Eduard Parellada

Metabolic profile of antipsychotic-naive individuals with non-affective psychosis

BACKGROUND Some studies suggest individuals with schizophrenia have an increased risk of diabetes prior to antipsychotic use. Small sample sizes and the potential for confounding by hypercortisolaemia have decreased confidence in those results. AIMS To examine diabetes-related factors in newly diagnosed, antipsychotic-naive people with non-affective psychosis. METHOD Participants with psychosis (the psychosis group; n = 50) and matched controls (the control group; n = 50) were given a 2 h oral glucose tolerance test. Fasting concentrations were also determined for adiponectin, interleukin-6 and C-reactive protein. RESULTS Compared with the control group, the psychosis group had significant increases in 2 h glucose and interleukin-6 concentrations, and in the prevalence of abnormal glucose tolerance (16% of psychosis group v. 0% of control group). Adiponectin and C-reactive protein concentrations did not differ significantly between the two groups. These findings could not be attributed to differences in cortisol concentrations, smoking, gender, neighbourhood of residence, body mass index, aerobic conditioning, ethnicity, socioeconomic status or age. CONCLUSIONS Individuals with non-affective psychosis appear to have an increased prevalence of abnormal glucose tolerance prior to antipsychotic treatment, as well as abnormalities in a related inflammatory molecule. These underlying problems may contribute to the metabolic side-effects of antipsychotic medications.

Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies

The maintained antipsychotic efficacy of risperidone long-acting injectable (RLAI) was investigated in patients with schizophrenia or other psychoses who were transitioned directly from their previous antipsychotic medication. Patients symptomatically stable, but considered to require a treatment change, received 25 mg of RLAI (increased to 37.5 or 50 mg, if necessary) every 2 weeks for 6 months. Assessments included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression–Severity (CGI-S), Global Assessment of Functioning (GAF), SF-36 Health-Related Quality of Life Questionnaire and Extrapyramidal Symptoms Rating Scale (ESRS). Of 1876 patients enrolled, 74% completed the 6-month study. The most frequent reasons for treatment change were non-compliance (38%), insufficient efficacy (33%) and side-effects (26%). There was a significant reduction from baseline to endpoint in mean total PANSS score and in the scores on all PANSS subscales and symptom factors (P<0.001). CGI-S improved significantly, as did mean GAF score, all factors on the SF-36 and patient satisfaction with treatment. Scores on ESRS showed significant, sustained improvements throughout the study period. Direct initiation of RLAI was effective and well tolerated. RLAI provides an advancement in the treatment options available for a wide range of patients requiring long-term antipsychotic therapy.

Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: A resting and activation SPECT study

Regional cerebral blood flow (rCBF) was measured with single photon emission computed tomography (SPECT) in six neuroleptic-naive, young, acute schizophrenic patients and six normal control subjects. We evaluated rCBF changes in prefrontal areas at rest and during a prefrontal activation task, the Wisconsin Card Sorting Test (WCST). Schizophrenic patients had significantly higher prefrontal blood flow than did control subjects during the resting conditions. During activation, the control group showed significant increases in prefrontal blood flow, whereas the schizophrenic group did not. These results suggest that at rest there is no evidence of hypofrontality, whereas hyperfrontality seems to be the most frequent pattern in our selected sample of young acute neuroleptic-naive schizophrenic patients. Furthermore, schizophrenic patients seem to be unable to increase prefrontal blood flow under conditions that challenge the prefrontal cortex.

Telomere Length and Pulse Pressure in Newly Diagnosed, Antipsychotic-Naive Patients With Nonaffective Psychosis

INTRODUCTION Recent studies suggest that in addition to factors such as treatment side effects, suicide, and poor health habits, people with schizophrenia may have an increased risk of diabetes prior to antipsychotic treatment. Diabetes is associated with an increased pulse pressure (PP) and a shortened telomere. We tested the hypothesis that prior to antipsychotic treatment, schizophrenia and related disorders are associated with a shortened telomere, as well as an increased PP. METHODS Telomere content (which is highly correlated with telomere length) and PP were measured in newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders on first clinical contact and in matched control subjects. Both groups were also administered an oral glucose tolerance test. RESULTS Compared with control subjects, the patients with psychosis had decreased telomere content and an increased PP. As previously reported, they also had increased glucose concentrations at 2 hours. These differences could not be attributed to differences in age, ethnicity, smoking, gender, body mass index, neighborhood of residence, socioeconomic status, aerobic conditioning, or an increased cortisol concentration in the psychotic subjects. DISCUSSION These results suggest that prior to antipsychotic use, nonaffective psychosis is associated with reduced telomere content and increased PP, indices that have been linked to an increased risk of diabetes and hypertension.

Progressive gray matter changes in first episode schizophrenia: A 4-year longitudinal magnetic resonance study using VBM

UNLABELLED Schizophrenia is a disabling illness, characterized by a heterogeneous course including clinical deterioration and poor outcome. Accumulating findings in schizophrenia suggest that it might involve two pathophysiologic processes, one early in life (neurodevelopmental), and one after onset of the illness (neurodegenerative). Longitudinal imaging studies after onset of the illness may help to clarify these pathophysiological aspects of schizophrenia, but so far, probably due to methodological differences, there have been no conclusive results. The present study sets out to investigate longitudinal gray matter changes in patients with first-episode schizophrenia relative to healthy subjects over the first 4 years of the illness and the relation of gray matter changes in patients with functional outcome, using an objective automatic method not biased to one particular structure to analyze gray matter changes. METHODS We included 28 first-episode neuroleptic-naïve patients with DSM-IV diagnosis of schizophreniform disorder or schizophrenia, and 17 controls. 15 patients and 11 controls completed the longitudinal study and were reevaluated after four years. Gray matter changes over time were measured with voxel-based morphometry (VBM) using SPM5. Functional outcome was measured with the global assessment functioning scale (GAF). RESULTS Excessive decrease in gray matter was found in patients as compared to healthy individuals in the left superior temporal gyrus and right orbitofrontal gyrus, and excessive increase in the bilateral lingual gyrus and right cuneus. Additionally, gray matter changes in patients in the left lingual gyrus, right insula and right cerebellum, were inversely related to functional outcome (p<0.001 uncorrected at voxel level, p<0.05 family-wise-error corrected at cluster level). CONCLUSIONS There are differing longitudinal gray matter changes in patients with schizophrenia during the first years of the illness as compared to healthy individuals. Some progressive gray matter changes in patients are related to functional outcome.

Regional cerebral blood flow pattern in normal young and aged volunteers: a99mTc-HMPAO SPET study

The aim of this study was to investigate the normal pattern of regional cerebral blood flow (rCBF) distribution in normal young and aged volunteers using technetium-99m hexamethylpropylene amine oxime (99m-Te-HMPAO) as a tracer. The region brain perfusion of young and aged subjects was compared, especially regarding rCBF differences due to age and gender, and interhemispheric rCBF asymmetries. Sixty-eight right-handed normal volunteers — 40 young (mean age 29.5±6.3 years) and 28 aged (mean age 71.2±4.3 years) — were included in the study. rCBF was estimated on the basis of a semiquantitative approach by means of a left/right index and two region/reference ratios, using the cerebellum and the whole brain activity as references. A good correlation between these two region/reference ratios was found (P<0.005 in all cerebral regions). The highest rCBF ratios corresponded to the cerebellum, followed by the occipital lobe. The remaining cortical regions (temporal, parietal, frontal and basal ganglia) showed slightly lower values. The white matter showed rCBF ratios substantially lower than the grey matter. In neither young nor aged subjects were significant rCBF differences between the genders found in any of the two region/reference indices employed. Aged subjects showed significantly lower rCBF ratios than young subjects in the left frontal lobe and in the posterior region of the left temporal lobe. In both young and aged subjects, lower perfusion was found in the left hemisphere, except for the white matter region in both age groups and the frontal lobe in the young subjects. Aged subjects presented a slightly higher interhemispheric asymmetry in the frontal lobe. However, interhemispheric asymmetry was minimal (−1.01% to 3.14%). Consequently, a symmetrical rCBF distribution can be assumed between homologous regions, independent of age.

Glucose abnormalities in the siblings of people with schizophrenia

BACKGROUND Some studies suggest that schizophrenia may be associated with an increased risk of diabetes, independently of antipsychotic medications and other confounding factors. Previous studies have also suggested that there is an increased prevalence of diabetes in the relatives of schizophrenia probands. METHOD First-degree siblings of schizophrenia probands (N=6) and control subjects (N=12) were administered a glucose tolerance test. Subjects were matched for gender, age, body mass index, neighborhood of residence, socio-economic status and smoking habits. RESULTS The siblings of schizophrenia probands had a significantly increased two-hour mean glucose concentration compared to the control subjects (respective means [SD] were 100.5 mg/dL [27.7] vs. 78.0 [12.3]; p<0.03). Baseline glucose concentrations did not differ. CONCLUSIONS Although confirmation with larger samples is needed, these results and other studies suggest that diabetes may share familial risk factors with schizophrenia.

Prolactin concentrations in newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis

BACKGROUND Previous studies have found increased prolactin concentrations in antipsychotic-naïve patients with schizophrenia. However, the roles of other hormones, and of potentially confounding variables such as gender and smoking, have not been considered. METHODS Blood from newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis (13 women and 20 men) and matched controls (12 women and 21 men) was assayed for prolactin, as well as three other hormones that impact prolactin concentrations: thyrotropin-stimulating hormone (TSH), ghrelin, and cortisol. RESULTS Patients had significantly higher prolactin concentrations: female patients had a mean [SD] of 37.1 ng/mL [24.9] vs. 13.5 ng/mL [7.2] for female control subjects (p=.001), while male patients had a mean of 15.3 ng/mL [9.5] vs. 7.6 ng/mL [2.2] for male control subjects (p=.006). Patients and control subjects did not differ on concentrations of TSH, ghrelin, or cortisol. The group differences could not be attributed to differences in age, gender, smoking, body mass index, ethnicity, or the socioeconomic status of the family of origin. CONCLUSIONS Increased prolactin concentrations in antipsychotic-naïve patients do not appear to be due to important confounding variables, or to the effects of elevated TSH, ghrelin, or cortisol.

Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics

INTRODUCTION Impaired dopamine transporter (DAT) function may be involved in antipsychotic (AP)-induced extrapyramidal symptoms (EPS). A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the DAT gene (SLC6A3). OBJECTIVE We studied whether the SLC6A3 VNTR polymorphism is a risk or protection factor for AP-induced EPS. We also investigated the relationship between the polymorphism and DAT availability in the schizophrenic patients brain. METHODS Sixty-one patients receiving AP therapy participated in the EPS study. Of these, thirty-two cases presented EPS (Simpson-Angus >3) and twenty-nine without EPS (Simpson-Angus < or =3). The DAT expression was studied in fifteen AP-naive patients by [(123)I] FP-CIT SPECT. RESULTS No significant differences were observed for the more common alleles ((*)9R and (*)10R) or for genotype frequencies between patients with EPS and those without EPS. The frequency of the (*)9R and (*)10R alleles was similar to that described in other European populations. There were no significant differences in striatal DAT binding among the three major VNTR genotype groups. CONCLUSIONS Our results suggest that the VNTR polymorphism did not influence AP-induced EPS and did not affect DAT gene expression or protein function.

A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms

We present a pharmacogenetic study of acute antipsychotic (AP)-induced extrapyramidal symptoms (EPS) using an extensive linkage disequilibrium mapping approach in seven-candidate genes with a well-established link to dopamine (DRD2, DRD3, ACE, COMT, DAT, MAO-A, MAO-B). From a cohort of 321 psychiatric inpatients, 81 cases presenting with EPS (Simpson–Angus >3) and 189 controls presenting without EPS (Simpson–Angus ⩽3) took part. Eighty-four-tag single nucleotide polymorphisms (SNPs) in candidate genes were genotyped. After extensive data cleaning, 70 SNPs were analyzed for association of single markers and haplotypes. AP dosage, AP-DRD2 blockade potency and age were identified as susceptibility factors for AP-induced EPS. One SNP of the DRD3 gene, rs167771, achieved significant association with EPS risk after Bonferroni correction (nominal P-value 1.3 × 10−4) in the patients treated with risperidone (132 patients). AP-induced EPS remains a serious public health problem. Our finding of a common SNP (rs167771) in the DRD3 gene provides a strong new candidate gene for risperidone-induced EPS.