Prediction of psychosis onset in Alzheimer disease: The role of cognitive impairment, depressive symptoms, and further evidence for psychosis subtypes.

BACKGROUND: Psychotic symptoms in Alzheimer disease (AD+P) identify a heritable phenotype associated with more rapid cognitive decline. The authors have proposed that AD+P is itself a composite of a misidentification and a paranoid subtype with increased cognitive impairment restricted to the misidentification type. Most prior studies of the clinical correlates of AD+P have been limited, however, by the inclusion of prevalent cases. METHODS: Subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis at study entry were assessed at the time of initial presentation and then annually. Psychotic symptoms were assessed using the CERAD Behavioral Rating Scale. Survival analyses used Cox proportional hazard models with time-dependent covariates to examine the predictors of psychosis onset. RESULTS: A total of 288 subjects completed at least one follow-up examination. Mean duration of follow-up was 22.1 months. The incidence of psychosis was 0.19 per person-year. Cognitive impairment was associated with onset of psychosis, largely as a result of its association with onset of the misidentification, but not the paranoid, subtype. Including psychotropic medication use in the model revealed an association of antidepressant use with the onset of psychosis. This latter association appeared to arise from an underlying association between depression and the risk of psychosis onset rather than from antidepressant treatment. CONCLUSION: These findings are consistent with the hypothesis that the misidentification and the paranoid subtypes each define a more biologically homogeneous group than AD+P as a whole. Further exploration of the relationship between depressive symptoms and psychosis in patients with AD is warranted.     

Young people at risk for psychosis: case finding and sample characteristics of the Oulu Brain and Mind Study

Aim: Set within the general population‐based Northern Finland Birth Cohort 1986, the Oulu Brain and Mind Study aims to explore the causes and pathogenesis of psychotic illness by following young people at risk for psychosis due to having a first‐degree relative with psychotic illness or due to having experienced psychotic‐like symptoms themselves. We report the study methods and explore the relationship between these definitions of high risk for psychosis and operational criteria for a prodromal psychosis syndrome based on interview. Methods: Prospectively collected data from earlier follow‐ups of this cohort were combined with health register data to categorize subjects as those with familial risk (n = 272), symptomatic risk (n = 117), psychosis (n = 78), attention deficit hyperactivity disorder (ADHD) (n = 103) and a sample of controls (n = 193) drawn randomly from the remaining cohort. The Structured Interview for Prodromal Syndromes (SIPS) was applied to all, 295 participants together with questionnaires measuring psychosis vulnerability and schizotypal traits. Results: There were 29 (10%) current prodromal cases. Criteria for the current prodromal syndrome were fulfilled by 12% of the familial risk group and 19% of the symptomatic risk group, compared with 5% of the ADHD group and 4% of controls. Conclusion: We successfully detected young people with a prodromal psychosis syndrome although relatively few subjects deemed to be at high risk met the full operational criteria according to the SIPS interview. Combining methods from familial, clinical and psychometric high‐risk approaches provides a tractable method for studying risk of psychosis in the general population.     

Cognitive alterations in groups at risk for psychosis: neutral markers of genetic risk or indicators of social disability?

OBJECTIVE: To investigate whether cognitive alterations associated with vulnerability to psychosis, are associated with expression of psychopathology and functional outcome in groups at different levels of risk for psychotic illness. METHOD: Neurocognition, psychopathology and functional outcome were measured in subjects with variable risk for psychosis: i) 29 patients with psychotic disorder, ii) 46 subjects at familial risk, iii) 41 subjects at psychometric risk and iv) 54 control subjects. RESULTS: Dose-response relationships between cognitive dysfunction and increasing risk for psychosis were found. Cognitive alterations were predicted by negative symptoms in patients and by positive psychotic experiences in the familial risk group. In both at risk groups, cognitive speed was associated with functional outcome. CONCLUSION: Some cognitive impairments serve as neutral endophenotypic marker across the psychosis continuum. However, other cognitive alterations associated with transmission of psychosis may have a direct impact on the pathway from risk to psychopathology and alterations in functioning.     

Affectively Salient Meaning in Random Noise: A Task Sensitive to Psychosis Liability

Stable differences in the tendency to attribute meaning and emotional value to experience may represent an indicator of liability to psychosis. A brief task was developed assessing variation in detecting affectively meaningful speech (speech illusion) in neutral random signals (white noise) and the degree to which this was associated with psychometric and familial vulnerability for psychosis. Thirty patients, 28 of their siblings, and 307 controls participated. The rate of speech illusion was compared between cases and controls. In controls, the association between speech illusion and interview-based positive schizotypy was assessed. The hypothesis of a dose-response increase in rate of speech illusion across increasing levels of familial vulnerability for psychosis (controls, siblings of patients, and patients) was examined. Patients were more likely to display speech illusions than controls (odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.4–11.7), also after controlling for neurocognitive variables (OR = 3.8, 95% CI = 1.04–14.1). The case-control difference was more accentuated for speech illusion perceived as affectively salient (positively or negatively appraised) than for neutrally appraised speech illusions. Speech illusion in the controls was strongly associated with positive schizotypy but not with negative schizotypy. In addition, the rate of speech illusion increased with increasing level of familial risk for psychotic disorder. The data suggest that the white noise task may be sensitive to psychometric and familial vulnerability for psychosis associated with alterations in top-down processing and/or salience attribution.     

Social Cognition Psychometric Evaluation: Results of the Initial Psychometric Study

Measurement of social cognition in treatment trials remains problematic due to poor and limited psychometric data for many tasks. As part of the Social Cognition Psychometric Evaluation (SCOPE) study, the psychometric properties of 8 tasks were assessed. One hundred and seventy-nine stable outpatients with schizophrenia and 104 healthy controls completed the battery at baseline and a 2–4-week retest period at 2 sites. Tasks included the Ambiguous Intentions Hostility Questionnaire (AIHQ), Bell Lysaker Emotion Recognition Task (BLERT), Penn Emotion Recognition Task (ER-40), Relationships Across Domains (RAD), Reading the Mind in the Eyes Task (Eyes), The Awareness of Social Inferences Test (TASIT), Hinting Task, and Trustworthiness Task. Tasks were evaluated on: (i) test-retest reliability, (ii) utility as a repeated measure, (iii) relationship to functional outcome, (iv) practicality and tolerability, (v) sensitivity to group differences, and (vi) internal consistency. The BLERT and Hinting task showed the strongest psychometric properties across all evaluation criteria and are recommended for use in clinical trials. The ER-40, Eyes Task, and TASIT showed somewhat weaker psychometric properties and require further study. The AIHQ, RAD, and Trustworthiness Task showed poorer psychometric properties that suggest caution for their use in clinical trials.Key words: schizophrenia, measurement, reliability, validity, emotion processing, social perception, mental state attribution     

Alzheimer disease subjects with psychosis have increased schizotypal symptoms before dementia onset.

BACKGROUND: Recent findings have demonstrated the familiality of psychotic symptoms occurring during Alzheimer disease (AD with psychosis, AD+P), particularly for subjects with multiple psychotic symptoms. We have proposed a model in which genes that confer a small risk for psychosis interact with neurodegenerative illness to yield manifest psychotic symptoms during AD. One prediction of this model would be that AD+P subjects would have evidence of increased degrees of subsyndromal psychosis before AD onset. METHODS: We used the psychosis (positive symptoms) and psychotic personality disorder sections (paranoid, schizoid, and schizotypal) of the Family Interview for Genetic Studies (FIGS) to interview the primary caregivers of AD subjects. Caregivers were specifically instructed to answer questions with regard to the subject's behavior before AD onset. Interviewers were blind to presence of psychosis during AD. Subjects were grouped by whether they had at least one or had multiple psychotic symptoms during AD. RESULTS: Scores on the FIGS subscales were generally low, reflecting a low frequency of endorsement of psychotic symptoms before AD. There was a trend for the schizotypal scores to be elevated in the AD+P group, which was highly significant in the AD+P group with multiple psychotic symptoms. There was no significant association of paranoid or schizoid scores with either group. CONCLUSIONS: Although limited by small sample size and retrospective design, these data are novel in that they indicate an association of subsyndromal psychotic symptoms before AD onset with psychosis in AD. Subsyndromal psychosis might be useful for classifying AD+P families for genetic mapping studies. Prospective confirmation is required.     

Family history study of posttraumatic stress disorder with secondary psychotic symptoms

OBJECTIVE: A family history approach was used to determine if posttraumatic stress disorder (PTSD) with secondary psychotic symptoms was associated with a familial vulnerability to schizophrenia and other psychoses. METHOD: Family history methods were used to compare rates of familial psychopathology in the first-degree relatives of three proband groups: 1) patients with DSM-IV PTSD with secondary psychotic symptoms, 2) patients with DSM-IV PTSD without psychotic symptoms, and 3) healthy matched comparison subjects. RESULTS: PTSD with secondary psychotic symptoms was not associated with an excess of familial psychotic disorder but was associated with a higher morbid risk for depression. CONCLUSIONS: PTSD with secondary psychotic symptoms was not associated with familial psychosis, suggesting it does not reflect the presence of an underlying psychotic disorder.     

Hearing impairment and psychosis: a replication in a cohort of young adults

Previous work has demonstrated an association between hearing impairment and psychosis. In the current study, this association was studied in a cohort of young people. In addition, it was studied to what degree duration of hearing problems (i.e. onset earlier in life) impacted on risk. Data were derived from the Greek National Perinatal Survey, a prospective birth cohort study of 11,048 neonates at baseline, 6594 seven-year olds at T1 and 3500 nineteen-year olds at T2. A significant association was found at age 19 years between the presence of hearing impairment and the presence of self-reported positive psychotic-like experiences (beta = 0.18, S.E. = 0.02, p < 0.000). In addition, this association was conditional on the duration of hearing problems, in that the association at age 19 years was stronger if hearing impairment had already been reported at age 7 years (test for interaction: p = 0.022). These results replicate previous findings of an association between hearing impairment and psychosis, extend it to the age range of late adolescence, and suggest that longer duration is associated with stronger risk.     

The Effect of State Anxiety on Paranoid Ideation and Jumping to Conclusions. An Experimental Investigation

Theoretical models of persecutory delusions have emphasized the impact of reasoning biases and negative emotion at the early stages of symptom formation. However, the causal mechanisms remain unclear. This study tests the hypothesis that state anxiety will increase paranoid ideation and that this increase will be moderated by the level of individual vulnerability and mediated by the tendency to jump to conclusions. Healthy participants (n = 90) with varying levels of vulnerability (psychosis symptoms assessed by the Community Assessment of Psychic Experiences) were randomly assigned to either an anxiety or a nonanxiety condition. Anxiety was induced by pictures from the International Affective Picture System and by in sensu exposure to individual anxiety-provoking situations. During each condition, symptoms of paranoia were assessed by a state-adapted version of the Paranoia Checklist. Jumping to conclusions (JTC) was assessed using a modified version of the beads task. Overall, participants in the anxiety condition reported significantly more paranoid thoughts and showed more JTC than participants in the neutral condition. Participants with higher baseline vulnerability were more likely to show an increase in paranoia as reaction to the anxiety manipulation. Moreover, the association of anxiety and paranoia was mediated by the increased tendency to jump to conclusions in the beads task. The results are in line with a threat anticipation conceptualization of paranoia and provide evidence for an interaction of anxiety and reasoning biases in the development of paranoid beliefs. A combination of meta-cognitive training directed at reasoning biases and promoting emotion regulation skills might prove beneficial in preventing symptoms.     

Social cognition and neurocognition as independent domains in psychosis

Patients with psychosis display alterations in social cognition as well as in the realm of neurocognition. It is unclear, however, to what degree these cognitive domains represent two separate dimensions of liability or the pleiotropic expression of a single deficit. The purpose of the present study was to investigate (i) to what extent alterations in social cognition represent an independent area of vulnerability to psychosis, separate from neurocognitive deficits and (ii) whether social cognition is one construct or can be divided into several subcomponents. Five social cognition and three neurocognitive tasks were completed by 186 participants with different levels of vulnerability for psychosis: 44 patients with psychotic disorder; 47 subjects at familial risk; 41 subjects at psychometric risk and 54 control subjects. The social cognition tasks covered important basic subcomponents of social cognition, i.e. mentalisation (or theory of mind), data gathering bias (jumping to conclusions), source monitoring and attribution style. Neurocognitive tasks assessed speed of information processing, inhibition, cognitive shifting and strategy-driven retrieval from semantic memory. The results of factor analysis suggested that neurocognition and social cognition are two separate areas of vulnerability in psychosis. Furthermore, the social cognition measures lacked significant overlap, suggesting a multidimensional construct. Cognitive liabilities to psychosis are manifold, and include key processes underlying basic person-environment interactions in daily life, independent of cognition quantified by neuropsychological tests.     

P50 suppression in individuals at risk for schizophrenia: the convergence of clinical, familial, and vulnerability marker risk assessment.

BACKGROUND: Identification of individuals at risk for the development of schizophrenia is important because it can lead to a greater understanding of the early stages of the illness. The aim of the present study was to determine whether individuals "at risk" for schizophrenia have deficits in P50 suppression, a preattentive measure of sensory gating. METHODS: Thirty-one at-risk and 21 normal comparison subjects were referred to the CARE (Cognitive Assessment and Risk Evaluation) Program at University of California San Diego. The primary aim of the CARE Program is to identify individuals who are at the greatest risk for conversion to psychosis, with a combination of clinical, familial, and vulnerability markers, including P50 suppression. RESULTS: As a group, the at-risk subjects had modestly lower levels (effect size=.43) of P50 suppression (55.1%, SD=39.8) relative to comparison subjects (71.5%, SD=34.7). At-risk subjects with a first-degree relative with schizophrenia had profoundly deficient P50 suppression (16.4%, SD=33.8) compared with other at-risk (p<.05) and comparison subjects (p<.005). CONCLUSIONS: Ongoing longitudinal follow-up studies will determine whether it is possible to improve the predictive validity of the clinical and familial variables by using P50 suppression alone or in combination with other measures in determining which individuals are at greatest risk for schizophrenia.     

Social cognitive impairments in first episode psychosis

BACKGROUND: Social cognition is a complex phenomenon involving several distinct processes. Numerous studies have shown that individuals with schizophrenia are largely impaired on this domain of cognition. However, most have focused on a single aspect of social cognition, namely "theory of mind" and/or included patients with long standing illness. OBJECTIVE: The main objective of the present study was to identify social cognition deficits in first episode of schizophrenia spectrum psychosis using a case control design and a comprehensive assessment that allowed the exploration of several dimensions of this phenomenon. SUBJECTS: 36 patients with a first episode of psychosis and 25 healthy controls participated in this study. MATERIAL: Measures of social cognition included the Hinting Task and the Four Factor Test of Social Intelligence. RESULTS: Significant group differences were found on both tasks, but the Four Factor Test of Social Intelligence revealed a stronger group effect and the effects observed remained significant once IQ was covaried. Social cognition did not show any correlations with level of symptoms. CONCLUSION: Social cognition deficits are present during the first episode of psychosis. These impairments do not seem to be a consequence of group differences in overall intellectual functioning and are likely to be state-independent.     

The epidemiology of functional psychoses of late onset

For the functional psychoses of late life, epidemiological information comes from two sources: studies of persons who have reached psychiatric services; and surveys of elderly persons sampled from the general population. A conspectus of published data from both sources leads to the following conclusions: States phenomenologically similar to those found in clinics do occur in the community in non-trivial numbers. There is no notable divergence in the information obtained from clinical series and from population-based surveys. These states are more common in women, they become more common with increasing age and are sometimes associated with decline in cognitive performance or with degenerative changes in the brain revealed by neuroimaging. Genetic factors appear to be less important than in early-onset psychoses but remain ill-defined, and the roles of social isolation and disorders of personality have not yet been sufficiently elucidated. Both clinical and community-based studies have found an association with sensory impairment. The community-based data suggest that paranoid symptoms may be detectable at subclinical level, and an association between them and cognitive impairment is demonstrable in individuals who are not diagnosable cases either of psychosis or of dementia. Differences exist between late-onset paranoid psychoses and affective psychoses in symptomatology and response to treatment. These observations confirm the importance of the late-onset psychoses for research directed towards uncovering the origins of psychotic symptoms in any age group.     

Investigating the association between neurocognition and psychosis in bipolar disorder: further evidence for the overlap with schizophrenia

Objectives: In schizophrenia, a distinction is made between psychosis with developmental and cognitive impairment on the one hand and psychosis without developmental impairment and positive symptoms on the other. In this study, we investigated whether this model can be extended to bipolar disorder by testing the hypothesis that neurocognitive functioning is inversely related to positive psychotic symptoms in bipolar disorder. Methods: Neurocognitive functioning and psychopathology were assessed in (i) 76 patients with bipolar disorder, (ii) 39 of their healthy first‐degree relatives, and (iii) 61 healthy controls. Cognitive performance of bipolar patients and their first‐degree relatives was investigated, taking into account the possible moderating effect of the level of expression of psychosis in patients and relatives. Results: Bipolar patients showed impaired cognitive performance on multiple cognitive domains, whereas performance of their relatives was comparable to that of controls. A history of psychotic symptoms in patients was suggestive of less likelihood of cognitive alterations in relatives, and the presence of subclinical psychotic symptoms within the group of relatives predicted better cognitive performance. Conclusions: The finding of similar psychosis‐cognition associations in bipolar disorder as implied by the two pathways leading to nonaffective psychotic disorders suggests that this model might be extended to the continuum spanning affective and nonaffective psychosis. This is in line with the idea of a partially overlapping vulnerability to bipolar disorder and schizophrenia and provides an explanation for the apparent differences in cognitive alterations in those at risk for the two disorders.     

Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer's disease.

The authors examined the association of Apolipoprotein-E (APO-E) genotype to symptoms of psychosis and depression in 501 patients diagnosed with probable (n=343) or possible (n=158) Alzheimer's disease (AD) according to NINCDS-ADRDA criteria. They observed the following APO-E genotypes: epsilon2/epsilon3 (n=19); epsilon2/epsilon4 (n=14); epsilon3/epsilon3 (n=228); epsilon3/epsilon4 (n=203); epsilon4/epsilon4 (n=37). In contrast to previous reports, the results did not indicate a relationship between either the epsilon4 allele or the epsilon2 allele and symptoms of mood disturbance in AD. However, an elevated risk for psychosis was shown, specifically, at the severe stage of cognitive impairment, among AD patients carrying the epsilon4 allele, after effects of age, gender, education, and level of cognitive impairment were controlled.     

Neurocognition in the Extended Psychosis Phenotype: Performance of a Community Sample of Adolescents With Psychotic Symptoms on the MATRICS Neurocognitive Battery

Neurocognitive dysfunction is well established in psychosis, but recent work suggests that processing speed deficits might represent a particularly important cognitive deficit. A number of significant confounds, however, such as disease chronicity and antipsychotic medication use, have been shown to affect processing speed, causing debate as to the core cognitive features of psychosis. We adopted a novel strategy of testing neurocognitive performance in the “extended psychosis phenotype,” involving community-based adolescents who are not clinically psychotic but who report psychotic symptoms and who are at increased risk of psychosis in adulthood. This allows investigation of the earliest cognitive factors associated with psychosis risk, while excluding potential confounds such as disease chronicity and antipsychotic use. A population sample of 212 school-going adolescents aged 11–13 years took part in this study. Psychotic symptoms were assessed using the psychosis section of the Schedule for Affective Disorders and Schizophrenia. Neurocognition was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus neurocognitive battery. Adolescents with psychotic symptoms performed significantly more poorly on 3 processing speed tasks: Trail Making Test-A (F = 3.3, P < .05), Trail Making Test-B (F = 3.1, P < .05), and digit symbol coding task (F = 7.0, P < .001)—as well as on a nonverbal working memory (spatial span) task (F = 3.2, P < .05). Our findings support the idea that neurocognitive impairment, and processing speed impairment in particular, is a core feature of psychosis risk. This group likely demonstrates some of the earliest cognitive impairments associated with psychosis vulnerability.Key words: epidemiology/adolescents/cognitionKey words: epidemiology, adolescents, cognition     

Subjective experience of cognitive failures as possible risk factor for negative symptoms of psychosis in the general population

Objective: The aim of this study was to examine whether proneness to subjective cognitive failure (cognitive based mistakes) increases the risk for the development of symptoms of psychosis and to what degree any association was familial. Methods: At baseline, the Cognitive Failure Questionnaire (CFQ) and the Community Assessment of Psychic Experiences (CAPE) questionnaire were administered in a general population sample of genetically related individuals (n = 755). Individuals scoring high (>75th percentile) or average on the CAPE (between 40th and 60th percentile) (n = 488) were reinterviewed with the CAPE and Structured Interview for Schizotypy—Revised (SIS-R) at follow-up (mean interval = 7.7 months, SD = 4.8 months). Results: Cross-trait, within-relative analysis showed a significant association between the CFQ and the negative dimension, assessed with both the CAPE and SIS-R, whereas no association was found between the CFQ and the positive dimension. Cross-trait, between-relative analyses showed no association between the CFQ in one relative and any of the dimensions of the subclinical psychosis phenotype in the other relative. Conclusion: Proneness to subjective cognitive failure possibly contributes to the development or persistence of negative symptoms and can be seen as potential risk factor for negative symptoms of psychosis. This overlap is due to individual effects rather than familial liability.     

Obstetric complications and transition to psychosis in an "ultra" high risk sample

OBJECTIVE: An association between birth and pregnancy complications and the later development of schizophrenia has been described for decades and obstetric complications (OCs) have been proposed as a vulnerability marker for psychosis in line with the neurodevelopmental hypothesis of psychotic disorders. Previous studies of OCs have focused on established schizophrenia. In this study, the association between OCs and the development of psychotic disorder was studied in a group of 74 young people identified as being at very high risk for the first onset of psychosis. METHOD: The "ultra" high risk (UHR) cohort was identified by the presence of subthreshold psychotic symptoms, or a combination of first-degree relative with a psychotic disorder and recent functional decline. Thirty-eight per cent of the cohort developed an acute psychotic episode over the 12-month period after recruitment. As a component of a larger research study, the level of OCs experienced by the UHR cohort was assessed at intake. RESULTS: Obstetric complications were not associated with the later development of psychosis in the UHR group included in this study. CONCLUSIONS: This study does not support a role for OCs as a risk factor for the later development of psychosis; however, we cannot conclude that they should be completely ignored as a candidate risk factor for onset of psychosis. A number of weaknesses of the study suggest that it may be premature to dismiss OCs as a risk factor for the development of psychosis and further research is urged in this area.     

Sensory gating and psychosis vulnerability in cocaine-dependent individuals: preliminary data.

BACKGROUND: Factors increasing vulnerability of a cocaine user to develop psychotic symptoms are unknown. Deficits in sensory gating and attention, such as those occurring in idiopathic psychosis, might represent experimentally tractable factors contributing to vulnerability to cocaine-induced paranoia. METHODS: Severity of cocaine-induced paranoid symptoms was assessed with the Cocaine Experience Questionnaire (CEQ) in 30 abstinent cocaine-dependent individuals. Sensory gating was assessed in a paired-click auditory evoked potential paradigm (S1 and S2) using the S2/S1 attenuation ratio of the P50 evoked response as the primary outcome measure. The Wender-Utah Rating Scale (WURS) for attention deficit was also administered. RESULTS: Subjects were divided into those with high CEQ scores (n = 10) and those with low CEQ scores (n = 20). The mean P50 ratios were significantly higher for the high CEQ subjects compared with the low CEQ group (F = 4.6, p <.04). The WURS did not correlate with the total CEQ but correlated with the CEQ Severity subscale, r =.432, p <.02. CONCLUSIONS: The data suggest that deficient P50 sensory gating and attention deficits may be associated with increased proneness to developing psychotic symptoms in the context of cocaine use. Further exploration of these factors seems warranted.