Progressive loss of cortical gray matter in first episode psychosis patients with auditory hallucinations.

BACKGROUND: Previous longitudinal magnetic resonance imaging studies have shown progressive gray matter (GM) reduction during the earliest phases of schizophrenia. It is unknown whether these progressive processes are homogeneous in all groups of patients. One way to obtain more valid findings is to focus on the symptoms. Auditory hallucinations (AHs) are frequent and reliable symptoms of psychosis. The present study aims to analyze whether longitudinal changes in structural abnormalities in cortical regions are related to the presence of AHs and the intensity of psychotic symptoms in a large sample. METHODS: A Magnetic Resonance (MR) voxel-based morphometry analysis was applied to a group of 128 first episodes psychosis (FEP) patients (63 patients with AHs and 65 patients without AHs) and 78 matched healthy controls at baseline and at a 2-year follow-up. RESULTS: At baseline, FEP patients exhibited significant GM volume reductions in the temporal, frontal and precentral regions. At follow-up, FEP patients exhibited GM volume changes in the temporal, Rolandic, frontal, precentral and insula regions. At baseline, no significant differences were found between FEP patients with and without AHs. At follow-up, while FEP patients with AHs showed less GM volume in temporal and frontal lobes, non-AH FEP patients showed reductions in the frontal, precentral and fusiform areas. PANSS scores showed statistically significant correlations with GM volume reductions at baseline and follow-up. CONCLUSIONS: Brain cortical loss in the early phases of psychosis is not associated with potentially transitory AHs; however, brain structural changes may emerge as AHs appear in chronic patients.

The polygenic basis of relapse after a first episode of schizophrenia.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study.

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness.

Relapse of first-episode schizophrenia patients and neurocognitive impairment: The role of dopaminergic and anticholinergic burden.

BACKGROUND: The prevention of relapse may be a key factor to diminish the cognitive impairment of first-episode schizophrenia (FES) patients. We aimed to ascertain the effects of relapse, and dopaminergic and anticholinergic treatment burdens on cognitive functioning in the follow-up. METHODS: Ninety-nine FES patients participated in this study. Cognitive assessments were performed at baseline and after 3 years of follow-up or, in those patients who relapsed, after >2 months of stabilization of the new acute psychotic episode. The primary outcomes were final cognitive dimensions. RESULTS: Repeated measures MANOVA analyses showed improvements in the whole sample on the end-point assessments in processing speed and social cognition. However, only impairment in social cognition showed a significant interaction with relapse by time in this sample. Relapse in FES patients was significantly associated with poor performance on end-point assessments of working memory, social cognition and global cognitive score. Anticholinergic burden, but not dopaminergic burden, was associated with verbal memory impairment. These significant associations resulted after controlling for baseline cognitive functioning, relapse and dopaminergic burden. CONCLUSIONS: The relationship between relapse and cognitive impairment in recovered FES patients seems to be particularly complex at the short-term follow-up of these patients. While relapse was associated with working memory, social cognition impairments and global cognitive score, anticholinergic burden might play an additional worsening effect on verbal memory. Thus, tailoring or changing antipsychotics and other drugs to reduce their anticholinergic burden may be a potential modifiable factor to diminish cognitive impairment at this stage of the illness.

Clinical and treatment predictors of relapse during a three-year follow-up of a cohort of first episodes of schizophrenia.

Relapses are frequent in the first years following a first episode of schizophrenia (FES), being associated with a higher risk of developing a chronic psychotic disorder, and poor clinical and functional outcomes. The identification and intervention over factors associated with relapses in these early phases are timely and relevant. In this study, 119 patients in remission after a FES were closely followed over three years. Participants came from the 2EPS Project, a coordinated, naturalistic, longitudinal study of 15 tertiary centers in Spain. Sociodemographic, clinical, treatment and substance abuse data were analyzed. 49.6% of the participants relapsed during the 3-years follow-up. None of the baseline demographic and clinical characteristics analyzed showed a statistically significant association with relapses. 22% of patients that finished the follow-up without relapsing were not taking any antipsychotic. The group that relapsed presented higher mean antipsychotics doses (381.93 vs. 242.29 mg of chlorpromazine equivalent/day, p = 0.028) and higher rates of antipsychotic polytherapy (28.6% vs. 13%, p < 0.001), benzodiazepines use (30.8% vs. 8.5%, p < 0.001), side effects reports (39.2% vs. 25%, p = 0.022), psychological treatment (51.8% vs. 33.9%, p = 0.03), and cannabis consumption (93.2% vs. 56.7%, p < 0.001). Clozapine use was notably higher in the group that reminded in remission (21.7% vs. 8.2%, p < 0.019). These findings may guide clinicians to detect subgroups of patients with higher risk to present a second episode of psychosis, focusing on measures to ensure an adequate treatment or facilitating cannabis use cessation. This study supports future research to identify relapse prevention strategies for patients in early phases of schizophrenia.

The role of BDNF and NGF plasma levels in first-episode schizophrenia: A longitudinal study.

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associations between these neurotrophins and the symptomatology severity through different stages after a FES in two independent cohorts. 2EPs-Cohort: 69 first-episode in clinical remission were included. BDNF/NGF plasma levels and symptom severity were measured at enrollment and at 3-year or at the time of the second episode/relapse. FLAMM-PEPs-Cohort: 65 first-episodes were also included. BDNF/NGF and symptom severity were obtained at enrollment and 2-year follow-up. Symptomatology was assessed with the Marder-PANSS-Factor scores. Plasma neurotrophins did not differ significantly over time and neither BDNF/NGF were predictors of relapse. Besides, in remission stages, baseline BDNF levels showed significant correlations with both positive and negative symptoms (p<0.05); NGF, with negative symptomatology (p<0.01). Similarly, in the FLAMM-PEPs-Cohort, baseline BDNF/NGF levels showed significant correlations with negative symptoms (and not positive symptomatology) at follow-up (p<0.05). In both cohorts, lower levels correlated with higher symptom severity. Findings did not support a role for BDNF/NGF plasma levels as biomarkers of relapse in FES patients. Nevertheless, baseline BDNF/NGF may lead to be considered potentially useful biomarkers of long-term severity in schizophrenia and of the underlying illness traits, specially of negative symptomatology severity. More longitudinal studies in FES samples and adding a control group are warranted to replicate these findings.

Motor abnormalities and basal ganglia in first-episode psychosis (FEP).

BACKGROUND: Motor abnormalities (MAs) are the primary manifestations of schizophrenia. However, the extent to which MAs are related to alterations of subcortical structures remains understudied. METHODS: We aimed to investigate the associations of MAs and basal ganglia abnormalities in first-episode psychosis (FEP) and healthy controls. Magnetic resonance imaging was performed on 48 right-handed FEP and 23 age-, gender-, handedness-, and educational attainment-matched controls, to obtain basal ganglia shape analysis, diffusion tensor imaging techniques (fractional anisotropy and mean diffusivity), and relaxometry (R2*) to estimate iron load. A comprehensive motor battery was applied including the assessment of parkinsonism, catatonic signs, and neurological soft signs (NSS). A fully automated model-based segmentation algorithm on 1.5T MRI anatomical images and accurate corregistration of diffusion and T2* volumes and R2* was used. RESULTS: FEP patients showed significant local atrophic changes in left globus pallidus nucleus regarding controls. Hypertrophic changes in left-side caudate were associated with higher scores in sensory integration, and in right accumbens with tremor subscale. FEP patients showed lower fractional anisotropy measures than controls but no significant differences regarding mean diffusivity and iron load of basal ganglia. However, iron load in left basal ganglia and right accumbens correlated significantly with higher extrapyramidal and motor coordination signs in FEP patients. CONCLUSIONS: Taken together, iron load in left basal ganglia may have a role in the emergence of extrapyramidal signs and NSS of FEP patients and in consequence in the pathophysiology of psychosis.

Is cognitive impairment associated with antipsychotic dose and anticholinergic equivalent loads in first-episode psychosis?

BACKGROUND: Cognitive deficits are a core feature of early stages in schizophrenia. However, the extent to which antipsychotic (AP) have a deleterious effect on cognitive performance remains under debate. We aim to investigate whether anticholinergic loadings and dose of AP drugs in first episode of psychosis (FEP) in advanced phase of remission are associated with cognitive impairment and the differences between premorbid intellectual quotient (IQ) subgroups. METHODS: Two hundred and sixty-six patients participated. The primary outcomes were cognitive dimensions, dopaminergic/anticholinergic load of AP [in chlorpromazine equivalents (Eq-CPZ) and the Anticholinergic Risk Scale (ARS), respectively]. RESULTS: Impairments in processing speed, verbal memory and global cognition were significantly associated with high Eq-CPZ and verbal impairment with high ARS score. Moreover, this effect was higher in the low IQ subgroup. CONCLUSIONS: Clinicians should be aware of the potential cognitive impairment associated with AP in advanced remission FEP, particularly in lower premorbid IQ patients.

Motor abnormalities and cognitive impairment in first-episode psychosis patients, their unaffected siblings and healthy controls.

Motor abnormalities (MAs) may be already evidenced long before the beginning of illness and are highly prevalent in psychosis. However, the extent to which the whole range of MAs are related to cognitive impairment in psychosis remains understudied. This study aimed to examine comparatively the relationships between the whole range of motor abnormalities and cognitive impairments in the first-episode of psychosis (FEP), their unaffected siblings and healthy control subjects. Fifty FEP patients, 21 of their healthy siblings and 24 age- and sex matched healthy controls were included. Motor assessment included catatonic, extrapyramidal and neurological soft signs (NSS) by means of standardized instruments. An exhaustive neuropsychological battery was also performed to extract the 7 cognitive dimensions of MATRICS initiative. Higher scores on NSS but not on extrapyramidal and catatonic signs showed significant associations with worse cognitive performance in the three study groups. However, the pattern of associations regarding specific cognitive functions was different among the three groups. Moreover, extrapyramidal signs showed significant associations with cognitive impairment only in FEP patients but not in their unaffected siblings and healthy controls. Catatonic signs did not show any significant association with cognitive functioning in the three study groups. These findings add evidence to the associations between motor abnormalities, particularly NSS and extrapyramidal signs, and cognitive impairment in first-episode psychosis patients. In addition, our results suggest that the specific pattern of associations between MAs and cognitive functioning is different in FEP patients from those of the unaffected siblings and healthy subjects.

Basal ganglia and ventricle volume in first-episode psychosis. A family and clinical study.

Patients with first-episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. We sought to compare ventricle and basal ganglia volumes in FEP patients (n = 50) with those in unaffected relatives (n = 21) and healthy controls (n = 24). Participants were assessed with a semistructured interview and underwent structural magnetic resonance imaging (MRI). Patients had significantly larger left lateral, right lateral and third ventricle volumes than their siblings and larger third ventricle volumes than controls. Additionally, they showed a trend toward significance by having larger right caudate nuclei than controls. Moreover, FEP patients showed lower caudate and putamen laterality indexes (leftward shifts) than healthy controls but not regarding their siblings. Besides, negative dimension was directly associated with lateral and third ventricle volumes and positive dimension with thalamus and ventral diencephalon nuclei. Our findings added evidence to the associations between early enlargement of brain ventricles and negative symptoms, and between early enlargement of thalamic and ventral-diencephalon nuclei and positive symptoms. Moreover, the cumulative exposition to antipsychotics in FEP patients might be related to enlargement of certain subcortical structures, such as the right nucleus accumbens and third ventricle.

Evidence for association between structural variants in lissencephaly-related genes and executive deficits in schizophrenia or bipolar patients from a Spanish isolate population.

There is evidence for an association between structural variants in genes for lissencephaly, which are involved in neuronal migration, and prefrontal cognitive deficits in schizophrenia and bipolar patients. On the basis of these intriguing findings, we analyzed 16 markers located in the lissencephaly critical region (LCR in chromosome 17p13.3) in 124 schizophrenic, 56 bipolar, and 141 healthy individuals. All recruits were from a Spanish population isolate of Basque origin that is characterized by low genetic heterogeneity. In addition, we examined whether structural genomic variations in the LCR were associated with executive cognition. Twenty-three patients (12.8%), but none of the controls, showed structural variants (deletions and insertions) in either of two markers related with lissencephaly (D17S1566 on tumor suppressor gene TP53: tumor protein p53 and D17S22 on SMG6 gene: Smg-6 homolog, nonsense mediated mRNA decay factor- Caenorhabditis elegans). These patients performed significantly worse in the Wisconsin Card Sorting Test-Categories in comparison with patients without such variations in lissencephaly-related genes. The presence of structural variants was related to completed categories, and accounted for 10.7% of the variance (P=0.001). Finally, logistic regression showed that poor Wisconsin Card Sorting Test-Categories performance was the only predictor of belonging to the positive LCR variations group. These new findings provide further evidence for the association between some lissencephaly-related genes and both schizophrenia and bipolar disorder, and influence on frontal executive functioning.

The high-activity Val allele of the catechol-O-methyltransferase gene predicts greater cognitive deterioration in patients with psychosis.

The objective of this study was to examine whether the functional genetic polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene influences cognitive deterioration in a sample of patients with psychosis under treatment with atypical antipsychotics. Eighty-seven patients with psychosis were genotyped for this polymorphism and were assessed with three Wechsler Adult Intelligence Scale (WAIS)-III subtests (Vocabulary, Information, and Digit Symbol-Coding). Performance on these three subtests was used to compute a 'cognitive deterioration index', and the effect of COMT genotype on this cognitive deterioration index was examined. A linear relationship between the number of Val alleles and the score on the cognitive deterioration index (i.e. the more Val alleles, the more cognitive deterioration) was observed. These results confirm the role of COMT genotype in the cognition of patients under treatment for psychosis, suggesting that it influences the extent of their cognitive deterioration.