Biomedical subjects
Publications and source records attributed to T H McGlashan.
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.
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A number of studies suggest that schizophrenia may arise from overzealous pruning of synapses that are an extension of normal developmental pruning during adolescence. Moreover, there has been a long history of studies suggesting that this disorder arises from alterations in the dopaminergic neuromodulatory systems. In order to further assess and compare these two hypotheses, a computer simulation of some aspects of speech perception was developed utilizing a recurrent, backpropagation model of working memory previously reported by Elman . This system was found to produce spontaneous percepts simulating hallucinated speech when the working memory component either was excessively pruned or when neuronal responses were modulated to simulatea hyperdopaminergic system. These hallucinogenic systems also demonstrated disruptions in processing input information when "phonetic information" was degraded. The perceptual performance of these systems were compared to that of actual hallucinating patients and normal controls while tracking (repeating while simultaneously listening to) speech that was phonetically degraded. We found that the neural network simulation producing the best match to speech tracking performance of human hallucinators was an overpruned system with compensatory hypodopaminergic adjustments. These data suggest that the primary pathophysiology of schizophrenia arises from curtailed connectivity in working memory systems and that dopaminergic alterations reflect secondary compensatory adjustments.
OBJECTIVE: Comorbidity among personality disorders is widely considered problematic. The validity of one proposed solution, diagnostic hierarchies, was investigated in the current study with respect to borderline, schizotypal, avoidant, and obsessive-compulsive personality disorders. METHOD: One approach used discriminant functions, derived from multiple psycho-social domains, that were used to classify comorbid individuals from the Collaborative Longitudinal Personality Disorder study (CLPS) to explore the possibility of hierarchical precedence of one personality disorder over another. A second approach examined the incremental increase in R(2)-value in predicting functioning and personality provided by each diagnosis over each other diagnosis. RESULTS: Obsessive-compulsive personality disorder was consistently subordinate to other diagnoses, whereas other indications of hierarchical relationships were domain-specific. CONCLUSION: Results indicate minimal support for an over-arching hierarchical pattern among studied personality disorders, and suggest the inclusion of all relevant diagnoses in clinical practice.
OBJECTIVE: Existing evidence from anxiety disorder research indicates that social phobics (SP) with avoidant personality disorder (AVPD) experience more anxiety and show more impairment than patients with SP alone. The purpose of this study was to examine whether in patients diagnosed with AVPD, the co-occurrence of SP adds to its severity. We hypothesized that the addition of SP will not add to the severity of AVPD alone. METHOD: Two groups of patients (AVPD=224; AVPD/SP=101) were compared at baseline and 2 years later on multiple demographic and clinical variables. RESULTS: Patients with AVPD and an additional diagnosis of SP differed little from patients with AVPD alone. CONCLUSION: These findings suggest that AVPD and SP may be alternative conceptualizations of the same disorder.
Data from the Scale of Prodromal Symptoms (SOPS) [Early Intervention in Psychotic Disorders, pp. 135-150] on 94 hitherto never-psychotic individuals were entered into a principal components analysis, revealing six components with an eigenvalue greater than 1.0. Based upon scree-plot analysis, further extractions were limited to three, then two, factors. Varimax rotation of the three-component extraction revealed factors with reasonable congruence with a priori content areas. All symptoms labeled as negative in the SOPS loaded on one factor, and four of five symptoms labeled as positive loaded on another. The remaining positive symptom, conceptual disorganization, has been found not to load with other positive-labeled symptoms in studies of schizophrenia using applicable instruments. All symptoms labeled as "general" in the SOPS loaded on a third factor, which appears to reflect the nonspecific psychological distress that might be expected in psychosis-naïve individuals experiencing the preliminary stages of a serious psychiatric disorder. The independence of this component from the positive and negative symptom factors suggests that the structure obtained suggests a clinical continuity between the at-risk presentations seen in this sample and established schizophrenia.
Thirty-six subjects aged 16 years or older judged at risk for a first episode of psychosis within a North American multi-site study of the schizophrenia prodrome [McGlashan et al., Schizophr. Res. (2003); Miller et al., Schizophr. Res. (2003)] performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Conversely, the finding that they do not show the levels of impairment commonly observed in schizophrenia, including within the first episode, suggests that prodromal interventions might conceivably prevent, delay, or lessen the severity of declines associated with first psychotic episodes.
OBJECTIVE: To examine the longitudinal diagnostic efficiency of the DSM-IV criteria for obsessive-compulsive personality disorder (OCPD). METHOD: At baseline, criteria and diagnoses were determined using diagnostic interviews, and blinded assessments were performed 24 months later with 550 participants. Diagnostic efficiency indices (conditional probabilities, total predictive power, and kappa) were calculated for each criterion determined at baseline, using the independent OCPD diagnosis at follow-up as the standard. RESULTS: Longitudinal diagnostic efficiencies for the OCPD criteria varied; findings suggested the overall predictive utility of 'preoccupied with details', 'rigid and stubborn', and 'reluctant to delegate'. CONCLUSION: These findings suggest the predictive validity of three cognitive-interpersonal OCPD criteria.
OBJECTIVE: While findings are contradictory, many studies report that long Duration of Untreated Psychosis (DUP) correlates with poorer outcome in first episode psychosis. In an outcome study of first-episode psychosis, we compared the patients who refused to participate in a follow-along with those who consented to estimate the importance of this factor in sample recruitment bias. Our questions were: (i) What is the percentage of refusers? (ii) Are there systematic differences between refusers and consenters on DUP and/or other admission variables? (iii) What is the risk of refusal for different values of DUP? METHOD: In an unselected group of consecutively admitted patients we compared follow-along refusers and consenters on the following admission variables: sex, age, diagnostic group, substance abuse, being in-patient, coming from an early detection site and DUP. We conducted a logistic regression analysis with refusal as the outcome variable. RESULTS: Ninety-three of 397 patients (23%) were refusers. In univariate analyses the only significant difference was found for DUP. The median DUP for consenters was 10 weeks and for refusers 32 weeks. DUP remained significant when all independent variables were controlled for. CONCLUSION: DUP was significantly related to risk for refusal. For tests of the impact of DUP on outcome, this may introduce a type II error bias.
OBJECTIVE: Although much attention has been given to the effects of adverse childhood experiences on the development of personality disorders (PDs), we know far less about how recent life events influence the ongoing course of functioning. We examined the extent to which PD subjects differ in rates of life events and the extent to which life events impact psychosocial functioning. METHOD: A total of 633 subjects were drawn from the Collaborative Longitudinal Personality Disorders Study (CLPS), a multi-site study of four personality disorders--schizotypal (STPD), borderline (BPD), avoidant (AVPD), obsessive-compulsive (OCPD)--and a comparison group of major depressive disorders (MDD) without PD. RESULTS: Borderline personality disorder subjects reported significantly more total negative life events than other PDs or subjects with MDD. Negative events, especially interpersonal events, predicted decreased psychosocial functioning over time. CONCLUSION: Our findings indicate higher rates of negative events in subjects with more severe PDs and suggest that negative life events adversely impact multiple areas of psychosocial functioning.
The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. This report presents the study rationale and design. Recent studies will be reviewed that have advanced our knowledge about the early course of schizophrenia and our ability to predict onset prospectively, advances that have rendered prodromal intervention research feasible and ethical. The study design has many novel features. It tests for prevention versus delay in psychosis onset, as well as for efficacy and safety in a newly defined clinical population. This has required the development of innovative clinical research assessment instruments and a new operational definition of psychosis onset. The integration of these novel elements into an otherwise typical clinical trial design is detailed. The companion report will address sample recruitment and the clinical phenomenology at baseline of this putative "prodromal" entity.
The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. The purpose of this report is to describe the study's "prodromally symptomatic" sample at baseline, i.e., at intake immediately prior to randomization and prior to receiving study medication. Sixty treatment-seeking patients meeting prodromal inclusion criteria were recruited across four sites: New Haven, CT (n=39), Toronto, Ontario (n=9), Calgary, Alberta (n=6), and Chapel Hill, NC (n=6). The sample was young (median age 16), largely male (65%), and came from families with high titers of serious mental illness (44%). Most patients (93%) met criteria for the Attenuated Positive Symptom (APS) prodromal syndrome and presented with significant but nonpsychotic suspiciousness, perceptual aberrations, unusual thought content, and conceptual disorganization. They presented with minimal to mild affective symptoms and substance use/abuse, but they were quite functionally compromised (mean Global Assessment of Functioning (GAF) score=42). The prodromal sample was compared with other clinical-trial samples of adolescent depression, adolescent mania, and first episode schizophrenia. Prodromal patients proved not to be depressed or manic. They were less severely ill than untreated first episode schizophrenia but more severely ill than treated first episode schizophrenia. While not psychotically disabled, these patients nevertheless present with a clinical syndrome. Subsequent reports will detail the effects of drug versus placebo on prodromal symptoms, neuropsychological profile, and the rate of conversion to psychosis.
The aim of this study was to describe the PROD-screen, an instrument for screening prodromal symptoms indicating risk for psychotic conversion in the near future. PROD-screen consists of 29 questions assessing performance and symptoms. Clinical construct validity was tested by comparing scores from the unselected general population (GP, n = 64) with those of general psychiatric patients from a community mental health centre (CMHC, n = 107). The concordant validity of PROD-screen for prodromal symptoms of psychosis was assessed in a large epidemiologically mixed sample of research subjects (n = 132) by comparing PROD-screen scores with the prodromal diagnosis made by Structured Interview for Prodromal Symptoms as a gold standard. Using the cut-off point of 2/12 specific symptoms, PROD-screen gave correct classification of prodromal status in 77% of cases, distinguishing prodromal from non-prodromal subjects with reasonable sensitivity (80%) and specificity (75%) in the epidemiologically mixed sample. According to subsample analysis PROD-screen functions well with first-degree relatives of schizophrenic patients and probably also with general population samples, but not with psychiatric outpatients. In conclusion, PROD-screen is a useful tool for screening prodromal symptoms of psychosis and selecting subjects for more extensive research interviews.
BACKGROUND: Assessment of neurocognitive dysfunction in schizophrenia is hampered by the multitude of tests used in the literature. AIMS: We aimed to identify the main dimensions of an assessment battery for patients with first-episode psychosis and to estimate the relationship between dimension scores and gender, age, education, diagnosis and symptoms. METHOD: Eight frequently used neuropsychological tests were used. We tested 219 patients 3 months after start of therapy or at remission, whichever occurred first. RESULTS: We identified five dimensions: working memory (WM); verbal learning (VL); executive function (EF); impulsivity (im); and motor speed (MS). Significant findings were that the MS score was higher for men, and the WM and VL scores were correlated with years of education. CONCLUSIONS: Neurocognitive function in first-episode psychosis is described by at least five independent dimensions.
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Screening a population of relatives of current schizophrenic patients could be an efficient means to accrue a sample of early first episode or prodromal patients for a prediction study or an intervention study. The risk of new onset schizophrenia cases in any one year in a population of relatives depends on the number of schizophrenic probands and three additional factors: (1) the age of onset distribution for schizophrenia; (2) the lifetime risk of the at-risk group of relatives selected; and (3) the number of at-risk relatives per proband and their age distribution. Estimates are made for each of these parameters, and calculations are presented. The base model suggests that screening all siblings and children of patients with schizophrenia would yield approximately 19 new cases of schizophrenia per year per 10,000 relatives screened. The results of the calculation are relatively insensitive to reasonable variation of most model parameter estimates. The yield of new cases obtained by screening relatives of current patients appears to be low if the purpose is to recruit a sample for an early intervention study over a relatively short period of time.
Some studies in first-episode schizophrenia correlate shorter duration of untreated psychosis (DUP) with better prognosis, suggesting that timing of treatment may be important. A three-site prospective clinical trial in Norway and Denmark is underway to investigate the effect of the timing of treatment in first-episode psychosis. One health care sector (Rogaland, Norway) is experimental and has developed an early detection (ED) system to reduce DUP. Two other sectors (Ullevål, Norway, and Roskilde, Denmark) are comparison sectors and rely on existing detection and referral systems for first-episode cases. The study ultimately will compare early detected with usual detected patients. This paper describes the study's major independent intervention variable, i.e. a comprehensive education and detection system to change DUP in first onset psychosis. System variables and first results from the four-year inclusion period (1997-2000) are described. It includes targeted information towards the general public, health professionals and schools, and ED teams to recruit appropriate patients into treatment as soon as possible. This plus easy access to psychiatric services via ED teams systematically changed referral patterns of first-episode schizophrenia. DUP was reduced by 1.5 years (mean) from before the time the ED system was instituted (to 0.5 years). The ED strategies appear to be effective and to influence directly the community's help-seeking behaviour.
Clinical trials have begun of antipsychotic treatments in persons who are prodromally symptomatic and at high risk for schizophrenia but who have not yet become psychotic. The ethical issues connected with intervening prior to making a diagnosis of psychosis are detailed. Compelling but tentative evidence suggests that early treatment may improve course and prognosis, and this has initiated a paradigm shift in thinking about the risks and benefits of early intervention. The nature of this evidence, its implications, its shortcomings, and its effect upon the ethics of treating schizophrenia are elaborated and discussed. It is concluded that clinical psychiatry is currently in a state of "equipoise" or genuine uncertainty about the comparative merits of early treatment, a state which endorses early intervention research, including intervention in the prodromal phase.