Signs and symptoms in the pre-psychotic phase: description and implications for diagnostic trajectories

BACKGROUND: Few studies have examined the underlying factor structure of signs and symptoms occurring before the first psychotic episode. Our objective was to determine whether factors derived from early signs and symptoms are differentially associated with non-affective versus affective psychosis. METHOD: A principal components factor analysis was performed on early signs and symptoms reported by 128 individuals with first-episode psychosis. Factor scores were examined for their associations with duration of untreated illness, drug abuse prior to onset of psychosis, and diagnosis (schizophrenia versus affective psychosis). RESULTS: Of the 27 early signs and symptoms reported by patients, depression and anxiety were the most frequent. Five factors were identified based on these early signs and symptoms: depression, disorganization/mania, positive symptoms, negative symptoms and social withdrawal. Longer duration of untreated illness was associated with higher levels of depression and social withdrawal. Individuals with a history of drug abuse prior to the onset of psychosis scored higher on pre-psychotic depression and negative symptoms. The two mood-related factors, depression and disorganization/mania, distinguished the eventual first-episode diagnosis of affective psychosis from schizophrenia. Individuals with affective psychosis were also more likely to have a 'mood-related' sign and symptom as their first psychiatric change than individuals later diagnosed with schizophrenia. CONCLUSIONS: Factors derived from early signs and symptoms reported by a full diagnostic spectrum sample of psychosis can have implications for future diagnostic trajectories. The findings are a step forward in the process of understanding and characterizing clinically important phenomena to be observed prior to the onset of psychosis.     

What does the Edinburgh high-risk study tell us about schizophrenia?

The Edinburgh High Risk Study concerns 162 young people aged 16 to 25 at ascertainment who have at least two close relatives with schizophrenia. They are compared with two control groups (1) of age-matched well subjects and (2) of age-matched subjects with first schizophrenic episodes. The interim results show that schizophrenia has developed in 10 high-risk subjects and no controls and that all categories of psychopathology are more marked in the high-risk subjects. Psychopathology shows no relationships with measures of genetic liability. Neuropsychological measures are most impaired in the individuals with first-episode schizophrenia, with high-risk subjects performing better and well controls better still. The greater the genetic liability of the high-risk subjects, the poorer the neuropsychological performance. Neuropsychological impairments occurred in more high-risk subjects than are expected to develop schizophrenia. Structural brain scans show significant differences between those with first-episode schizophrenia, high-risk subjects, and well controls. Brain structure is related to genetic liability in that high-risk subjects with higher genetic liability have smaller right and left prefrontal lobes and smaller right and left thalami. In those high-risk subjects with two scans, there was a significantly greater reduction in temporal lobe size in those with psychotic symptoms than in those without. It is suggested that in high-risk subjects, the change from vulnerability to psychosis may be preceded by reduction in size and deteriorating function of the temporal lobe.     

A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia

BACKGROUND: Diffusion tensor imaging (DTI) can be used to investigate cerebral structural connectivity in never-medicated individuals with first-episode schizophrenia. METHOD: Subjects with first-episode schizophrenia according to DSM-IV-R who had never been exposed to antipsychotic medication (n=25) and healthy controls (n=26) were recruited. Groups were matched for age, gender, best parental socio-economic status and ethnicity. All subjects underwent DTI and structural magnetic resonance imaging (MRI) scans. Voxel-based analysis was performed to investigate brain regions where fractional anisotropy (FA) values differed significantly between groups. A confirmatory region-of-interest (ROI) analysis of FA scores was performed in which regions were placed blind to group membership. RESULTS: In patients, FA values significantly lower than those in healthy controls were located in the left fronto-occipital fasciculus, left inferior longitudinal fasciculus, white matter adjacent to right precuneus, splenium of corpus callosum, right posterior limb of internal capsule, white matter adjacent to right substantia nigra, and left cerebral peduncle. ROI analysis of the corpus callosum confirmed that the patient group had significantly lower mean FA values than the controls in the splenium but not in the genu. The intra-class correlation coefficient (ICC) for independent ROI measurements was 0.90 (genu) and 0.90 (splenium). There were no regions where FA values were significantly higher in the patients than in the healthy controls. CONCLUSIONS: Widespread structural dysconnectivity, including the subcortical region, is already present in neuroleptic-naive patients in their first episode of illness.     

Reduced visual P300 amplitudes in individuals at ultra-high risk for psychosis and first-episode schizophrenia

The purpose of this study was to investigate whether individuals at ultra-high risk (UHR) for psychosis and patients experiencing first-episode schizophrenia had impairments in visual information processing as indexed by the visual P300 event-related potential. Sixteen UHR individuals, 21 first-episode schizophrenia patients, and 16 healthy controls were included. Participants were asked to perform a visuospatial oddball task while undergoing an electroencephalogram. The UHR and first-episode groups showed reduced P300 amplitudes in comparison to healthy controls. P300 amplitudes were negatively correlated with severity of negative symptoms in both the UHR and first-episode groups. These results suggest that the visual P300 may be a neurobiological vulnerability marker, reflecting neurophysiological abnormalities associated with enduring negative symptoms in schizophrenia.     

Preserved priming effect in individuals with schizophrenia: cues towards rehabilitation

Introduction. Individuals with schizophrenia and affective disorders show relatively intact implicit memory as compared to declarative memory. Implicit memory is usually assessed with skill learning and priming tasks. Whereas priming is thought to involve storage changes in the posterior neocortex, skill learning is thought to rely more on the corticostriatal pathway. Since frontostriatal and frontotemporal dysfunctions are, respectively, found in schizophrenia and affective disorders, we hypothesised that individuals with schizophrenia and first-episode psychosis would exhibit disturbances in skill learning, but not priming.

Methods. Thirty-five patients (11 first-episode psychosis; 11 schizophrenia; 13 affective disorders) and 10 controls completed a procedural learning and priming task. Participants had to identify fragmented images throughout five training sessions. The improvement of the threshold at which the images could be identified between the first and last session was used as an index of procedural learning. In a final session, the identification thresholds for old and new images were compared to assess the priming effect.

Results. Whereas individuals with schizophrenia and first-episode psychosis showed impaired skill learning, the priming effect was similar in all groups.

Conclusion. Even though some aspects of learning and memory are affected in schizophrenia, our results suggest that the posterior cortical pathway remains efficient at modulating the priming effect. This intact ability could be used to guide the elaboration of new rehabilitation programmes.     

Resting EEG in first-episode schizophrenia patients, bipolar psychosis patients, and their first-degree relatives

We evaluated the resting electroencephalogram (EEG) of 50 first-episode schizophrenia patients and 55 of their relatives, 31 first-episode bipolar patients and 35 of their relatives, and 113 nonpsychiatric subjects and 42 of their relatives. The frequency characteristics of the EEG showed moderate stability for a subgroup of these subjects (n= 106) who were tested twice, approximately 9 months apart. Both the schizophrenia and bipolar patients showed a generalized pattern of increased delta and theta and decreased alpha activity. The bipolar patients demonstrated additional right hemisphere activity that was not present among the schizophrenia patients and nonpsychiatric subjects, a finding consistent with hypotheses concerning nondominant hemisphere involvement in the regulation of elated mood. The schizophrenia patients' female relatives and/or relatives with affective disorders and the bipolar patients had significantly reduced peak alpha frequencies. This finding may be related to reduced information processing capacity among these subjects.     

Schizophrenia, temporal lobe epilepsy and psychosis: an in vivo magnetic resonance spectroscopy and imaging study of the hippocampus/amygdala complex

BACKGROUND: We have used proton magnetic resonance imaging and spectroscopy to measure hippocampus/amygdala volumes and anterior hippocampal metabolite concentrations (N-acetyl aspartate (NAA), creatine/phosphocreatine and choline) in subjects with temporal lobe epilepsy (TLE), schizophrenia and in normal controls. METHOD: Four groups of right-handed patients were selected: 12 with TLE and psychosis (EP), 12 with TLE and no psychosis (ENP), 26 with schizophrenia, and 38 normal controls. Imaging and spectroscopy were performed with a 1.5T Signa GE scanner. RESULTS: The schizophrenia group showed a significant left-sided reduction in all metabolites. In the epilepsy groups NAA was reduced bilaterally. The NAA reduction in the EP group was greater than in the ENP group, especially on the left, although the result did not reach significance. Total hippocampus/amygdala volumes showed no significant differences in any of the groups when compared with normal controls. When compared with controls significant, specific regional volume reductions were present bilaterally in the EP group and in the left hippocampus/amygdala in schizophrenia. The regional volume reduction found in schizophrenia was also present in EP but not in ENP. CONCLUSION: Spectroscopic abnormalities were more pronounced in the epilepsy groups and were bilateral, and abnormalities in schizophrenia were left sided. Specific regional hippocampus/amygdala volume reductions were more marked in the EP group and were bilateral. Left-sided regional volume reduction identified in the dominant hemisphere of schizophrenics was also present in EP patients, but not in ENP, suggesting that this region in the left temporal lobe may be significant in the aetiology of psychosis. This is further supported by the predominantly left-sided NAA reduction in schizophrenia. High resolution morphometric studies may identify specific regions of the brain associated with the development of psychosis.     

Minor physical anomalies in non-familial unipolar recurrent major depression

BACKGROUND: The prevalence of minor physical anomalies (MPAs) was evaluated in patients with unipolar recurrent major depression to get indirect data on the possible role of aberrant neurodevelopment in the aetiology of major depression. One published study [Lohr et al., Am. J. Geriatr. Psychiatry 5 (1997) 318] on the MPA prevalence in unipolar depression, evaluated by the recently widely criticized Waldrop-scale, reports on a significantly higher MPA rate among patients. METHODS: A scale developed by Méhes [Prog. Clin. Biol. Res. 163 (1985) 45] was used to detect the presence or absence of 57 MPAs in 30 patients with major depression and in 30 matched controls. RESULTS: The depressive sample did not differ significantly from the control group (P=0.200). By comparing each MPA individually we could not find any significant differences between the depressive and the control sample. LIMITATIONS: Patients and control subjects had a negative family history in connection with affective disorders; a high-risk population should give significant positive results. CONCLUSIONS: The results do not support the role of an 'early neurodevelopmental origin' in unipolar depression.     

Does treatment delay in first-episode psychosis really matter?

BACKGROUND: Relatively few predictors of outcome in first-episode psychosis are potentially malleable and duration of untreated psychosis (DUP) is one. However, the degree to which DUP is mediated by other predictors of outcome is unclear. This study examines the specific effects of DUP on 12-month outcome after adjusting for effects of potential confounders and moderating variables. METHOD: The sample comprised 354 first-episode psychosis patients followed up 12-months after remission/stabilization of their psychotic symptoms. Outcome measures included functional outcome, severity of positive symptoms and negative symptoms. Hierarchical multiple regression assessed whether DUP significantly predicted 12-month outcome after adjusting for other predictors. Contrast analysis further clarified the differential effects of DUP on 12-month outcome. RESULTS: DUP remained a significant predictor of outcome after adjusting for the effects of other variables. This finding remained robust for the subset of patients with schizophrenia or schizophreniform disorder. Functional outcome appeared to decline substantially even after very short treatment delays (> 7 days), with more gradual deterioration in functioning until very long DUP (> 1 year). Good outcome was variably associated with good pre-morbid adjustment, female gender, diagnosis of affective disorder, short duration of prodromal symptoms, and treatment within the Early Psychosis Prevention and Intervention model in contrast to other models of care. CONCLUSIONS: DUP consistently predicts outcome independently of other variables, and is not simply a proxy for other factors. As one of the few potentially malleable factors influencing outcome, DUP could prove to be a target for secondary preventive efforts in early psychosis.     

Cannabis abuse is associated with decision-making impairment among first-episode patients with schizophrenia-spectrum psychosis

BACKGROUND: Cannabis use appears to be a risk factor for schizophrenia. Moreover, cannabis abusers show impaired decision-making capacities, linked to the orbitofrontal cortex (OFC). Although there is substantial evidence that first-episode schizophrenia patients show impairments in cognitive tasks associated with the dorsolateral prefrontal cortex (DLPFC), it is not clear whether decision making is impaired at schizophrenia onset. In this study, we examined the association between antecedents of cannabis abuse and cognitive impairment in cognitive tasks associated with the DLPFC and the OFC in a sample of first-episode patients with schizophrenia-spectrum disorders.MethodOne hundred and thirty-two patients experiencing their first episode of a schizophrenia-spectrum psychosis were assessed with a cognitive battery including DLPFC-related tasks [backward digits, verbal fluency (FAS) and the Trail Making Test (TMT)] and an OFC-related task [the Iowa Gambling Task (GT)]. Performance on these tasks was compared between patients who had and had not abused cannabis before their psychosis onset. RESULTS: No differences were observed between the two groups on the performance of any of the DLPFC-related tasks. However, patients who had abused cannabis before their psychosis onset showed a poorer total performance on the gambling task and a lower improvement on the performance of the task compared to no-abusers. CONCLUSIONS: Pre-psychotic cannabis abuse is associated with decision-making impairment, but not working memory and executive function impairment, among first-episode patients with a schizophrenia-spectrum psychosis. Further studies are needed to examine the direction of causality of this impairment; that is, does the impairment make the patients abuse cannabis, or does cannabis abuse cause the impairment?     

首发精神分裂症及其健康同胞神经心理功能的比较

目的:探讨首发精神分裂症患者及其健康同胞神经心理功能差异。方法:采用范畴流利测验、连线测验(TMT)、数字符号编码测验和Stoop测验对在92例首发精神分裂症患者、56例健康同胞及62例健康对照者进行测评。结果:首发精神分裂症患者及其健康同胞所有神经心理测验成绩均差于健康对照组(P<0.05)。与健康同胞组比较,首发精神分裂症患者组除范畴流利测验外,其他神经心理测验成绩差异均有统计学意义(P<0.05)。结论:首发精神分裂症患者及其健康同胞存在认知损害,语义流畅性功能可能是精神分裂症的潜在内表型。     

Impaired verbal self-monitoring in psychosis: effects of state, trait and diagnosis

BACKGROUND: Cognitive models propose that auditory verbal hallucinations arise through defective self-monitoring and external attribution of inner speech. We used a paradigm that engages verbal self-monitoring to examine how deficits in this process are related to symptoms and diagnosis in patients with psychosis. METHOD: We tested 45 patients with schizophrenia. Fifteen had current auditory hallucinations, 15 had a history of (but no current) auditory hallucinations, and 15 had delusions but neither current nor previous hallucinations. We also tested 10 patients with affective psychosis and current auditory hallucinations, and 20 healthy volunteers. Participants read single adjectives aloud while the source and the pitch of the on-line auditory verbal feedback was manipulated, then immediately identified the source of the speech they heard ('self'/'other'/'unsure'). RESULTS: When reading aloud with distorted feedback of their own voice, patients with schizophrenia who had auditory hallucinations were more likely than controls to misidentify its source as 'other'. Patients with delusions but no current hallucinations displayed a similar deficit, although there was a trend for this to be less marked. Patients with a history of hallucinations did not differ from controls. Patients with hallucinations in the context of an affective disorder made more unsure responses rather than misattributions. CONCLUSIONS: Difficulty with source monitoring was related to the acute psychotic state rather than a predisposition to hallucinations, and was evident in patients with affective psychosis as well as schizophrenia. External misattribution of source may reflect an impairment in verbal self-monitoring and/or the appraisal of ambiguous sensory material.     

Obsessive-compulsive disorder in bipolar disorder patients with first manic episode

BACKGROUND: Evidence indicates that obsessive--compulsive disorder (OCD) co-occurs with schizophrenia and bipolar disorder (BD) at a higher rate than in the general population. The inflated rate of comorbidity may result from chronic illness, antipsychotic therapy or treatment-seeking behavior. To control for these factors we evaluated the prevalence of OCD in patients with first-episode acute mania who met DSM-IV criteria for BD-I, and compared them with our previously reported group of first-episode schizophrenia patients. METHOD: Fifty-six BD-I patients with a first-episode of acute mania were screened for OCD and additional comorbid disorders using the Structured Clinical Interview for DSM-IV Axis-I disorders and appropriate rating scales. RESULTS: Only one patient (1.8%) met DSM-IV criteria for OCD, and two (3.6%) met criteria for sub-threshold OCD. In contrast, there was a substantial aggregation of substance use disorders 32.1% (N=8), anxiety disorders, other than OCD 26.8% (N=15) and eating disorders 14.3% (N=8). LIMITATIONS: Small sample size, cross-sectional nature of the assessments and the inclusion of only BD-I patients. CONCLUSION: The rate of OCD in first-episode BD-I patients did not differ significantly from that found in the general population and was substantially lower than in previously reported first-episode schizophrenia patients (1.8% vs. 14%). We suggest that a preferential association of OCD with schizophrenia early in the course of illness represents a pathophysiological linkage between the two disorders, and putatively a specific schizo-obsessive subtype. In contrast, OCD in BD-I may stand for "true" comorbidity. Large-scale parallel comparative evaluations of comorbidity in BD-I and schizophrenia may contribute to the search for specific pathophysiological mechanisms of distinct comorbid-related subsets in either disorder.     

Cycloid psychosis: a clinical and nosological study

BACKGROUND: Despite its clinical relevance, the diagnosis of cycloid psychosis has been relatively neglected in the psychiatric literature and in the current nosological systems. This study examined the clinical validity and nosological status of the cycloid psychosis concept. METHOD: Six-hundred and sixty psychotic in-patients were assessed for psychosis-related variables and diagnosed according to DSM-III-R, DSM-IV, ICD-10 and the Perris & Brockington criteria forcycloid psychosis. The cycloid psychosis diagnosis (N = 68, 10.3%) was examined in regard to its discriminant validity, concordance with other psychotic disorders, and predictive validity in relation to schizophrenia and psychotic mood disorders. To address putative heterogeneity within cycloid psychosis, affective (N = 38) and non-affective (N = 30) subgroups were examined. RESULTS: Cycloid psychosis had good discriminant validity regarding other psychoses (95% of correctly classified cases) and poor concordance with individual diagnoses from the formal diagnostic systems (K < 0.22). Cycloid patients had levels of psychotic, disorganization and first-rank symptoms comparable to schizophrenia, and levels of affective symptoms in-between schizophrenia and mood disorders. Regarding most clinical variables and morbidity risk of mood disorders, cycloid psychosis was closer to mood disorders. Cycloid psychosis had higher psychosocial stressors than schizophrenia and mood disorders. Affective and non-affective groups of cycloid psychosis differed in a number of variables indicating an overall better outcome for the non-affective group. CONCLUSIONS: Cycloid psychosis does not correspond closely to any DSM-III-R, DSM-IV or ICD-10 category of psychosis, and more specifically this nosological concept is not well represented by the different formal definitions of remitting psychotic disorders. Cycloid psychosis seems to be an heterogeneous condition in that affective and non-affective subgroups can be differentiated.     

Antisaccade deficit is present in young first-episode patients with schizophrenia but not in their healthy young siblings

BACKGROUND: Results of studies on antisaccade (AS) deficit in relatives of patients with schizophrenia are inconclusive. We hypothesized that AS performance in siblings of patients with schizophrenia is worse than in healthy controls and better than in patients with schizophrenia. METHOD: We included 55 first-episode patients with schizophrenia, 28 healthy siblings and 36 healthy controls to evaluate AS performance. Eye movements were measured electromagnetically by the double magnetic induction (DMI) method. RESULTS: Patients with schizophrenia had a significantly higher error rate than siblings (d=0.86, p<0.0001) and controls (d=1.35, p<0.0001). Siblings had a higher mean error rate than healthy controls but this did not reach significance (d=0.56, p=0.29). The intra-class correlation (ICC) was 0.33 for the error rate. Mean AS gain was higher in siblings than in patients (d=0.75, p=0.004) and controls (d=0.6, p=0.05). The ICC was 0.08. CONCLUSION: As parameters in strictly screened healthy young siblings of young first-episode patients with schizophrenia are comparable to results found in studies investigating older relatives. However, the statistical results (i.e. the ICCs) suggest that there is little evidence of shared environmental or genetic factors on error rate variation.     

Social outcome in early psychosis

BACKGROUND: It has been demonstrated that patients experiencing their first-episode of psychosis have social functioning deficits that are equivalent to those seen in patients with a more chronic course of illness. The purpose of this study is to examine social functioning over the course of the first year after admission to an early psychosis programme. METHOD: The social functioning of 177 first-episode subjects was assessed on admission and 1 year later and compared with that of 40 non-psychiatric controls. Assessment measures included the Quality of Life Scale (QLS). RESULTS: At the 1-year follow-up there was significant improvement in quality of life. However, even those first-episode patients experiencing a remission from positive symptoms had lower QLS scores than the non-psychiatric controls. CONCLUSIONS: These results are encouraging and supportive of early intervention. There is room for more improvement in the application and development of psychological interventions for these young patients.     

Evaluation of risk loci for schizophrenia derived from genome‐wide association studies in a German population

In the genome‐wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053–1055] a UK‐sample of 479 cases with DSM‐IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK‐sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP‐marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 × 10^?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome‐wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93–1.26 95% CI) for the schizophrenia sample and 1.04 (0.90–1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta‐analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. © 2011 Wiley‐Liss, Inc.     

首发精神分裂症女性患者雌激素与事件相关电位的相关性

目的：研究首发精神分裂症女性患者雌激素与事件相关电位（ERP）P300的关系。方法：采用放射免疫法测定30例首发精神分裂症女性患者（患者组）与20名正常女性（对照组）的血清雌激素水平;并用ERPP300（即P3波）评定患者认知功能。结果：①患者组雌二醇（E2）水平低于对照组,差异有统计学意义（P〈0．05）;②与正常对照组比较,患者组靶刺激N1、N2和P3波及非靶刺激P2波潜伏期延迟,靶刺激P3波及非靶刺激P2波波幅降低;③患者组E2水平与P300潜伏期呈显著负相关（r=-0．43,P=0．02）。结论：首发精神分裂症女性患者存在雌激素水平下降,以及注意力、记忆力缺陷和认知加工缓慢等认知障碍,雌激素水平与认知功能呈显著相关。     

Hypofrontality in subjects at high genetic risk of schizophrenia with depressive symptoms

BACKGROUND: Subjects at high risk of schizophrenia for genetic reasons were found to demonstrate increased levels of depressive symptoms compared to controls. The current study sought to investigate the neural correlates of depression in these subjects. We hypothesised abnormal activation of dorsolateral prefrontal regions in those at high risk with depression. METHODS: Depression was rated according to DSM-IV criteria. FMRI data was available from 90 high risk subjects, comprising 78 not depressed (HRD-) and 12 depressed (HRD+) subjects. Activation during the Hayling Sentence Completion Task was compared to 25 healthy control subjects without depression. RESULTS: The HRD+ group demonstrated reduced activation of the right middle/superior frontal gyrus compared to both healthy controls and the HRD- group. Increased left superior temporal gyrus activation was also found in the HRD+ group versus the HRD- group. These results survived controlling for the presence of positive psychotic symptoms at the time of the scan. CONCLUSION: Reduced activation of dorsolateral prefrontal regions, widely reported in established schizophrenia and seen here in people at high familial risk with depressive features, may be related to the presence of affective symptoms of the disorder rather than to the presence of positive psychotic symptoms. Since studies have indicated that depressive symptoms antecede illness, these findings may be relevant to the early features of developing psychosis.