Childhood trauma and cognitive functioning in individuals at clinical high risk (CHR) for psychosis.

Evidence suggests that early trauma may have a negative effect on cognitive functioning in individuals with psychosis, yet the relationship between childhood trauma and cognition among those at clinical high risk (CHR) for psychosis remains unexplored. Our sample consisted of 626 CHR children and 279 healthy controls who were recruited as part of the North American Prodrome Longitudinal Study 2. Childhood trauma up to the age of 16 (psychological, physical, and sexual abuse, emotional neglect, and bullying) was assessed by using the Childhood Trauma and Abuse Scale. Multiple domains of cognition were measured at baseline and at the time of psychosis conversion, using standardized assessments. In the CHR group, there was a trend for better performance in individuals who reported a history of multiple types of childhood trauma compared with those with no/one type of trauma (Cohen d = 0.16). A history of multiple trauma types was not associated with greater cognitive change in CHR converters over time. Our findings tentatively suggest there may be different mechanisms that lead to CHR states. Individuals who are at clinical high risk who have experienced multiple types of childhood trauma may have more typically developing premorbid cognitive functioning than those who reported minimal trauma do. Further research is needed to unravel the complexity of factors underlying the development of at-risk states.

Persistent negative symptoms in youth at clinical high risk for psychosis: A longitudinal study.

BACKGROUND: Severity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample. METHOD: CHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS). RESULTS: The PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis. CONCLUSIONS: PNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments.

Longitudinal changes in social cognition in individuals at clinical high risk for psychosis: An outcome based analysis.

Social cognition deficits have been observed in individuals at clinical high risk (CHR) for psychosis. Longitudinal change in social cognition were analyzed in CHR individuals from the North American Prodrome Longitudinal Study (NAPLS2) based on outcome at 24 months. Individuals (n = 359) were classified into remission, symptomatic, prodromal progression and transition to psychosis (CHR-T) groups. Social cognition was assessed using theory of mind, emotion perception, and social perception tasks. There were no differences at baseline or 24 months between the groups on social cognition. Non-transition groups improved significantly over time on social cognition, but CHR-T did not show this effect.

Insights into psychosis risk from leukocyte microRNA expression.

Dysregulation of immune system functions has been implicated in schizophrenia, suggesting that immune cells may be involved in the development of the disorder. With the goal of a biomarker assay for psychosis risk, we performed small RNA sequencing on RNA isolated from circulating immune cells. We compared baseline microRNA (miRNA) expression for persons who were unaffected (n=27) or who, over a subsequent 2-year period, were at clinical high risk but did not progress to psychosis (n=37), or were at high risk and did progress to psychosis (n=30). A greedy algorithm process led to selection of five miRNAs that when summed with +1 weights distinguished progressed from nonprogressed subjects with an area under the receiver operating characteristic curve of 0.86. Of the five, miR-941 is human-specific with incompletely understood functions, but the other four are prominent in multiple immune system pathways. Three of those four are downregulated in progressed vs. nonprogressed subjects (with weight -1 in a classifier function that increases with risk); all three have also been independently reported as downregulated in monocytes from schizophrenia patients vs. unaffected subjects. Importantly, these findings passed stringent randomization tests that minimized the risk of conclusions arising by chance. Regarding miRNA-miRNA correlations over the three groups, progressed subjects were found to have much weaker miRNA orchestration than nonprogressed or unaffected subjects. If independently verified, the leukocytic miRNA biomarker assay might improve accuracy of psychosis high-risk assessments and eventually help rationalize preventative intervention decisions.

Substance use in individuals at clinical high risk of psychosis.

BACKGROUND: A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed. METHOD: At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models. RESULTS: CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment. CONCLUSIONS: In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone.

Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample.

OBJECTIVE: Cannabis use has been examined as a predictor of psychosis in clinical high-risk (CHR) samples, but little is known about the impact of other substances on this relationship. METHOD: Substance use was assessed in a large sample of CHR participants (N = 370, mean age = 18.3) enrolled in the multisite North American Prodrome Longitudinal Study Phase 1 project. Three hundred and forty-one participants with cannabis use data were divided into groups: No Use (NU, N = 211); Cannabis Use without impairment (CU, N = 63); Cannabis Abuse/Dependence (CA/CD, N = 67). Participants (N = 283) were followed for ≥2 years to determine psychosis conversion. RESULTS: Alcohol (45.3%) and cannabis (38.1%) were the most common substances. Cannabis use groups did not differ on baseline attenuated positive symptoms. Seventy-nine of 283 participants with cannabis and follow-up data converted to psychosis. Survival analysis revealed significant differences between conversion rates in the CA/CD group compared with the No Use (P = 0.031) and CU group (P = 0.027). CA/CD also significantly predicted psychosis in a regression analysis, but adjusting for alcohol use weakened this relationship. CONCLUSION: The cannabis misuse and psychosis association was confounded by alcohol use. Non-impairing cannabis use was not related to psychosis. Results highlight the need to control for other substance use, so as to not overstate the cannabis/psychosis connection.

Attenuated psychosis syndrome: ready for DSM-5.1?

Prodromal features of the schizophrenia syndrome have been described for a century, and work in the past two decades has produced a substantial literature based on these features to identify individuals at increased risk for developing a psychotic disorder. Sometimes conceptualized as a "risk state" and sometimes as early manifestations of a "disorder," the work has been conducted with several related but different constructs. Early in the preparation of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) public comment was sought on the proposal to create a new disorder termed attenuated psychosis syndrome (APS), and a range of issues emerged that generated interesting and important controversies. In this review, these criticisms are fully discussed, the APS concept is explicated; data relating to reliability, validity, and treatment are updated; the heterogeneity of APS is considered; and alternative views of the construct are presented with an emphasis on developmental pattern with timing for primary and secondary prevention and early treatment. Areas of future research are identified, and a potential roadmap for inclusion in DSM-5.1 is traced.

Comparison of alternative models for personality disorders, II: 6-, 8- and 10-year follow-up.

BACKGROUND: Several conceptual models have been considered for the assessment of personality pathology in DSM-5. This study sought to extend our previous findings to compare the long-term predictive validity of three such models: the five-factor model (FFM), the schedule for nonadaptive and adaptive personality (SNAP), and DSM-IV personality disorders (PDs). METHOD: An inception cohort from the Collaborative Longitudinal Personality Disorder Study (CLPS) was followed for 10 years. Baseline data were used to predict long-term outcomes, including functioning, Axis I psychopathology, and medication use. RESULTS: Each model was significantly valid, predicting a host of important clinical outcomes. Lower-order elements of the FFM system were not more valid than higher-order factors, and DSM-IV diagnostic categories were less valid than dimensional symptom counts. Approaches that integrate normative traits and personality pathology proved to be most predictive, as the SNAP, a system that integrates normal and pathological traits, generally showed the largest validity coefficients overall, and the DSM-IV PD syndromes and FFM traits tended to provide substantial incremental information relative to one another. CONCLUSIONS: DSM-5 PD assessment should involve an integration of personality traits with characteristic features of PDs.

The association of personality disorders with the prospective 7-year course of anxiety disorders.

BACKGROUND: This study prospectively examined the natural clinical course of six anxiety disorders over 7 years of follow-up in individuals with personality disorders (PDs) and/or major depressive disorder. Rates of remission, relapse, new episode onset and chronicity of anxiety disorders were examined for specific associations with PDs. METHOD: Participants were 499 patients with anxiety disorders in the Collaborative Longitudinal Personality Disorders Study, who were assessed with structured interviews for psychiatric disorders at yearly intervals throughout 7 years of follow-up. These data were used to determine probabilities of changes in disorder status for social phobia (SP), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder and panic disorder with agoraphobia. RESULTS: Estimated remission rates for anxiety disorders in this study group ranged from 73% to 94%. For those patients who remitted from an anxiety disorder, relapse rates ranged from 34% to 67%. Rates for new episode onsets of anxiety disorders ranged from 3% to 17%. Specific PDs demonstrated associations with remission, relapse, new episode onsets and chronicity of anxiety disorders. Associations were identified between schizotypal PD with course of SP, PTSD and GAD; avoidant PD with course of SP and OCD; obsessive-compulsive PD with course of GAD, OCD, and agoraphobia; and borderline PD with course of OCD, GAD and panic with agoraphobia. CONCLUSIONS: Findings suggest that specific PD diagnoses have negative prognostic significance for the course of anxiety disorders underscoring the importance of assessing and considering PD diagnoses in patients with anxiety disorders.

Early detection of psychosis: positive effects on 5-year outcome.

BACKGROUND: During the last decades we have seen a new focus on early treatment of psychosis. Several reviews have shown that duration of untreated psychosis (DUP) is correlated to better outcome. However, it is still unknown whether early treatment will lead to a better long-term outcome. This study reports the effects of reducing DUP on 5-year course and outcome. METHOD: During 1997-2000 a total of 281 consecutive patients aged >17 years with first episode non-affective psychosis were recruited, of which 192 participated in the 5-year follow-up. A comprehensive early detection (ED) programme with public information campaigns and low-threshold psychosis detection teams was established in one healthcare area (ED-area), but not in a comparable area (no-ED area). Both areas ran equivalent treatment programmes during the first 2 years and need-adapted treatment thereafter. RESULTS: At the start of treatment, ED-patients had shorter DUP and less symptoms than no-ED-patients. There were no significant differences in treatment (psychotherapy and medication) for the 5 years. Mixed-effects modelling showed better scores for the ED group on the Positive and Negative Syndrome Scale negative, depressive and cognitive factors and for global assessment of functioning for social functioning at 5-year follow-up. The ED group also had more contacts with friends. Regression analysis did not find that these differences could be explained by confounders. CONCLUSIONS: Early treatment had positive effects on clinical and functional status at 5-year follow-up in first episode psychosis.

Early identification of non-remission in first-episode psychosis in a two-year outcome study.

OBJECTIVE: To identify predictors of non-remission in first-episode, non-affective psychosis. METHOD: During 4 years, we recruited 301 patients consecutively. Information about first remission at 3 months was available for 299 and at 2 years for 293 cases. Symptomatic and social outcomes were assessed at 3 months, 1 and 2 years. RESULTS: One hundred and twenty-nine patients (43%) remained psychotic at 3 months and 48 patients (16.4%) remained psychotic over 2 years. When we compared premorbid and baseline data for the three groups, the non-remitted (n = 48), remitted for <6 months (n = 38) and for more than 6 months (n = 207), duration of untreated psychosis (DUP) was the only variable that significantly differentiated the groups (median DUP: 25.5, 14.4 and 6.0 weeks, respectively). Three months univariate predictors of non-remission were being single, longer DUP, core schizophrenia, and less excitative and more negative symptoms at baseline. Two-year predictors were younger age, being single and male, deteriorating premorbid social functioning, longer DUP and core schizophrenia. In multivariate analyses DUP, negative and excitative symptoms predicted non-remission at 3 months, but only DUP predicted at 2 years. CONCLUSION: Long DUP predicted both 3 month and 2-year non-remission rates in first-episode psychosis.

Are multi family groups appropriate for patients with first episode psychosis? A 5-year naturalistic follow-up study.

OBJECTIVE: To compare outcome over 5 years for patients who participated in multi family groups (MFGs) to those who refused or were not offered participation. METHOD: Of 301 first episode psychotic patients aged 15-65 years, 147 participated in MFGs. Outcome was measured by drop-out rates, positive and negative syndrome scale (PANSS) symptom scores, and duration of psychotic episodes during the follow-up period. RESULTS: Multi family group participants had a significantly lower drop-out rates at 5-year follow-up than patients who did not participate. However, the MFG participants had significantly less improvement in PANSS positive and excitative symptoms and had significantly longer duration of psychotic symptoms during the follow-up period. CONCLUSION: Multi family groups appear to increase the chance of retaining patients in a follow-up study, but adjustment of the programme may be necessary with first episode psychosis patients to meet their needs better.

A 2-year follow-up of involuntary admission's influence upon adherence and outcome in first-episode psychosis.

OBJECTIVE: To see, if voluntary admission for treatment in first-episode psychosis results in better adherence to treatment and more favourable outcome than involuntary admission. METHOD: We compared consecutively first-admitted, hospitalised patients from a voluntary (n = 91) with an involuntary (n = 126) group as to psychopathology and functioning using Positive and Negative Syndrome Scale and Global Assessment of Functioning Scales at baseline, after 3 months and at 2 year follow-up. Moreover, duration of supportive psychotherapy, medication and number of hospitalisations during the 2 years were measured. RESULTS: More women than men were admitted involuntarily. Voluntary patients had less psychopathology and better functioning than involuntary patients at baseline. No significant difference as to duration of psychotherapy and medication between groups was found. No significant difference was found as to psychopathology and functioning between voluntarily and involuntarily admitted patients at follow-up. CONCLUSION: Legal admission status per se did not seem to influence treatment adherence and outcome.

Personality traits as prospective predictors of suicide attempts.

OBJECTIVE: To examine higher order personality factors of negative affectivity (NA) and disinhibition (DIS), as well as lower order facets of impulsivity, as prospective predictors of suicide attempts in a predominantly personality disordered sample. METHOD: Data were analyzed from 701 participants of the Collaborative Longitudinal Personality Disorders Study with available follow-up data for up to 7 years. Cox proportional hazards regression analyses was used to examine NA and DIS, and facets of impulsivity (e.g. urgency, lack of perseverance, lack of premeditation and sensation seeking), as prospective predictors of suicide attempts. RESULTS: NA, DIS and all facets of impulsivity except for sensation seeking were significant in univariate analyses. In multivariate models which included sex, childhood sexual abuse, course of major depressive disorder and substance use disorders, only NA and lack of premeditation remained significant in predicting suicide attempts. DIS and the remaining impulsivity facets were not significant. CONCLUSION: NA emerged as a stronger and more robust predictor of suicide attempts than DIS and impulsivity, and warrants greater attention in suicide risk assessment. Distinguishing between facets of impulsivity is important for clinical risk assessment.

Baseline profiles of adolescent vs. adult-onset first-episode psychosis in an early detection program.

OBJECTIVE: Psychotic disorders often start in adolescence. We aim to investigate premorbid and baseline differences characterizing patients with an onset of psychosis in adolescence versus adulthood. METHOD: We compare first-episode, DSM-IV non-affective psychosis with onset before (n = 43) and after (n = 189) 18 years on duration of untreated psychosis (DUP), level of symptoms, suicidal behaviour, and other baseline clinical and demographic characteristics. RESULTS: Adolescent onset patients had poorer premorbid functioning, a longer DUP, higher suicidality, and more depressive symptoms. They also had better cognition, fewer psychotic symptoms, and were more likely to be treated on an out-patient basis. CONCLUSION: Adolescents with first-episode psychosis may have a slower and more silent, i.e. insidious onset, and are at risk of experiencing longer treatment delays than adults. They fit the description of what used to be labeled process (versus reactive) schizophrenia.

Improvement in borderline personality disorder in relationship to age.

OBJECTIVE: It is commonly believed that some features of borderline personality disorder (BPD) improve as individuals reach their late 30s and 40s. This study examined age-related change in borderline criteria and functional impairment, testing the hypothesis that older age would be associated with relatively more improvement than younger age. METHOD: A total of 216 male and female participants with BPD were followed prospectively with yearly assessments over 6 years. RESULTS: Participants showed similar rates of improvement in borderline features regardless of age. A significant age by study year interaction showed functioning in older subjects to reverse direction and begin to decline in the latter part of the follow-up, in contrast to younger subjects who maintained or continued improvement over the 6 years. Despite the decline, functioning for the older subjects was comparable with or slightly better at year 6 than at year 1. CONCLUSION: Improvement in borderline features is not specific to the late 30s and 40s. There may be a reversal of improvement in functioning in some borderline patients in this older-age range.

Premorbid adjustment, onset types, and prognostic scaling: still informative?

Efforts emerged to describe, quantify, and predict prognosis once it became clear that the outcomes of Kraepelinian dementia praecox could vary. The concepts and scales that have evolved focus on types of premorbid adjustment and illness onset. Enduring highlights of this literature will be described, and its current and future utility will be discussed.

Clinical epidemiologic first-episode psychosis: 1-year outcome and predictors.

OBJECTIVE: To describe 1-year outcome in a large clinical epidemiologic sample of first-episode psychosis and its predictors. METHOD: A total of 301 patients with first-episode psychosis from four healthcare sectors in Norway and Denmark receiving common assessments and standardized treatment were evaluated at baseline, at 3 months, and at 1 year. RESULTS: Substantial clinical and social improvements occurred within the first 3 months. At 1-year 66% were in remission, 11% in relapse, and 23% continuously psychotic. Female gender and better premorbid functioning were predictive of less severe negative symptoms. Shorter DUP was predictive for shorter time to remission, stable remission, less severe positive symptoms, and better social functioning. Female gender, better premorbid social functioning and more education also contributed to a better social functioning. CONCLUSION: This first-episode sample, being well treated, may be typical of the early course of schizophrenia in contemporary centers.

Is active psychosis neurotoxic?

Positive symptoms of psychosis disrupt mentation. Do they also engineer brain cell death and deterioration? This hypothesis is currently popular as an explanation of the duration of untreated psychosis effect in early schizophrenia. The clinical and neurobiological evidence for its validity is visited and found wanting. Synaptic plasticity, not neurotoxicity, appears to be the mediating process.