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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Testing DSM-III symptom criteria for schizotypal and borderline personality disorders.

Schizotypal and borderline personality disorders (SPD and BPD, respectively) appear to be different at follow-up, yet they are poorly discriminated from each other by current DSM-III symptom criteria. In the Chestnut Lodge Follow-up Study, three axis II study cohorts (pure SPD, n = 10; pure BPD, n = 81; mixed SPD/BPD, n = 18) with distinctive outcomes are defined using current borderline systems. This study compares the relative frequency with which individual symptom criteria from each system discriminate across study cohorts. Findings suggest that for SPD, the most characteristic (core) DSM-III symptoms are odd communication, suspiciousness/paranoid ideation, and social isolation, while the least discriminating symptom is illusions/depersonalization/derealization; the core DSM-III symptoms for BPD are unstable relationships, impulsivity, and self-damaging acts, while the least discriminating symptoms are inappropriate anger and intolerance of aloneness; depression as a symptom does not discriminate between SPD and BPD; and transient psychoses and brief paranoid experiences and/or regression in treatment discriminate for SPD but against BPD and therefore fit better as SPD criteria. Results support the retention of some, but the elimination of other, DSM-III symptom criteria for the diagnosis of SPD and BPD.

The Chestnut Lodge follow-up study. III. Long-term outcome of borderline personalities.

This report elaborates the long-term course and outcome for systematically rediagnosed patients with borderline personality disorder (n = 81) from the Chestnut Lodge follow-up study. They were assessed and are described from multiple outcome perspectives. Schizophrenic (n = 163) and unipolar affective disorder (n = 44) cohorts serve for comparison. Borderline patients were comparable with unipolar patients and scored significantly better than schizophrenic patients on most indexes of outcome. Outcome also varied over time, with borderline patients functioning best in the second decade after discharge.

Schizotypal personality disorder. Chestnut Lodge follow-up study: VI. Long-term follow-up perspectives.

This study reports the first long-term follow-up of patients with schizotypal personality disorder (SPD) as defined by DSM-III. Patients with the pure syndrome (SPD, n = 10) were compared with patients with schizophrenia (S, n = 53) and borderline personality disorder (BPD, n = 81). Three "mixed" cohorts (S/SPD, n = 61; S/SPD/BPD, n = 30; SPD/BPD, n = 18) were added to investigate the effect of schizotypal disorder on the longitudinal course of comparison groups. Schizotypal personality disorder proved to be common in the Chestnut Lodge follow-up study patients, although it was rare as a pure syndrome. From the perspective of follow-up, SPD appeared related to S but not to BPD. The mixed axis II borderline syndrome (SPD/BPD) had a long-term profile closer to BPD than to SPD, and adding SPD to S appeared (unexpectedly) to enhance outcome.

The prediction of outcome in chronic schizophrenia. IV. The Chestnut Lodge follow-up study.

Predictors of long-term outcome were identified among a sample (n = 163) of largely chronic DSM-III schizophrenic patients (80% ill for more than two years) from the Chestnut Lodge follow-up study using three methods of analysis (correlation, multiple regression, and discriminant function). Predictors accounted for approximately one third of the outcome variance across six outcome dimensions. The following variables regularly (ie, individually and as components in multivariate equations) predicted better global outcome: less family history of schizophrenia, better premorbid instrumental functioning (interests and skills), more affective signs and symptoms (especially depression) in the manifest psychopathology, and absence of psychotic assaultiveness.

The borderline syndrome. I. Testing three diagnostic systems.

Diagnostic systems require testing on several factors: reliability, comprehensiveness, concordance with established use, specificity, and validity. Three sets of diagnostic criteria for the borderline have been proposed recently: the Gunderson et al criteria, the DSM-III criteria for borderline personality (BP) disorder, and the DSM-III criteria for schizotypal personality (SP) disorder. This article reviews work to date testing these systems on these factors. New data are presented from the retrospective application of these criteria to the clinical records of 400 diagnostically heterogeneous former inpatients at Chestnut Lodge, Rockville, Md; 330 of them also received systematic follow-up by interview an average of 15 years after discharge. Results strongly supported the validity of the DSM-III division of borderline into BP and SP. Although the BP and Gunderson et al criteria demonstrated high concordance, the latter appeared to offer some slight advantages for defining BP disorder.

The borderline syndrome. II. Is it a variant of schizophrenia or affective disorder?

Recent studies question whether the borderline syndrome represents two entities: borderline schizophrenia (or schizotypal personality) as a variant of schizophrenia and borderline personality disorder as a variant of primary affective disorder. Relevant data are presented from the long-term follow-up of patients at the Chestnut Lodge, Rockville, Md, receiving systematic diagnoses by the retrospective application of diagnostic criteria. Studied were (1) diagnostic overlap at index admission, (2) diagnostic change over follow-up period, and (3) comparative long-term functional outcome between borderline samples and other diagnostic groups. Findings supported the hypothesis that schizotypal personality (as defined by DSM-III) is a variant of schizophrenia but borderline personality disorder (as defined by the DSM-III and Gunderson et al criteria) is not. An affiliation of borderline personality disorder with primary affective disorder is suggested although not conclusive.