Ignacio Mata

Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at one-year follow-up.

OBJECTIVE Many studies have reported that cognitive ability may be predictive of the functional outcome for patients with schizophrenia. However, no study has prospectively examined these aspects in schizophrenia and bipolar disorders simultaneously. The present study attempted to analyze if neurocognition and clinical status predicts the real-life functioning for patients with schizophrenia or bipolar I disorder, using a longitudinal design. METHOD Forty-seven schizophrenic and 43 bipolar I outpatients were assessed twice with a neurocognitive battery (Executive Functions, Working Memory, Verbal Memory, Visual Memory, Visual-Motor Processing, Vigilance, Vocabulary and Motor Speed tasks), clinical scales (the Positive and Negative Symptom Scale, the Hamilton Rating Scale for Depression and the Clinician Administered Rating Scale for Mania) and functional outcome measures (the Global Assessment of Functioning Scale, the WHOs Disability Assessment Scale and occupational adaptation level) over a one-year follow-up period. The cognitive performance of the patients was compared, at baseline and one year later, with that of 25 healthy subjects. RESULTS In schizophrenia patients, global functioning one year later was predicted by a composite neurocognitive score and three specific domain (verbal memory, motor speed, vocabulary). Symptoms appeared to explain less of the variance in functioning. In bipolar I patients, changes in the composite neurocognitive score over one year, deficits in the visual/motor processing domain, severity of symptoms (psychotic, excitatory and affective symptoms) and premorbid adjustment at the first assessment were the variables that better predicted functioning or disability changes over follow-up period. CONCLUSIONS Although the relationships between cognition, symptoms and functional capacity differ for schizophrenia or bipolar I patients, neuropsychological performance seems to be a principal longitudinal predictor of functioning in both disorders. Baseline neurocognition and cognitive changes over 12 months predicted changes in functioning over the same period, but only in bipolar I patients. These cognitive domains could be potential neurocognitive endophenotypes (endophenocognitypes) with regard to bipolar I disorder.

White Matter Integrity and Cognitive Impairment in First-Episode Psychosis

OBJECTIVE Impaired cognitive function has been identified as a core feature of schizophrenia. However, a significant proportion of patients do not show any cognitive deficits. The aim of this study was to assess if there were differences in white matter integrity between patients with and without cognitive impairment. METHOD A diffusion tensor imaging study and neurocognitive assessment were conducted in 49 patients with first-episode psychosis and 41 healthy comparison subjects. Subjects were assessed using the Continuous Performance Test, the Grooved Pegboard Test, the Rey Auditory Verbal Learning Test, and the Trail Making Test Part B. For each test, the patient sample was subdivided according to performance, with those scoring more than one standard deviation below the normative mean categorized as impaired. For each cognitive domain, white matter fractional anisotropy in deficit and nondeficit subgroups was compared using a voxel-based analysis. A nonparametric statistical method, controlling for multiple comparisons, was applied. RESULTS Impairment on the Trail Making Test Part B was associated with reduced fractional anisotropy in the right/left anterior thalamic radiation and inferior fronto-occipital fasciculus, forceps minor, and left superior and inferior longitudinal fasciculi. Patients exhibiting Grooved Pegboard Test impairment showed reduced fractional anisotropy in the forceps minor, inferior fronto-occipital fasciculus, anterior thalamic radiation, and corticospinal and corticopontine tracts. Impaired performance on the Rey Auditory Verbal Learning Test and Continuous Performance Test was not associated with significant differences in fractional anisotropy. CONCLUSION Deficits in executive and motor functioning in patients with first-episode psychosis are associated with reductions in white matter integrity in the major fasciculi that connect the frontal and temporal cortices as well as in pathways connecting cortical and subcortical regions. Their presence at the onset of illness, in minimally medicated patients, indicates that these findings are not attributable to effects of chronic illness or its treatment.

White matter defects in first episode psychosis patients: A voxelwise analysis of diffusion tensor imaging ☆

OBJECTIVE Disruptions in white matter structure have consistently been shown in schizophrenia--but mainly in patients in whom the illness is well-established. In order to determine whether white matter abnormalities are present at illness onset, and to minimise the potentially confounding effects of chronic illness and treatment, we used diffusion tensor imaging to study a large cohort of first episode psychotic patients who were medication-naive. METHODS Sixty two first episode patients and 54 controls matched on age, sex, years of education and laterality index underwent diffusion tensor imaging. Data were acquired on a GE Signa NVi 1.5 Tesla System. Fractional anisotropy maps were generated on a voxel-by-voxel basis. An optimized voxel-based morphometry technique was conducted with two-stage registration approach. Group differences were examined using a non-parametric statistical method. RESULTS The voxelwise analysis revealed four clusters where fractional anisotropy values were significantly lower in patients than controls. These were localised bilaterally to regions of white matter corresponding to superior and inferior longitudinal fasciculus, forceps major, anterior and superior thalamic radiation and corpus callosum. CONCLUSIONS Reductions in white matter integrity are present early in the course of the schizophrenia and localised in fascicule that connect brain regions implicated in the disorder.

Epidemiological factors associated with treated incidence of first‐episode non‐affective psychosis in Cantabria: insights from the Clinical Programme on Early Phases of Psychosis

Aim: The aim of the study was to analyse the treated incidence of schizophrenia in Cantabria (Northern Spain) and the sociodemographic risk factors associated with the illness onset.

Clinical applications of pharmacogenetics in psychiatry.

Abstract. Pharmacogenetic research has identified response-related mutant variants in metabolic enzymes and drug-targeted receptors. Allelic variants of dopaminergic and serotonergic receptors have been associated with clinical outcome and adverse events such as movement disorders. Deficient metabolic enzymes have been related to drug accumulation and toxic events. This information will help to design safer and more efficient drugs. However, the field is moving rapidly towards a new goal: the application of pharmacogenetics as a clinical tool for the prediction of treatment outcome. The first studies in this direction have proved the feasibility of using genetic information for the prediction of response to antipsychotic drugs and to treatment of Alzheimers disease. New strategies investigating genes related to specific symptoms and side-effects have produced encouraging results that can contribute to the improvement of the levels and accuracy of the predictions. This review tries to summarise recent advances and provides an overview of future clinical applications.

Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naive population

OBJECTIVE This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment. METHODS A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol). RESULTS 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated. CONCLUSIONS Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Effect of antipsychotics on peptides involved in energy balance in drug-naive, psychotic patients after 1 year of treatment

Weight gain has become one of the most common and concerning side effects of antipsychotic treatment. The mechanisms whereby antipsychotics induce weight gain are not known. It has been suggested that peptides related to food intake and energy balance could play a role in weight gain secondary to antipsychotic therapy. To better understand the pathophysiology of antipsychotic-induced weight gain, we studied the effects of 3 antipsychotic drugs (haloperidol, olanzapine, and risperidone) on peptides involved in energy balance (insulin, ghrelin, leptin, adiponectin, visfatin, and resistin) in a population of drug-naive patients with first episode of psychosis. A significant increase in weight (10.16 kg [SD, 8.30 kg]; P < 0.001), body mass index (3.56 kg/m2 [SD, 2.89 kg/m2]; P < 0.001), and fasting insulin (3.93 &mgr;U/mL [SD, 3.93 &mgr;U/mL]; P = 0.028), leptin (6.76 ng/mL [SD, 7.21 ng/mL]; P < 0.001), and ghrelin (15.47 fmol/mL [SD, 47.90 fmol/mL]; P = 0.009) plasma levels were observed. The increments in insulin and leptin concentrations were highly correlated with the increment in weight and body mass index and seem to be a consequence of the higher fat stores. The unexpected increase in ghrelin levels might be related with the causal mechanism of weight gain induced by antipsychotics. Finally, the 3 antipsychotics had similar effects in all parameters evaluated.

Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use

Although cannabis is the most widely used illicit drug in the world, the long-term effect of its use in the brain remains controversial. In order to determine whether adolescence and early-adulthood cannabis use is associated with gross volumetric and gyrification abnormalities in the brain, we set up a cross-sectional study using structural magnetic resonance imaging in a sample of general population subjects. Thirty cannabis-using subjects (mean age, 25.7 years; mean duration of regular use, 8.4 years, range: 3-21) with no history of polydrug use or neurologic/mental disorder and 44 non-using control subjects (mean age, 25.8 years) were included. Cannabis users showed bilaterally decreased concavity of the sulci and thinner sulci in the right frontal lobe. Among non-users, age was significantly correlated with decreased gyrification (i.e., less concave sulci and more convexe gyri) and decreased cortical thickness, supporting the notion of age-related gyrification changes. However, among cannabis users gyrification indices did not show significant dependency on age, age of regular cannabis use initiation, or cumulative exposure to cannabis. These results suggest that cannabis use in adolescence and early-adulthood might involve a premature alteration in cortical gyrification similar to what is normally observed at a later age, probably through disruption of normal neurodevelopment.

Neurocognitive effectiveness of haloperidol, risperidone, and olanzapine in first-episode psychosis: a randomized, controlled 1-year follow-up comparison.

OBJECTIVE To investigate the neurocognitive effectiveness of haloperidol, risperidone, and olanzapine in first-episode schizophrenia-spectrum disorders. METHOD This prospective, randomized, open-label study was conducted from February 2001 to February 2005. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention program of first-episode psychosis (DSM-IV criteria) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred four patients randomly assigned to haloperidol (N = 35), olanzapine (N = 30), or risperidone (N = 39) who completed clinical and cognitive evaluations at baseline, 6 months, and 1 year were included in the final analysis. Thirty-seven healthy individuals were also longitudinally assessed. A neuropsychological battery that comprised 9 cognitive domains was used. The contribution of clinical changes, concomitant medications, and the severity of motor side effects to cognitive changes was controlled. The main outcome measure was cognitive changes at 1-year follow-up. RESULTS The 3 treatment groups showed a significant improvement in cognitive scores after 1 year. The differential cognitive effectiveness between antipsychotics was insignificant. The magnitude of cognitive changes was similar in the 3 treatment groups and controls, although a greater improvement on the Finger Tapping Test, Trail Making Test B, and Rey Complex Figure Test was found in the treatment groups. Clinical changes, use of concomitant medications, and the emergence of motor side effects did not significantly account for cognitive changes over time. CONCLUSION Haloperidol, olanzapine, and risperidone were equally effective in treating cognitive deficits of psychosis. The effect of practice clearly contributes to cognitive score improvements after treatment with antipsychotics. Our results provide important information regarding the practical utility of antipsychotic treatments to improve cognition and could have implications for developing novel approaches for cognitive pharmacotherapy in schizophrenia.

A neuregulin 1 variant is associated with increased lateral ventricle volume in patients with first-episode schizophrenia.

BACKGROUND Structural brain abnormalities are already present at early phases of psychosis and might be the consequence of neurodevelopmental deviance. Neuregulin 1 gene (NRG1) is a candidate gene for schizophrenia, and its protein has different roles in nervous system development and plasticity. A single nucleotide polymorphism (SNP) within NRG1, SNP8NRG243177, has been associated with brain function among healthy and high-risk subjects and with reduced cell migration among patients with schizophrenia. We examined whether variations in this polymorphism influence brain volumes in first-episode schizophrenia subjects. METHODS Ninety-five minimally medicated patients experiencing their first episode of schizophrenia underwent genotyping of three SNPs within the NRG1 gene and structural brain magnetic resonance imaging (MRI). A comparison of volumes of lobar gray matter (GM), lateral ventricles, and cortical cerebrospinal fluid (CSF) was made between the groups according to their genotype after controlling for total intracranial volume. RESULTS The SNP8NRG243177 risk T allele was significantly associated, in an allele copy number-dependent fashion, with increased lateral ventricle volume. Genotype explained 7% of the variance of lateral ventricle volume. No significant differences in GM lobar or cortical CSF volumes were found among subgroups. CONCLUSIONS Our findings suggest that genetic variations of the NRG1 gene can contribute to the enlargement of the lateral ventricles described in early phases of schizophrenia. These results suggest novel lines of research into potential mechanisms by which schizophrenia susceptibility genes might exert their effect on brain structure.