by
Jean Addington;
Danijela Piskulic;
Lu Liu;
Jonathan Lockwood;
Kristin S. Cadenhead;
Tyrone D. Cannon;
Barbara A. Cornblatt;
Thomas H. McGlashan;
Diana O. Perkins;
Larry J. Seidman;
Ming T. Tsuang;
Elaine Walker;
Carrie E. Bearden;
Daniel H. Mathalon;
Scott W. Woods
Several studies have demonstrated that youth at clinical high risk (CHR) of developing psychosis have a high prevalence of comorbid psychiatric disorders. Less is known about the impact of comorbid diagnoses on later conversion to psychosis and the change over time. The aim of this study was to determine the frequency and distribution of psychiatric diagnoses at baseline and over time in the North American Prodrome Longitudinal Study (NAPLS 2) and the role of comorbid diagnoses in conversion to psychosis. The NAPLS 2 sample consisted of 744 CHR youth and 276 healthy controls. Only 21% of the CHR group did not have a comorbid diagnosis with many have 2–3 DSM-IV comorbid diagnoses. The most common diagnoses were anxiety and depressive disorders, which did improve over time. The only diagnosis at baseline that differentiated the converters from the non-converters was cannabis misuse. Comorbidity, except for cannabis use, was essentially independent of clinical outcome. It is possible that those with comorbid diagnoses are preferentially the help-seeking individuals that present for help in our clinics and research projects and that those who at risk but do not have a comorbid diagnosis may not be seeking help in the prodromal phase.
The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology.
by
Benjamin B. Brodey;
Ragy R. Girgis;
Oleg V. Favorov;
Jean Addington;
Diana O. Perkins;
Carrie E. Bearden;
Scott W. Woods;
Elaine Walker;
Barbara A. Cornblatt;
G. Brucato;
Barbara Walsh;
Kathryn A. Elkin;
Inger S. Brodey
Machine learning techniques were used to identify highly informative early psychosis self-report items and to validate an early psychosis screener (EPS) against the Structured Interview for Psychosis-risk Syndromes (SIPS). The Prodromal Questionnaire–Brief Version (PQ-B) and 148 additional items were administered to 229 individuals being screened with the SIPS at 7 North American Prodrome Longitudinal Study sites and at Columbia University. Fifty individuals were found to have SIPS scores of 0, 1, or 2, making them clinically low risk (CLR) controls; 144 were classified as clinically high risk (CHR) (SIPS 3–5) and 35 were found to have first episode psychosis (FEP) (SIPS 6). Spectral clustering analysis, performed on 124 of the items, yielded two cohesive item groups, the first mostly related to psychosis and mania, the second mostly related to depression, anxiety, and social and general work/school functioning. Items within each group were sorted according to their usefulness in distinguishing between CLR and CHR individuals using the Minimum Redundancy Maximum Relevance procedure. A receiver operating characteristic area under the curve (AUC) analysis indicated that maximal differentiation of CLR and CHR participants was achieved with a 26-item solution (AUC = 0.899 ± 0.001). The EPS-26 outperformed the PQ-B (AUC = 0.834 ± 0.001). For screening purposes, the self-report EPS-26 appeared to differentiate individuals who are either CLR or CHR approximately as well as the clinician-administered SIPS. The EPS-26 may prove useful as a self-report screener and may lead to a decrease in the duration of untreated psychosis. A validation of the EPS-26 against actual conversion is underway.
by
Bradley Pearce;
Sydney Hubbard;
Hilda N. Rivera;
Patricia P. Wilkins;
Marylynn C. Fisch;
Myfanwy H. Hopkins;
Wendy Hasenkamp;
Robin Gross;
Nancy G. Bliwise;
Jeffrey L. Jones;
Erica Duncan
The prevalence of Toxoplasma gondii (TOXO) infection in schizophrenia (SCZ) is elevated compared to controls (odds ratio = 2.73). TOXO infection is associated with psychomotor slowing in rodents and non-psychiatric humans. Latency of the acoustic startle response, an index of neural processing speed, is the time it takes for a startling stimulus to elicit the reflexive response through a three-synapse subcortical circuit. We report a significant slowing of latency in TOXO seropositive SCZ vs. seronegative SCZ, and in TOXO seropositive controls vs. seronegative controls. Latency was likewise slower in SCZ subjects than in controls. These findings indicate a slowing of neural processing speed with chronic TOXO infection; the slowest startle latency was seen in the TOXO seropositive SCZ group.
Objective
Longitudinal analysis is crucial in determining the ability of new interventions to successfully reduce negative symptoms in schizophrenia. However, there are still conflicting reports as to whether there are significant treatment effects on these symptoms and the extent of these effects. We examine the possible effects of analysis method on these questions.
Method
We use generalized linear mixed models (GLMM) to assess the change in specific negative symptom items following treatment changes in two separate cohorts of schizophrenia patients, one chronic and one first-episode.
Results
Both data sets indicate that examining the change in prevalence of moderate to severe symptoms provides a useful estimate of the effect size associated with changes in treatment that often differs from that given using analysis of means.
Conclusions
The use of categorical longitudinal methods may be critical to determining the responsiveness of negative symptoms to treatment as well as determining the stability of these symptoms over time.
by
Maju Mathew Koola;
William A Brown Jr.;
Clifford Qualls;
Bruce Cuthbert;
Jeffrey P. Hollis;
Deanna L. Kelly;
Ngoc-Anh Le;
Jeffrey Raines;
Erica Duncan
Background: Peripheral arterial compliance is a measure of elasticity of the arteries that has been found to be a robust predictor of prevalent arteriosclerosis as well as incident stroke and myocardial infarction. Psychiatric diagnoses and second generation antipsychotics may contribute to cardiovascular risk and stroke, but effects on peripheral arterial compliance are unknown. This study compared peripheral arterial compliance in healthy male controls to male patients with psychiatric diagnoses who were treated with quetiapine or risperidone or off antipsychotics at time of testing. Methods: The groups consisted of 63 patients with mental illness taking quetiapine, risperidone, or no antipsychotics. There were 111 males in the control group. Mean thigh and calf arterial compliance among four groups were compared by ANCOVA, adjusting for body mass index and Framingham Risk Score. All patients were also compared to the control group. Compliance was measured with a computerized plethysmography device. Results: Patients (. n=. 63) had significantly lower arterial compliance in both thigh and calf than the controls. Arterial compliance in the calf was significantly lower in the subgroups of quetiapine (. n=. 16) and risperidone (. n=. 19) treated, and in unmedicated (. n=. 28) patients than in controls. In the thigh, patients taking either quetiapine or risperidone had significantly lower arterial compliance than controls. These subgroups did not differ from each other in arterial compliance. Conclusion: The presence of psychiatric diagnoses is associated with reduced arterial compliance. A large study may be required to measure any specific affects of antipsychotics such as quetiapine and risperidone on compliance compared to controls.
Objectives
Persons with serious mental illnesses (SMI) have elevated rates of comorbid medical conditions, but may also face challenges in effectively managing those conditions.
Methods
The study team developed and pilot-tested the Health and Recovery Program (HARP), an adaptation of the Chronic Disease Self-Management Program (CDSMP) for mental health consumers. A manualized, six-session intervention, delivered by mental health peer leaders, helps participants become more effective managers of their chronic illnesses. A pilot trial randomized 80 consumers with one or more chronic medical illness to either the HARP program or usual care.
Results
At six month follow-up, participants in the HARP program had a significantly greater improvement in patient activation than those in usual care (7.7% relative improvement vs. 5.7% decline, p=0.03 for group*time interaction), and in rates of having one or more primary care visit (68.4% vs. 51.9% with one or more visit, p=0.046 for group*time interaction). Intervention advantages were observed for physical health related quality of life (HRQOL), physical activity, medication adherence, and, and though not statistically significant, had similar effect sizes as those seen for the CDSMP in general medical populations. Improvements in HRQOL were largest among medically and socially vulnerable subpopulations.
Conclusions
This peer-led, medical self-management program was feasible and showed promise for improving a range of health outcomes among mental health consumers with chronic medical comorbidities. The HARP intervention may provide a vehicle for the mental health peer workforce to actively engage in efforts to reduce morbidity and mortality among mental health consumers.
Introduction: Increased inflammatory markers have been found in patients with chronic schizophrenia, and have been associated with negative symptoms. The deficit syndrome is a distinct subtype of schizophrenia, characterized by primary and enduring negative symptoms.
Method: We measured inflammatory markers in patients with and without deficit schizophrenia and controls. Results: Using multivariate analyses, tumor necrosis factor (TNF)-α and interleukin-6 were associated with the deficit syndrome, and TNF-α predicted blunted affect, alogia, and total negative symptoms.
Conclusions: Findings suggest that deficit schizophrenia subtype is associated with increased inflammation and immunotherapies may be a novel target for negative symptoms.
by
Kristin S. Cadenhead;
Amedeo Minichino;
Skylar Kelsven;
Jean Addington;
Carrie Bearden;
Tyrone D. Cannon;
Barbara A. Cornblatt;
Dan Mathalon;
Thomas H. McGlashan;
Diana O. Perkins;
Larry J. Seidman;
Ming Tsuang;
Elaine Walker;
Scott W. Woods;
Jeff Yao
Objective: Patients with schizophrenia have a high prevalence of metabolic disorders and cardiovascular mortality. It is possible that a vulnerability to metabolic abnormalities is associated with risk for psychosis, symptoms and functionality. In this study, we evaluate demographic information, cardiometabolic indices, symptoms and functioning in an antipsychotic free cohort at Clinical High Risk (CHR) for psychosis from the NAPLS Omega 3 fatty acid clinical trial. Method: Subjects received physical exams and metabolic monitoring prior to randomization into the Omega 3 versus Placebo trial. Anthropometrical measures, vital signs, glucose, and lipids were assessed along with symptoms, functioning, dietary Omega 3 fatty acids, erythrocyte polyunsaturated fatty acid content and a measure of lipid peroxidation (TBARS, Thiobarbituric acid-reactive substances). Results: The sample included 113 CHR subjects (42.1% female; 17.5% Latino) ages 12–29. The mean BMI was 24.3 with a trend toward higher BMI and a higher incidence of metabolic syndrome in Latino subjects; 36% of the sample was obese/overweight; 37.6% met criteria for prehypertension/hypertension; 4.2% met criteria for prediabetes/diabetes; 9.6% showed evidence of insulin resistance and 44.7% had dyslipidemia. The TBARS was elevated at 9.8 μM ± 6.1 (normal 1.86–3.94 μM). Metabolic parameters and a diet low in Omega 3 rich foods were significantly associated with prodromal symptoms and poor functioning. Conclusions: CHR subjects show a high percentage of metabolic abnormalities prior to exposure to antipsychotic medication. These findings reinforce that early detection of metabolic disturbances and food insecurity is crucial since these factors are modifiable with the potential for significant gains in terms of quality of life, physical and mental health.
by
Eva Velthorst;
Eric C. Meyer;
Anthony J. Giuliano;
Jean Addington;
Kristin S. Cadenhead;
Tyrone D. Cannon;
Barbara A. Cornblatt;
Thomas H. McGlashan;
Diana O. Perkins;
Ming T. Tsuang;
Elaine Walker;
Scott W. Woods;
Carrie E. Bearden;
Larry J. Seidman
Background: Most studies of neurocognitive functioning in Clinical High Risk (CHR) cohorts have examined group averages, likely concealing heterogeneous subgroups. We aimed to identify neurocognitive subgroups and to explore associated outcomes. Methods: Data were acquired from 324 participants (mean age 18.4) in the first phase of the North American Prodrome Longitudinal Study (NAPLS-1), a multi-site consortium following individuals for up to 2 1/2 years. We applied Ward's method for hierarchical clustering data to 8 baseline neurocognitive measures, in 166 CHR individuals, 49 non-CHR youth with a family history of psychosis, and 109 healthy controls. We tested whether cluster membership was associated with conversion to psychosis, social and role functioning, and follow-up diagnosis. Analyses were repeated after data were clustered based on independently developed clinical decision rules. Results: Four neurocognitive clusters were identified: Significantly Impaired (n = 33); Mildly Impaired (n = 82); Normal (n = 145) and High (n = 64). The Significantly Impaired subgroup demonstrated the largest deviations on processing speed and memory tasks and had a conversion rate of 58%, a 40% chance of developing a schizophrenia spectrum diagnosis (compared to 24.4% in the Mildly Impaired, and 10.3% in the other two groups combined), and significantly worse functioning at baseline and 12-months. Data clustered using clinical decision rules yielded similar results, pointing to high convergent validity. Conclusion: Neurocognitive profiles vary substantially in their severity and are associated with diagnostic and functional outcome, underscoring neurocognition as a predictor of illness outcomes. These findings, if replicated, are a first step toward personalized treatment for individuals at-risk for psychosis.