Albana Dassori

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families

CONTEXT Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes. OBJECTIVE To adjudicate neurocognitive endophenotypes for bipolar disorder. DESIGN All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status. SETTING Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas. PARTICIPANTS Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia. MAIN OUTCOME MEASURE Neurocognitive test performance. RESULTS Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory. CONCLUSION This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

A Novel Missense Mutation in the Transmembrane Domain of Neuregulin 1 is Associated with Schizophrenia

BACKGROUND Although genetic factors are known to play an important role in schizophrenia, the identification of genes involved in this disorder has remained elusive. The neuregulin 1 gene is among the few candidate genes to have been implicated in schizophrenia susceptibility in several populations. However, no causal mutations within this gene have been identified. METHODS In attempts to identify polymorphisms within the neuregulin 1 gene, we performed DNA sequencing using 12 subjects with a history of psychosis from the Central Valley of Costa Rica. DNA genotyping and association studies were then performed in an extended cohort of 142 affected individuals and their relatives from the same population. RESULTS We identified a novel missense mutation (Val to Leu) in exon 11, which codes for the transmembrane region of the neuregulin 1 protein. Association analysis by the Family Based Association Test (FBAT) revealed that this mutation is associated with psychosis (p = .0049) and schizophrenia (p = .0191) in this population. CONCLUSIONS We report the finding of a missense mutation in the neuregulin 1 gene associated with schizophrenia. Additional analyses of an independent sample as well as detailed functional studies should be performed to determine the relevance of this novel polymorphism to the pathophysiology of schizophrenia.

Cannabinoid Receptor 1 Gene (CNR1) and Susceptibility to a Quantitative Phenotype for Hebephrenic Schizophrenia

Functional alterations of components of the endogenous cannabinoid system, in particular of the cannabinoid receptor 1 protein (CB1), are hypothetical contributors to many of the symptoms seen in schizophrenia. Variants within the cannabinoid receptor 1 gene (CNR1) have been shown to be directly associated with the hebephrenic form of schizophrenia in a Japanese population. This finding, however, has yet to be replicated. In the present study we sought to study the same (AAT)n‐repeat microsatellite of the CNR1 gene which showed association to hebephrenic schizophrenia in Japan, and to investigate whether this microsatellite showed association to a hebephrenic type of schizophrenia in a family‐based association study in a population of the Central Valley of Costa Rica. The Lifetime Dimensions of Psychosis Scale and a best estimate consensus process were utilized to identify subjects with schizophrenia who had an elevated lifetime dimensional score for negative and disorganized symptoms, which we used as a proxy for “hebephrenia.” Using the Family Based Association Test we found association of these hebephrenic subjects and the (AAT)n‐repeat marker of the CNR1 (multi‐allelic P = 0.0368). Our hypothesis that an association with the (AAT)n‐repeat marker of CNR1 would not be found with the more general type of schizophrenia was also confirmed. Schizophrenic subjects with prominent lifetime scores for disorganization and negative symptoms (dimension for hebephrenia) are associated with the CNR1 gene and present a type of symptomatology that resembles chronic cannabinoid‐induced psychosis. The current finding points to the possibility of different genetic and pathophysiologic mechanisms underlying different types of schizophrenia.

Suicidal indicators in schizophrenia

The clinical and sociodemographic profile of suicidal and nonsuicidal schizophrenia patients was investigated in 801 patients with this diagnosis seen at a comprehensive psychiatric facility between 1983 and 1987. Suicidal patients tended to exhibit depression, aggressiveness, substance abuse and a severe and progressive impairment in adaptive functioning.

Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population

Objective:  This study used the population of the Central Valley of Costa Rica (CVCR) and phenotyping strategies alternative to DSMIV classifications to investigate the association of neuregulin 1 with schizophrenia.

Concurrent and predictive validity of the allen cognitive levels assessment

The present study examined the concurrent and predictive validity of the Allen Cognitive Levels (ACL) Assessment in a sample of 110 medicated patients with schizophrenia who received the ACL at discharge from a state psychiatric facility. Subsamples within this group of patients had received an Activities of Daily Living assessment (n = 64) and a comprehensive neuropsychological test battery (n = 48) at discharge, or a battery of community follow-up measures (n = 30) 1-3.5 years following discharge as part of other investigations. Positive correlations were found between the ACL and concurrent measures of adaptive and cognitive function. With respect to cognitive variables, stepwise multiple regression analysis revealed that the majority of the variance in ACL scores was predicted by neuropsychological test scores assessing higher level cognitive processes, such as visual organization, manipulation of information in working memory, and ability to inhibit a response to a prepotent stimulus. Finally, results revealed positive relationships between the ACL obtained at discharge and community functioning at follow-up. The results of this study provide some evidence for the concurrent and predictive validity of the ACL for patients with schizophrenia and suggest that further study of this assessment tool would be important to pursue in future investigations.

Heritability of age of onset of psychosis in schizophrenia

Schizophrenia is a genetically complex illness with heterogeneous clinical presentation, including variable age of onset. In this study, the heritability, or proportion of variation in age of onset of psychotic symptoms due to genetic factors, was estimated using a maximum likelihood method. The subjects were 717 members of families with more than one member affected with schizophrenia from Mexican and Central American populations. Age of onset of psychosis was determined by best‐estimate consensus diagnosis based on the Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, and each subjects medical records. Mean age of onset was 21.44 years (SD 8.07); 20.55 years for males (SD 6.90), and 22.67 for females (SD 9.34). Variance components were estimated using a polygenic model in the SOLAR software package. The sex of the participant was a significant covariate (P = 0.010) accounting for 0.02 of the total variance in age of onset. The heritability of age of onset of psychosis was 0.33 (SE = 0.09; P = 0.00004). These findings suggest that genetic factors significantly contribute to the age of onset of psychotic symptoms in individuals with schizophrenia and that sex influences this trait as well.

A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry.

Schizophrenia is a complex psychiatric disorder, likely to be caused in part by multiple genes. In this study, linkage analyses were performed to identify chromosomal regions most likely to be associated with schizophrenia and psychosis in multiplex families of Mexican and Central American origin. Four hundred and fifty‐nine individuals from 99 families, containing at least two siblings with hospital diagnoses of schizophrenia or schizoaffective disorder, were genotyped. Four hundred and four microsatellite markers were genotyped for all individuals and multipoint non‐parametric linkage analyses were performed using broad (any psychosis) and narrow (schizophrenia and schizoaffective disorder) models. Under the broad model, three chromosomal regions (1pter‐p36, 5q35, and 18p11) exhibited evidence of linkage with non‐parametric lod (NPL) scores greater than 2.7 (equivalent to empirical P values of less than 0.001) with the peak multipoint NPL = 3.42 (empirical P value = 0.00003), meeting genomewide evidence for significant linkage in the 1pter‐p36 region. Under the narrow model, the same three loci showed (non‐significant) evidence of linkage. These linkage findings (1pter‐p36, 18p11, and 5q35) highlight where genes for psychosis and schizophrenia are most likely to be found in persons of Mexican and Central American ancestry, and correspond to recent linkages of schizophrenia or psychosis in other populations which were formed in part from emigrants from the Spanish empire of the 15th and 16th centuries.

A national cohort study of the association between the polytrauma clinical triad and suicide-related behavior among US veterans who served in Iraq and Afghanistan

OBJECTIVES We examined the association of posttraumatic stress disorder (PTSD), traumatic brain injury, and chronic pain-the polytrauma clinical triad (PCT)-independently and with other conditions, with suicide-related behavior (SRB) risk among Operation Enduring Freedom (OEF; Afghanistan) and Operation Iraqi Freedom (OIF) veterans. METHODS We used Department of Veterans Affairs (VA) administrative data to identify OEF and OIF veterans receiving VA care in fiscal years 2009-2011; we used International Classification of Diseases, Ninth Revision, Clinical Modification codes to characterize 211652 cohort members. Descriptive statistics were followed by multinomial logistic regression analyses predicting SRB. RESULTS Co-occurrence of PCT conditions was associated with significant increase in suicide ideation risk (odds ratio [OR] = 1.9; 95% confidence interval [CI]=1.5, 2.4) or attempt and ideation (OR=2.6; 95% CI=1.5, 4.6), but did not exceed increased risk with PTSD alone (ideation: OR=2.3; 95% CI=2.0, 2.6; attempt: OR=2.0; 95% CI=1.4, 2.9; ideation and attempt: OR=1.8; 95% CI=1.2, 2.8). Ideation risk was significantly elevated when PTSD was comorbid with depression (OR=4.2; 95% CI=3.6, 4.8) or substance abuse (OR=4.7; 95% CI = 3.9, 5.6). CONCLUSIONS Although PCT was a moderate SRB predictor, interactions among PCT conditions, particularly PTSD, and depression or substance abuse had larger risk increases.