Latent class cluster analysis of symptom ratings identifies distinct subgroups within the clinical high risk for psychosis syndrome

© 2017 The clinical-high-risk for psychosis (CHR-P) syndrome is heterogeneous in terms of clinical presentation and outcomes. Identifying more homogenous subtypes of the syndrome may help clarify its etiology and improve the prediction of psychotic illness. This study applied latent class cluster analysis (LCCA) to symptom ratings from the North American Prodrome Longitudinal Studies 1 and 2 (NAPLS 1 and 2). These analyses produced evidence for three to five subgroups within the CHR-P syndrome. Differences in negative and disorganized symptoms distinguished among the subgroups. Subgroup membership was found to predict conversion to psychosis. The authors contrast the methods employed within this study with previous attempts to identify more homogenous subgroups of CHR-P individuals and discuss how these results could be tested in future samples of CHR-P individuals

Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder

The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB - COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB - COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60; P = 0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81; P = 0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB - COMT in schizophrenia and bipolar disorder patients compared with the controls (P = 0.02) with an accompanying inverse correlation between MB - COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB - COMT hypomethylation in the patients. These findings suggest that MB - COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder. © Copyright 2006 Oxford University Press

Tobacco use and psychosis risk in persons at clinical high risk

Aim: To evaluate the role of tobacco use in the development of psychosis in individuals at clinical high risk. Method: The North American Prodrome Longitudinal Study is a 2-year multi-site prospective case control study of persons at clinical high risk that aims to better understand predictors and mechanisms for the development of psychosis. The cohort consisted of 764 clinical high risk and 279 healthy comparison subjects. Clinical assessments included tobacco and substance use and several risk factors associated with smoking in general population studies. Results: Clinical high risk subjects were more likely to smoke cigarettes than unaffected subjects (light smoking odds ratio [OR] = 3.0, 95% confidence interval [CI] = 1.9-5; heavy smoking OR = 4.8, 95% CI = 1.7-13.7). In both groups, smoking was associated with mood, substance use, stress and perceived discrimination and in clinical high risk subjects with childhood emotional neglect and adaption to school. Clinical high risk subjects reported higher rates of several factors previously associated with smoking, including substance use, anxiety, trauma and perceived discrimination. After controlling for these potential factors, the relationship between clinical high risk state and smoking was no longer significant (light smoking OR = 0.9, 95% CI = 0.4-2.2; heavy smoking OR = 0.3, 95% CI = 0.05-2.3). Moreover, baseline smoking status (hazard ratio [HR] = 1.16, 95% CI = 0.82-1.65) and categorization as ever smoked (HR = 1.3, 95% CI = 0.8-2.1) did not predict time to conversion. Conclusion: Persons at high risk for psychosis are more likely to smoke and have more factors associated with smoking than controls. Smoking status in clinical high risk subjects does not predict conversion. These findings do not support a causal relationship between smoking and psychosis

Psychotropic medication use in youth at high risk for psychosis: Comparison of baseline data from two research cohorts 1998-2005 and 2008-2011

Background: Antipsychotic medication use rates have generally been rising among youth with psychiatric disorders, but little is known about use rates of antipsychotics or other psychotropic medications in patients at high risk for psychosis. Method: Baseline psychotropic medication use rates were compared in two research cohorts of patients at high risk for psychosis that enrolled between 1998-2005 (n. = 391) and 2008-2011 (n. = 346). Treatment durations and antipsychotic doses were described for cohort 2. Results: Median age was 17. years in cohort 1 and 18. years in cohort 2. The rate of prescription of any psychotropic at baseline was roughly 40% for each cohort. Antipsychotic prescription rates were 24% among sites that permitted baseline antipsychotic use in cohort 1 and 18% in the cohort 2; the decline did not quite reach statistical significance (p. = 0.064). In cohort 2 the mean. ±. SD baseline chlorpromazine-equivalent dose was 121. ±. 108. mg/d, and lifetime duration of antipsychotic treatment was 3.8. ±. 5.9. months. Discussion: Although the rate of antipsychotic prescription among high-risk youth may have fallen slightly, the nearly one-in-five rate in the second cohort still constitutes a significant exposure. Mitigating factors were that doses and durations of treatment were low. As for other nonpsychotic conditions, it is incumbent on our field to develop alternative treatments for high-risk patients and to generate additional evidence for or against the efficacy of antipsychotics to help define their appropriate role if alternative treatments fail

Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: A preliminary report

DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns. Evidence from several studies has suggested that in schizophrenia and bipolar disorder, mRNA of the reelin gene (RELN), which encodes a protein necessary for neuronal migration, axonal branching, synaptogenesis, and cell signaling, is severely reduced in post-mortem brains. Therefore, we investigated the methylation status of the RELN promoter region in schizophrenic patients and normal controls as a potential mechanism for down regulation of its expression. Ten post-mortem frontal lobe brain samples from male schizophrenic patients and normal controls were obtained from the Harvard Brain Tissue Resources Center. DNA was extracted using a standard phenol-chloroform DNA extraction protocol. To evaluate differences between patients and controls, we applied methylation specific PCR (MSP) using primers localized to CpG islands flanking a potential cyclic AMP response element (CRE) and a stimulating protein-1 (SP1) binding site located in the promoter region. For each sample, DNA extraction, bisulfite treatment, and MSP were independently repeated at least four times to accurately determine the methylation status of the target region. Forty-three PCR trials were performed on the test and control samples. MSP analysis of the RELN promoter revealed an unmethylated signal in all reactions (43 of 43) using DNA from the frontal brain tissue, derived from either the schizophrenic patients or normal controls indicating that this region of the RELN promoter is predominantly unmethylated. However, we observed a distinct methylated signal in 73 of the trials (16 of 22) in schizophrenic patients compared with 24 (5 of 21) of controls. Thus, the hypermethylation of the CpG islands flanking a CRE and SP1 binding site observed at a significantly higher level (t = -5.07, P = 0.001) may provide a mechanism for the decreased RELN expression, frequently observed in post-mortem brains of schizophrenic patients. We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR. Despite the small sample size, these studies indicate that promoter hypermethylation of the RELN gene could be a significant contributor in effecting epigenetic alterations and provides a molecular basis for the RELN gene hypoactivity in schizophrenia. Further studies with a larger sample set would be required to validate these preliminary observations. © 2005 Wiley-Liss, Inc

Characterizing Covariant Trajectories of Individuals at Clinical High Risk for Psychosis across Symptomatic and Functional Domains

Objective: The authors sought to characterize differences in outcomes among help-seeking individuals at clinical high risk for psychosis by identifying covariant longitudinal patterns of symptoms and functioning. Methods: Group-based multitrajectory modeling was applied to longitudinal ratings of four symptom domains (positive, negative, disorganized, general) and general functioning among clinical high-risk individuals in an initial discovery sample (N=422). An independent sample (N=133) was used to test replicability. Results: Three trajectory groups were identified among clinical high-risk individuals in the discovery sample: group 1 (30%) exhibited substantial improvement across all domains, with half reaching positive outcomes for both functioning and positive symptoms; group 2 (49%) exhibited moderate impairments across domains, with approximately one-quarter meeting criteria for positive outcomes; the remaining participants (group 3; 22%) exhibited consistent levels of severe impairment across domains and did not experience positive outcomes. These trajectory groups and remission patterns were replicated in an independent sample. Conclusions: Replicable subgroups of help-seeking clinical high-risk cases can be ascertained based on distinctive profiles of change over time in symptoms and functioning. Within each of the three identified subgroups, similar patterns of change (i.e., rapid, moderate, or no improvement) were observed across the four symptom domains and functioning. This consistency of change over time across domains within each subgroup is a novel observation supporting the syndrome consistency of clinical high-risk symptoms and signs. The observed trajectory subgroups are suggestive of different degrees of need for clinical interventions, ranging from minimal or supportive for about one-third of cases to increasingly intensive among the remainder

Latent class cluster analysis of symptom ratings identifies distinct subgroups within the clinical high risk for psychosis syndrome

The clinical-high-risk for psychosis (CHR-P) syndrome is heterogeneous in terms of clinical presentation and outcomes. Identifying more homogenous subtypes of the syndrome may help clarify its etiology and improve the prediction of psychotic illness. This study applied latent class cluster analysis (LCCA) to symptom ratings from the North American Prodrome Longitudinal Studies 1 and 2 (NAPLS 1 and 2). These analyses produced evidence for three to five subgroups within the CHR-P syndrome. Differences in negative and disorganized symptoms distinguished among the subgroups. Subgroup membership was found to predict conversion to psychosis. The authors contrast the methods employed within this study with previous attempts to identify more homogenous subgroups of CHR-P individuals and discuss how these results could be tested in future samples of CHR-P individuals

Duration of the psychosis prodrome

The recognition of a prodromal period preceding the onset of frank psychosis dates back to its first descriptions. Despite insights gained from a prospective approach to the study of the Clinical High Risk syndrome for psychosis (CHR-P), a prospectively-based understanding of the duration of the psychosis prodrome and the factors that may influence is not well-established. Here we analyze data from the second North American Prodrome Longitudinal Study (NAPLS-2) to characterize prodrome duration in those who converted to psychosis. Of the 764 participants identified as being at CHR-P, 94 converted to psychosis and 92 of these had recorded estimates of prodrome onset. Estimates of prodrome duration were derived from CHR-P syndrome onset and conversion dates from the Structured Interview for Psychosis-risk Syndromes. Results identified a mean prodrome duration of 21.6 months. Neither CHR-P sub-syndrome nor medication exposure was found to significantly influence prodrome duration in this sample. These results provide the most precise estimate of prodrome duration to date, although results are limited to prodromes identified by ascertainment as being at CHR-P. Our findings also suggest a rule of thirds with regard to prodrome duration in those followed for two years: one third of CHR-P patients who convert will do so by 1 year after CHR-P syndrome onset, another third 1–2 years after onset, and the final third more than 2 years after onset

Sleep problems and attenuated psychotic symptoms in youth at clinical high-risk for psychosis

There has been growing interest on the effect of sleep problems on psychotic and prodromal symptoms. The current study investigated cross-sectional relations between sleep problems and attenuated psychotic symptoms in a large sample of 740 youth at Clinical High Risk (CHR) for psychosis in an attempt to replicate previous findings and assess whether findings from general population samples and psychotic samples extend to this CHR sample. Sleep problems were found to be significantly positively associated with attenuated psychotic symptom severity. Sleep problems were also found to be more closely associated with certain specific prodromal symptoms (e.g., suspiciousness and perceptual abnormalities) than other attenuated psychotic symptoms. Further, we found that depression mediated the cross-sectional association between sleep problems and paranoid symptoms only. This adds to a growing body of evidence suggesting the mediation role of depression is more pronounced for paranoid-type psychotic symptoms as compared to other psychotic symptoms (e.g., hallucinations)

Incorporating cortisol into the NAPLS2 individualized risk calculator for prediction of psychosis

Background: Risk calculators are useful tools that can help clinicians and researchers better understand an individual's risk of conversion to psychosis. The North American Prodrome Longitudinal Study (NAPLS2) Individualized Risk Calculator has good predictive accuracy but could be potentially improved by the inclusion of a biomarker. Baseline cortisol, a measure of hypothalamic-pituitary-adrenal (HPA) axis functioning that is impacted by biological vulnerability to stress and exposure to environmental stressors, has been shown to be higher among individuals at clinical high-risk for psychosis (CHR–P) who eventually convert to psychosis than those who do not. We sought to determine whether the addition of baseline cortisol to the NAPLS2 risk calculator improved the performance of the risk calculator. Methods: Participants were drawn from the NAPLS2 study. A subset of NAPLS2 participants provided salivary cortisol samples. A multivariate Cox proportional hazards regression evaluated the likelihood of an individual's eventual conversion to psychosis based on demographic and clinical variables in addition to baseline cortisol levels. Results: A total of 417 NAPLS2 participants provided salivary cortisol and were included in the analysis. Higher levels of cortisol were predictive of conversion to psychosis in a univariate model (C-index = 0.59, HR = 21.5, p-value = 0.004). The inclusion of cortisol in the risk calculator model resulted in a statistically significant improvement in performance from the original risk calculator model (C-index = 0.78, SE = 0.028). Conclusions: Salivary cortisol is an inexpensive and non-invasive biomarker that could improve individual predictions about conversion to psychosis and treatment decisions for CHR-P individuals