long-term neuroadaptations that occur after exposure to cannabis derivatives.

Background: Anticonvulsant drugs have been used in the treatment of alcohol addiction with relatively good results. The purpose of the present study was to evaluate tolerance and safety of topiramate in patients presenting alcohol dependence. Methods: We studied 24 patients that fulfilled alcohol-dependence criteria (DSM-IV) and presented other psychiatric disorders for which the use of topiramate was indicated. During the 12 weeks of the study, the patients received topiramate (262 mg/ day) plus the psychoactive drugs they were taking for the other disorders. Carbohydrate-deficient transferrin (CDT) values and measures of craving and alcohol use were taken every 2 weeks. Results: Baseline rating of amount and frequency of craving and alcohol use decreased significantly by week 2, and CDT values decreased from week 6. Topiramate was well tolerated, and there were only three dropouts due to adverse events. Conclusion: Topiramate is safe and well tolerated, and may be beneficial in the treatment of alcohol dependence. A placebo-controlled study would be of interest.

A multitude of factors, that either singly, interactively, or sequentially influence the gene-environment interplay in affective and dementia states, include several phases of neurodevelopmental liability in both humans and laboratory animals. Genetic vulnerability for both affective disorders and dementia describes a scenario distinguished by progressive need for concern, particularly in view of the interplay between these areas of ill-health. The contribution of emotional and cognitive expression to personal outcomes, e.g., as a function of affective personality type, a state-dependent analysis of personality characteristics, appears to pervade both the individual's experience of social and physical environments and the performance of cognitive tasks. The role of the endocannabinoids in mental health may offer insights for the psychopharmacology of both cognition and affect. Maladaptive emotional reactions and a defective cognitive ability will contribution to unsatisfactory/maladaptive coping strategies, in turn, leading to further complications of an affective and dysfunctional nature, eventually with a clinical psychopathological outcome. These considerations impinge upon critical issues concerning predisposition and vulnerability. Classical eye-blink conditioning provides a highly established procedure for assessment of defective physiology in models of Alzheimer's dementia. In order to develop a consideration of the array of situations presenting the variation of outcome due to type of affective personality, the role of fear and anxiety and stress in affective states influencing cognition are examined and the critical role of brain circuits mediating emotions influencing cognitive outcomes is discussed.

The TaqIA1 allele of the dopamine receptor gene D2 (DRD2) has been associated with alcoholism, as well as with other addictive behaviours. The exact nature of how the presence of this allele can be a vulnerability factor in the development of alcoholism remains unclear. In this study we found that the presence in the DRD2 genotype of the TaqIA1 allele in Spanish alcoholics is associated with higher levels of urine homovanillic acid (HVA) when compared to patients homozygous for the TaqIA2 allele. A sample of 142 Spanish male alcoholic patients was split into 2 groups on the basis of the presence or absence of the A1 allele in their genotype. The urine sample was analyzed by high performance liquid cromatography (HPLC), and the concentration of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vanilylmandelic acid (VMA) was determined. We found a statistical difference in the concentration of HVA between the groups, that suggests this polymorphism could be related to the variance of urine HVA levels.

Clozapine alleviates the symptoms of a significant proportion of treatment-resistant schizophrenic patients. Previous studies suggest that the response to clozapine may be associated with prefrontal and temporal anatomy as well as with prefrontal, basal ganglia and thalamic metabolism. A sample of 25 treatment-resistant (TR) schizophrenic patients underwent magnetic resonance imaging (MRI) and 18F-deoxyglucose positron emission tomography (PET) before and after treatment with clozapine. We investigated the association between changes in positive, disorganized, and negative schizophrenic syndromes with clozapine treatment and a set of cerebral variables that included total intracranial volume (ICV); hippocampal, dorsolateral prefrontal (DLPF) and temporal gray-matter volume and metabolism; and metabolic activity of the thalamus, pallidum/putamen, and caudate head. Improvement in positive symptoms with clozapine was directly related to temporal gray-matter volume, whereas improvement of disorganization symptoms was inversely related to ICV and hippocampal volume. Patients with high baseline DLPF cortical volume and metabolic activity were more likely to experience improvement in their negative symptoms. We conclude that clinical improvement with clozapine may be related with the anatomy and metabolic activity of specific brain areas, with the structural integrity of the DLPF and temporal regions showing the maximum predictive capacity.

Background. –Presence of A1 allele of the DRD2 gene has been associated with a predisposition for alcoholism although there are limited data about its phenotypic expression in alcoholism.Objectives. –To determine the importance of the A1 allele in clinical variables of alcohol dependence.Methodology. –A sample of 103 alcohol-dependent males was studied. All patients were recruited consecutively from the general hospital and community settings. The diagnostics were made with the structured clinical interview for DSM-III-R (SCID); and the International Personality Disorder Examination (IPDE). Diagnosis of family alcoholism was made by direct interview or with the Research Diagnostic Criteria-Family History (RDC-FH). The Addiction Severity Index (ASI) and the Severity of Alcohol Dependence Scale (SADS) were used to assess alcohol dependence severity. Genotyping was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods.Results. –Approximately 39% of the sample carried the A1 allele (A1+ group). This group had higher prevalences of antisocial personality disorder (60% vs. 15.9%); and alcoholism family history (72.5% vs. 52.4%). Also A1+ had early onset alcohol abuse and more drinking problems. The presence of A1+ was the main factor to explain the diagnosis of antisocial personality disorder, but the weight of this factor was not sufficient to explain the complications assessed by the ASI.Conclusions. –Our results support the existence of an association between the A1 allele and factors resulting from dopaminergic deficiency, otherwise denominated reward deficiency syndrome.

This paper compares the metabolic changes associated with risperidone treatment in schizophrenia to those induced by haloperidol, as a representative typical neuroleptic. A group of 11 schizophrenic patients of recent onset underwent two [ 18 F] fluoro-desoxi-glucose (FDG)-positron emission tomography (PET) scans at rest: the first one at the moment of the diagnosis, after a minimal treatment with haloperidol followed by wash-out, and the second one after 6 months on risperidone. The study also included 34 patients on chronic haloperidol for comparison. PET images were analyzed using Statistical Parametric Mapping (SPM′99) methods. The only change after treatment with risperidone with respect to the baseline was a slight increase in activity in the primary visual area and the right insula. Patients on chronic haloperidol showed increased activity in the motor cortex and cerebellum, as compared to both minimally treated and risperidone-treated patients. The pattern of metabolic changes induced by risperidone appears to be different from that produced by typical antipsychotics.

Naltrexone is widely used in therapeutic programs with abstinence as a goal. However, it has been used in only a few studies aimed at reducing alcohol consumption. The purpose of this study was to evaluate the efficacy of naltrexone as an adjunct in controlled drinking programs. This was an open randomized study of 12 weeks duration that compared two therapeutic strategies: use of naltrexone in a controlled drinking program (NTX+CD) and the controlled drinking program alone (CD), without NTX. Each group comprised 30 male patients with mild alcohol dependence. During treatment, there were no differences between groups in drinking behavior, though the NTX+CD group showed significantly less craving. In the 12-month follow-up period, the NTX+CD group showed significantly fewer drinking days and heavy drinking days and less craving than the CD group. The results of this study suggest a role for naltrexone in controlled drinking programs.

Changes in sulcal cerebrospinal fluid (CSF) volume have been related to the neurodegeneration hypothesis in schizophrenia. Fifty-three (24 neuroleptic-naive) schizophrenics and a control group (n=26) were studied with MRI to assess regional sulcal CSF values relative to the total volume of brain lobes (prefrontal, orbital, temporal, parietal, and occipital). Segmentation of brain structures was performed using an automatic Talairach-based method. Relative CSF volumes were adjusted for age by means of linear regression from normal subjects; the corrected values were used to assess their relationship with illness duration and age of onset (AOS). The volume of sulcal CSF on prefrontal and temporal lobes (bilateral) was significantly greater in schizophrenic patients and showed a significant positive correlation with illness duration not found in the other regions studied. No significant association between CSF volumes and AOS was found in any region. Our findings support the existence of a degenerative process in schizophrenia located in prefrontal and temporal areas.

Genome wide association studies (GWAS) has allowed the discovery of some interesting risk variants for schizophrenia (SCZ). However, this high-throughput approach presents some limitations, being the most important the necessity of highly restrictive statistical corrections as well as the loss of statistical power inherent to the use of a Single Nucleotide Polymorphism (SNP) analysis approach. These problems can be partially solved through the use of a polygenic approach. We performed a genotyping study in SCZ using 86 previously associated SNPs identified by GWAS of SCZ, bipolar disorder (BPD) and autistic spectrum disorder (ASD) patients. The sample consisted of 3063 independent cases with DSM-IV-TR diagnosis of SCZ and 2847 independent controls of European origin from Spain. A polygenic score analysis was also used to test the overall effect on the SCZ status. One SNP, rs12290811, located in the ODZ4 gene reached statistical significance (p = 1.7 x 10(-4), Allelic odds ratio = 1.21), a value very near to those reported in previous GWAS of BPD patients. In addition, 4 SNPs were close to the significant threshold: rs3850333, in the NRXN1 gene; rs6932590, at MHC; rs2314398, located in an intergenic region on chromosome 2; and rs1006737, in the CACNA1C gene. We also found that 74% of the studied SNPs showed the same tendency (risk or protection alleles) previously reported in the original GWAS (p < 0.001). Our data strengthen the polygenic component of susceptibility to SCZ. Our findings show ODZ4 as a risk gene for SCZ, emphasizing the existence of common vulnerability in psychosis. (C) 2014 Published by Elsevier B. V.

The purpose of this study was to examine the time course effects of extinction of cocaine self-administration behavior on proenkephalin (PENK) gene expression in caudate-putamen nucleus (ST), nucleus accumbens (Acc), olfactory tubercle (Tu), piriform cortex (Pir), ventromedial hypothalamic nucleus (VMN), and central amygdala (Ce) as measured by in situ hybridization histochemistry. Seventy-two littermate male Lewis rats were randomly assigned in triads to one of three conditions: (1) contingent intravenous self-administration of 1 mg/kg/injection of cocaine (CONT); (2) noncontingent injections of either 1 mg/kg/injection of cocaine (NONCONT); or (3) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement for a minimum of 3 weeks. After stable baseline levels of drug intake had been reached, saline was substituted for drug. Following this first extinction period, cocaine self-administration was reinstated for an additional period of 2 weeks. Immediately after cessation of the last session of cocaine self-administration (day 0) and 1-, 5-, and 10-day after the second extinction period, animal brains in each triad were removed to be processed for in situ hybridization. PENK mRNA levels were significantly higher in the cocaine groups when compared with SALINE group in the ST, Acc, Pir, and Tu regions on days 0, 1, 5, and 10 of the extinction and lower in the Ce region of CONT group when compared to NONCONT and SALINE groups on days 1, 5, and 10 of the extinction period. In the VMN nucleus, PENK mRNA content in CONT group versus NONCONT and SALINE groups was also lower, but there were statistically significant differences only on day 5. These results suggest that changes in PENK gene expression after contingent cocaine administration might be involved in cocaine withdrawal states.

In first-episode patients with psychosis, clozapine may be potentially valuable as an initial treatment seeking to limit early on clinical and cognitive deterioration. Nevertheless, until recently its restricted use has limited the study of this possibility. Our research group is developing a non-commercial, multicentric and open label study on the differential efficacy between clozapine and risperidone in first-episode schizophrenia. In this paper, we present the results related to clinical variables after a one-year follow-up. So far, we have recruited 30 patients diagnosed with schizophrenia or schizophreniform disorder with illness duration of less than two years. The patients had not received any previous treatment and they were randomized to treatment with clozapine or risperidone. Our results indicate that on average, patients on clozapine adhered to their original treatment for a longer time period than patients on risperidone. By last observation carried forward (LOCF) analysis, patients on clozapine and risperidone displayed similar clinical improvements, although marginally greater improvements in positive and total symptoms scores were found in the clozapine group. At the 12-month point we observed a marginal improvement in negative symptom scores in patients on clozapine. Subjective secondary effects, as measured with the Udvalg for KliniskeUndersogelser (UKU) scale, correlated negatively with negative symptoms at follow-up. Our data, although preliminary, suggest that clozapine may have a slightly superior efficacy in the initial year of treatment of first-episode treatment-naive patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

Different exploratory and confirmatory factorial analyses of the Positive and Negative Syndrome Scale (PANSS) have found a number of factors other than the original positive, negative, and general psychopathology. Based on a review of previous studies and using confirmatory factor analyses (CFA), Wallwork et al. (Schizophr Res 2012; 137: 246–250) have recently proposed a consensus five-factor structure of the PANSS. This solution includes a cognitive factor which could be a useful measure of cognition in schizophrenia. Our objectives were 1) to study the psychometric properties (factorial structure and reliability) of this consensus five-factor model of the PANSS, and 2) to study the relationship between executive performance assessed using the Wisconsin Card Sorting Test (WCST) and the proposed PANSS consensus cognitive factor (composed by items P2-N5-G11). This cross-sectional study included a final sample of 201 Spanish outpatients diagnosed with schizophrenia. For our first objective, CFA was performed and Cronbach's alphas of the five factors were calculated; for the second objective, sequential linear regression analyses were used. The results of the CFA showed acceptable fit indices (NNFI = 0.94, CFI = 0.95, RMSEA = 0.08). Cronbach's alphas of the five factors were adequate. Regression analyses showed that this five-factor model of the PANSS explained more of the WCST variance than the classical three-factor model. Moreover, higher cognitive factor scores were associated with worse WCST performance. These results supporting its factorial structure and reliability provide robustness to this consensus PANSS five-factor model, and indicate some usefulness of the cognitive factor in the clinical assessment of schizophrenic patients.

Background: Negative symptoms and cognitive dysfunction are of crucial functional and prognostic importance in schizophrenia. However, the nature of the relationship between them and the factors that may influence it have not been well established. Aims: To investigate whether the relationship between negative symptoms and executive function changes according to the duration of illness in schizophrenia. Methods: The Positive and Negative Syndrome Scale was used to assess psychopathology and the Wisconsin Card Sorting Test (WCST) to evaluate executive function in a sample of 200 schizophrenic patients who were classified in 3 groups according to their duration of illness: up to 5 years (short duration group), 6-20 years (intermediate duration group) and over 20 years of illness (long duration group). Results: Medium-sized correlations were found between negative symptoms and WCST performance as assessed by the number of completed categories in all 3 groups. However, differences were found according to the duration of schizophrenia. For patients in the short duration group, negative symptoms correlated with WCST nonperseverative errors, but for those in the long duration group the correlation was with perseverative errors. Conclusion: We found a differential relationship between negative and cognitive symptoms in different stages of schizophrenia. Illness duration should be considered when studying the relationship between negative symptoms and cognition.

Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to Δ 9 -tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [ 3 H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located. This downregulation phenomenon was also observed in the ventral mesencephalon, the area where cell bodies for both dopaminergic neuronal systems are clustered, but the decrease was smaller and nonsignificant. No modifications were seen in the affinity of these receptors by chronic exposure to THC. In summary, a chronic treatment with THC produced downregulation of cannabinoid receptors in the striatum and limbic forebrain and a nonsignificant trend in the ventral mesencephalon. This observation might explain the tolerance phenomena observed in the effects of THC on motor and limbic behaviors after chronic exposures.

The maintenance of self-reported quality of life (QL) among people on the liver transplantation waiting list is one of the priority objectives of transplantation teams. Although there are different determinant factors of QL, results are not conclusive. In our study, the goal was to evaluate both the influence of cirrhosis etiology (ethylic and non-ethylic) and the coping strategies used concerning QL. A sample of 93 patients was selected, divided into two groups: ethylic cirrhosis (EC) and non-ethylic cirrhosis (NEC). QL was evaluated through the SF-36 Health Survey, and coping strategies through the Medical Coping Modes Questionnaire (MCMQ). Our results indicated that subjects with EC obtained similar QL levels to subjects with NEC, on all the SF-36 and MCMQ subscales. Furthermore, negative correlations were found between avoidance and acceptance-resignation coping strategies with the SF-36 components. Consequently, the acceptance-resignation strategy was associated with a worse perception of physical functioning, general and mental health, and vitality and role-emotional. Overall, these results suggest that cirrhosis etiology is not a determinant factor of QL, whereas the acceptance-resignation coping strategy might lead to lower self-perception of QL.

Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder.

Tardive dyskinesia (TD) is a severe and potential irreversible side effect of antipsychotic treatment. Treatment of established TD is often unsuccessful. In this article, we report three cases of psychogeriatric patients who suffered from TD as a side effect of long-term treatment with haloperidol that resolved after switching treatment to aripiprazole. Potential psychopharmacological mechanisms explaining this finding are briefly discussed.

Functional neuroimaging studies carried out on healthy volunteers while performing different n-back tasks have shown a common pattern of bilateral frontoparietal activation, especially of the dorsolateral prefrontal cortex (DLPFC). Our objective was to use functional magnetic resonance imaging (fMRI) to compare the pattern of brain activation while performing two similar n-back tasks which differed in their presentation modality. Thirteen healthy volunteers completed a verbal 2-back task presenting auditory stimuli, and a similar 2-back task presenting visual stimuli. A conjunction analysis showed bilateral activation of frontoparietal areas including the DLPFC. The left DLPFC and the superior temporal gyrus showed a greater activation in the auditory than in the visual condition, whereas posterior brain regions and the anterior cingulate showed a greater activation during the visual than during the auditory task. Thus, brain areas involved in the visual and auditory versions of the n-back task showed an important overlap between them, reflecting the supramodal characteristics of working memory. However, the differences found between the two modalities should be considered in order to select the most appropriate task for future clinical studies. © 2009 Elsevier B.V. All rights reserved.

The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy–Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population. © 2009 Wiley-Liss, Inc.

Symptoms and syndromes in neuropathology, whether expressed in conscious or nonconscious behaviour, remain imbedded in often complex diagnostic categories. Symptom-based strategies for studying brain disease states are driven by assessments of presenting symptoms, signs, assay results, neuroimages and biomarkers. In the present account, symptom-based strategies are contrasted with existing diagnostic classifications. Topics include brain areas and regional circuitry underlying decision-making and impulsiveness, and motor and learned expressions of explicit and implicit processes. In three self-report studies on young adult and adolescent healthy individuals, it was observed that linear regression analyses between positive and negative affect, self-esteem, four different types of situational motivation: intrinsic, identified regulation, extrinsic regulation and amotivation, and impulsiveness predicted significant associations between impulsiveness with negative affect and lack of motivation (i.e., amotivation) and internal locus of control, on the one hand, and non-impulsiveness with positive affect, self-esteem, and high motivation (i.e., intrinsic motivation and identified regulation), on the other. Although presymptomatic, these cognitive-affective characterizations illustrate individuals' choice behaviour in appraisals of situations, events and proclivities essentially of distal perspective. Neuropathological expressions provide the proximal realities of symptoms and syndromes with underlying dysfunctionality of brain regions, circuits and molecular mechanisms.

Comorbidity between a substance use disorder (SUD) and another psychiatric disorder is known as dual diagnosis. It is of great relevance due to its important clinical consequences and costs of care. There are practically no published studies on dual diagnosis prevalence in patients admitted to psychiatric hospitalization units in general hospitals (PHUGH) in our country. The objectives were to estimate the prevalence of dual diagnosis in psychiatric inpatients admitted consecutively to a Psychiatric Hospitalization Unit (Hospital Universitario 12 de Octubre, Madrid, Spain) in one year, to compare clinical and sociodemographic variables between the dual diagnosis group (DD group) and the group with a psychiatric disorder but no SUD (PD group), and to study the types of substances used. This is a retrospective study, based on the review of the clinical charts of the 257 patients admitted to this PHUGH in one year. The results showed that, excluding nicotine dependence, 24.9% of our inpatients had a SUD as well as another psychiatric disorder. A statistically significant predominance of men was found in the DD group, as well as a younger age at the time of the study, at the beginning of their psychiatric attention and on their first psychiatric admission, and they had received diagnoses of schizophrenia or related psychoses more often than the PD group, who had mostly affective disorders. The substances most frequently used in the DD group were alcohol (78.1%), cannabis (62.5%), and cocaine (51.6%). Due to the high prevalence and repercussions of dual diagnosis, it would be advisable to have specialized therapeutic programs for its treatment.