Iluminada Corripio

Striatal D2 receptor binding as a marker of prognosis and outcome in untreated first-episode psychosis

In a preliminary 123I-IBZM SPECT study in first-episode psychosis, a relationship between striatal dopaminergic D2 receptor (D2R) binding and premorbid adjustment was suggested. These results were replicated in the present study (n = 18), and D2R binding at diagnosis predicted a high probability for schizophrenia outcome by 2-year follow-up. The present findings contribute to the evidence of abnormal D2R binding in schizophrenia and suggest that SPECT might be useful for outcome prediction in first-episode psychosis.

Resting-state functional connectivity alterations in the default network of schizophrenia patients with persistent auditory verbal hallucinations

To understand the neural mechanism that underlies treatment resistant auditory verbal hallucinations (AVH), is still an important issue in psychiatric research. Alterations in functional connectivity during rest have been frequently reported in patients with schizophrenia. Though the default mode network (DN) appears to be abnormal in schizophrenia patients, little is known about its role in resistant AVH. We collected resting-state functional magnetic resonance imaging (R-fMRI) data with a 3T scanner from 19 schizophrenia patients with chronic AVH resistant to pharmacological treatment, 14 schizophrenia patients without AVH and 20 healthy controls. Using seed-based correlation analysis, we created spherical seed regions of interest (ROI) to examine functional connectivity of the two DN hub regions (posterior cingulate cortex and anteromedial prefrontal cortex) and the two DN subsystems: dorsomedial prefrontal cortex subsystem and medial temporal lobe subsystem (p<0.0045 corrected). Patients with hallucinations exhibited higher FC between dMPFC ROI and bilateral central opercular cortex, bilateral insular cortex and bilateral precentral gyrus compared to non hallucinating patients and healthy controls. Additionally, patients with hallucinations also exhibited lower FC between vMPFC ROI and bilateral paracingulate and dorsal anterior cingulate cortex. As the anterior cingulate cortex and the insula are two hubs of the salience network, our results suggest cross-network abnormalities between DN and salience system in patients with persistent hallucinations.

Pharmacokinetics and time-course of D2 receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients

The 123I-IBZM SPECT measured D2 receptor occupancy (D2RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D2 receptor occupancy (D 2RO) and plasma concentration (C P) in stabilized schizophrenic patients on clinically relevant doses using 123I-IBZM SPECT; 2) To investigate the time course of AP-induced D2RO and corresponding C P. Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D 2RO and C P were measured over time following a sparse-sampling experimental design, and individual PK and D2RO-time profiles were estimated using a population approach. Observed striatal D2RO and C P ranges were 28—75% and 9.4—60.5 ng/mL for risperidone, 22—84% and 8.6—89.5 ng/mL for olanzapine, 5—53% and 41.6—818.2 ng/mL for clozapine and 0—64% and 37.9—719.6 ng/mL for quetiapine. A PK—D2RO relationship was found for the four APs. D2RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D2RO and C P at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D2RO below 65%. D2RO patterns over time differ between AP. These results should be considered for accurate interpretation of D2RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

One-year, randomized, open trial comparing olanzapine, quetiapine, risperidone and ziprasidone effectiveness in antipsychotic-naive patients with a first-episode psychosis

The aim of this study was to compare the 12-month effectiveness of several second-generation antipsychotic drugs, with that of haloperidol in never-treated patients with first-episode psychosis. In total, 114 patients without life time exposure to any psychotropic medication were randomized to haloperidol, olanzapine, risperidone, quetiapine or ziprasidone. Primary outcome was time to all-cause discontinuation. Secondary outcomes included discontinuation rates and symptom change as measured by the Positive and Negative Syndrome Scale (PANSS). The overall discontinuation rate 64%. At 12 months, the proportion of patients discontinuing treatment was 40.0% for olanzapine, 56.5% for quetiapine, 64.0% for risperidone, 80.0% for ziprasidone and 85.7% for haloperidol. Mean time to antipsychotic discontinuation was higher in patients randomized to second-generation antipsychotics than in those taking haloperidol. Significantly lower discontinuation was noted in patients on olanzapine than on haloperidol, or ziprasidone. Our results suggest that olanzapine might lead to longer treatment continuation in treatment naïve FEP patients than haloperidol and, possibly ziprasidone. Global psychopathology was significantly less reduced by haloperidol than with each individual SGA in this earliest phase of treatment.

Dopamine D2 receptor occupancy by risperidone: Implications for the timing and magnitude of clinical response

The objective of the study is to investigate whether dopamine D2 receptor occupancy by risperidone and plasma levels over time can account for therapeutic efficacy and the latency period to response. Thirty-eight examinations with (123)I-IBZM single photon emission computed tomography were performed on 22 patients with schizophrenia, at diagnosis, 48 h after starting risperidone treatment and at a stable dose. Risperidone plasma levels were determined and psychopathologic evaluations (Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale) were carried out. No differences in the striatal/occipital (S/O) ratio or plasma levels were found between examinations at the 48-h time point and when a stable dose level had been established, so these parameters could not account for the latency period required for clinical response. D2 receptor occupancy at 48 h correlated positively with clinical improvement after 2 weeks of treatment. Therefore, if these results are confirmed, D2 receptor occupancy at the beginning of treatment with risperidone may be a predictor of subsequent clinical response.

Predictors of schizophrenia in patients with a first episode of psychosis

Early identification of schizophrenia in patients with a first episode of psychosis (FEP) may help to avoid inappropriate treatment and may enhance long-term outcome by addressing issues such as family network, treatment adherence and functional and symptomatic outcome. It was the aim of the study to determine baseline variables that significantly predicted a diagnosis of schizophrenia in patients with FEP. The sample consisted of 133 FEP patients hospitalized for at least 6 weeks, in whom a DSM-IV diagnosis was confirmed after 1 year follow-up. Patients were divided into two groups, those with a diagnosis of schizophrenia (Schizophrenia group, n=63; 47.8%), and those with other psychosis, who were grouped under Non-Schizophrenic Psychosis (NSP, n=70; 52.2%). Sociodemographic (marital status, educational level) and clinical variables were recorded for each patient. Substance use (alcohol, cannabis and cocaine) did not statistically differ between the two groups. Absence of characteristics defined as criteria for good prognosis, lack of > or = 20% improvement in the total Positive and Negative Syndrome Scale score at 6 weeks, and a poor premorbid adjustment as determined by the Premorbid Adjustment Scale score significantly predicted the presence of schizophrenia. The regression model including these three variables achieved a predictive value of 76.3%, with a sensitivity of 74.6% and a specificity of 77.9%.

Density of striatal D2 receptors in untreated first-episode psychosis: an I123-IBZM SPECT study.

There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway - yielding to an increase of the postsynaptic D2 receptors - may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n=37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F=10.2, p<0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p=0.006), and between schizophrenia and control groups (p<0.001) but no differences between non-schizophrenia and control groups (p=0.9). The logistic regression model showed that D2R binding (p=0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p=0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R(2)=0.59; X(2)=11.08, p=0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.

Preliminary evidence of striatal D2 receptor density as a possible biological marker of prognosis in naive schizophrenic patients.

UNLABELLED With the aim of investigating a possible biological marker of prognosis in schizophrenia, the relationship between striatal dopaminergic D2 receptor (D2R) density and clinical prognostic factors was studied in an initial sample of nine neuroleptic-naive schizophrenic patients. Previous psychosocial adaptation was evaluated by means of the Premorbid Adjustment Scale (PAS). Based on the four DSM-IV criteria in schizophreniform disorder for good prognosis, patients were divided in two groups: good prognosis if > or =2 criteria were met (n=5) and poor prognosis if <2 criteria were met (n=4). D2R density was assessed by means of 123I-IBZM single photon emission computed tomography (SPECT) and striatum/occipital uptake ratios (S/O). S/O ratios previously obtained from a control group of nine age- and sex-matched healthy volunteers were used for comparison. RESULTS Patients with poor prognosis showed a higher S/O ratio (mean=1.94, range=1.93-1.98) than patients with good prognosis (mean=1.64, range=1.52-1.79) and the control group (mean=1.69, range=1.51-1.85) [analysis of variance (ANOVA) F=10.628, df=2, P=.001, post hoc Scheffé P<.005]. PAS scores were significantly different between patients with good and poor prognosis (40+/-9.39 vs. 84.25+/-26, Mann-Whitney U-test P=.014). A direct correlation of S/O ratios with PAS scores was found (Spearman r=.72, P=.028). CONCLUSIONS Striatal D2R density in naive schizophrenic patients may be related to DSM-IV prognostic factors and premorbid adjustment criteria (PAS). If these preliminary results are confirmed, striatal D2R density might predict premorbid and clinical features associated with poor prognosis in neuroleptic-naive patients.

Cannabis use and striatal D2 receptor density in untreated first-episode psychosis: An in vivo SPECT study

The biological basis of the association between cannabis-induced dopamine dysregulation and psychosis remains poorly understood. This (123)I-IBZM SPECT study assessed striatal dopamine D2 receptor (D2R) binding in 37 untreated first-episode psychosis (FEP) subjects, and 18 healthy controls. The aim was to examine if there were differences between FEP subjects with (n=14) and without (n=23) cannabis use in uptake ratios in the D2R. Striatal/Frontal cortex (S/F) uptake ratios were obtained. Healthy controls showed the lowest D2R binding ratios. No differences were found in S/F ratios between users and non-users, suggesting similar dopaminergic mechanisms underlying psychotic symptoms in both groups.

Double-Blind, Placebo-Controlled Study of the Efficacy of Reboxetine and Citalopram as Adjuncts to Atypical Antipsychotics for Negative Symptoms of Schizophrenia

OBJECTIVE In this study, we assessed the efficacy of 2 pharmacodynamically different antidepressants, citalopram (a selective serotonin reuptake inhibitor) and reboxetine (a norepinephrine reuptake inhibitor), as adjunctive therapy to risperidone and olanzapine for the treatment of negative symptoms in schizophrenia. METHOD We performed a 6-month, multicenter, double-blind, randomized, placebo-controlled clinical trial. The recruitment period was from November 2008 to December 2011.The sample comprised 90 patients with a diagnosis of schizophrenia (DSM-IV criteria) who exhibited negative symptoms. The patients were recruited from 10 centers in different cities of the Spanish State. The primary efficacy measure was change in score on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) between baseline and 6-month assessment. Other efficacy measures were changes in the PANSS subscales and total score, as well as the Scale for the Assessment of Negative Symptoms (SANS) subscales and total score. RESULTS For statistical analysis, we employed mixed-effects models. We did not find statistically significant differences between the placebo group and the 2 treatment groups at 6-month assessments for the PANSS total (P=.6511), any PANSS subscale (negative [P=.5533], positive [P=.1723], or general psychopathology [P=.2083]), or the SANS (P= .5884). Cohen d measure showed a small effect size below the 0.5 threshold for all comparisons. CONCLUSIONS In conclusion, our results do not support adjunctive use of citalopram or reboxetine with risperidone or olanzapine for the treatment of negative symptoms in schizophrenia. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01300364.