Jai Shah

Are structural brain abnormalities associated with suicidal behavior in patients with psychotic disorders

Suicide represents a major health problem world-wide. Nevertheless, the understanding of the neurobiological underpinnings of suicidal behavior remains far from complete. We compared suicide attempters to non-attempters, and high vs. low lethality attempters, to identify brain regions associated with suicidal behavior in patients with psychotic disorders. 489 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I and 262 healthy controls enrolled in the B-SNIP study were studied. Groups were compared by attempt history and the highest medical lethality of previous suicide attempts. 97 patients had a history of a high lethality attempt, 51 of a low lethality attempt and 341 had no attempt history. Gray matter volumes were obtained from 3T structural MRI scans using FreeSurfer. ANCOVAs were used to examine differences between groups, followed by Hochberg multiple comparison correction. Compared to non-attempters, attempters had significantly less gray matter volume in bilateral inferior temporal and superior temporal cortices, left superior parietal, thalamus and supramarginal regions, right insula, superior frontal and rostral middle frontal regions. Among attempters, a history of high lethality attempts was associated with significantly smaller volumes in the left lingual gyrus and right cuneus. Compared to non-attempters, low lethality attempters had significant decreases in the left supramarginal gyrus, thalamus and the right insula. Structural brain abnormalities may distinguish suicide attempters from non-attempters and high from low lethality attempters among individuals with psychotic disorders. Regions in which differences were observed are part of neural circuitries that mediate inhibition, impulsivity and emotion, visceral, visual and auditory perception.

Multivariate prediction of emerging psychosis in adolescents at high risk for schizophrenia.

BACKGROUND Accurate prediction of psychosis development in high-risk populations is an important but thus far elusive goal. Of the many diverse etiologic and risk factors identified thus far, few have been combined into prospective multivariate risk ascertainment models. We tested the predictive power of familial, neurobiological, socioenvironmental, cognitive and clinical risk factors through an integrative biopsychosocial model for emerging psychosis in young relatives at familial risk for schizophrenia. METHODS 96 young first- and second- degree relatives of schizophrenia probands were followed for an average of 2.38 (SD=0.98) years to examine their trajectory towards psychosis. Iterative structural equation modelling utilizing multiple etiologic and risk factors was employed to estimate their joint contribution to prediction of psychosis development. RESULTS The rate of conversion to psychosis over the study period was 12.5%. In the final model, clinical measures of schizotypy were directly predictive of conversion, with early (familial, biological, socioenvironmental) and cognitive risk factors indirectly predictive of psychosis through increased baseline clinical symptomatology. Our model provided an excellent fit to the observed data, with sensitivity of 0.17, specificity of 0.99, positive predictive value of 0.67 and negative predictive value of 0.89. CONCLUSIONS Integrative modeling of multivariate data from familial, neurobiological, socioenvironmental, cognitive and clinical domains represents a powerful approach to prediction of psychosis development. The high specificity and low sensitivity found using a combination of such variables suggests that their utility may be in confirmatory testing among already selected high-risk individuals, rather than for initial screening. These findings also highlight the importance of data from a broad array of etiologic and risk factors, even within a familial high-risk population. With further refinement and validation, such methods could form key components of early detection, intervention and prevention programs.

Economic and regulatory considerations in pharmacogenomics for drug licensing and healthcare

As the first products based on pharmacogenomics emerge, economic and regulatory considerations will affect—and be affected by—drug approval, licensing and delivery long before medicines are prescribed by a physician.

Is early intervention for psychosis feasible and effective

Services that provide comprehensive, early intervention (EI) have shown promise in improving long-term outcomes in schizophrenia. This article reviews the rationale and salient concepts relevant to understanding the growing EI literature. A selective review of studies evaluating the effectiveness of integrated EI is followed by a discussion of feasibility, especially in the US context. Finally, the authors present a framework that seeks to integrate activities traditionally categorized and separated as discovery and implementation. This framework is offered as a way to advance both goals.

The four dimensions: a model for the social aetiology of psychosis

Recently, there has been increasing focus on prevention of mental illness, early intervention and the promotion of mental health. The social determinants of health and public health approaches are considered key. Early intervention has focused on psychotic disorders but prevention has not. This may in part reflect the fact that public health planners do not have a clear model for how social determinants influence the risk of developing a psychotic illness. Drawing on biological, genetic and epidemiologic evidence regarding the relationship between social risk factors and psychosis, this paper outlines a conceptual framework for understanding how individual and ecological factors contribute and interact to modulate the risk of developing psychotic illness. The framework asserts that there are four dimensions: individual factors; ecological factors; the interaction between individual and ecological factors; and time. It may help those considering interventions to understand the multilevel and multifactorial effects of social factors on the aetiology of psychotic illness, to develop targeted strategies for the prevention of psychotic illness and serve as a template for the assessment of initiatives.

Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder.

Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.

Much ado about much: Stress, dynamic biomarkers and HPA axis dysregulation along the trajectory to psychosis

OBJECTIVES In the context of a stress-vulnerability framework, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is thought contribute to the risk, onset and course of psychotic illness. However, recent reports regarding static and dynamic features of the HPA axis suggest a more complex set of phenomena at play in the early phases of psychosis. METHODS We review literature regarding structural and functional aspects of the HPA axis in subjects at risk for or experiencing the first episode of psychosis, including evidence favoring as well as that which contradicts a model of HPA axis hyperactivation. RESULTS Static measures of diurnal cortisol and hippocampal/pituitary volumes suggest that the HPA axis is in a hyperactivated state in early phases of psychosis. In contrast, the dynamic cortisol response to encountered or anticipated stress is blunted in the same populations. These incongruent findings need to be better understood. CONCLUSIONS We consider potential explanations for the seemingly contradictory elevation and blunting of HPA biomarkers in the early course of psychosis. Finally, we propose and explore implications of a conceptual model of tonic HPA hyperactivation and phasic HPA blunting that integrates and reconciles these data.

Psychosis prediction and clinical utility in familial high-risk studies: selective review, synthesis, and implications for early detection and intervention

Accurate prediction of which high‐risk individuals will go on to develop psychosis would assist early intervention and prevention paradigms. We sought to review investigations of prospective psychosis prediction based on markers and variables examined in longitudinal familial high‐risk (FHR) studies.

Is the Clinical High-Risk State a Valid Concept? Retrospective Examination in a First-Episode Psychosis Sample

OBJECTIVE One reason for worldwide interest in the clinical high-risk (CHR) state for psychosis is its potential as a target for prevention. However, the feasibility and utility of early intervention initiatives that are focused on this stage involve an untested assumption: that most patients with a first episode of psychosis (FEP) experience earlier CHR symptoms. The objective of this study was to identify and characterize the proportion of FEP patients who had experienced such symptoms prior to the onset of their psychosis. METHODS Semistructured interviews of 351 patients and families with the Circumstances of Onset and Relapse Schedule were supplemented by chart reviews in a catchment area-based sample of FEP patients. Information was extracted regarding pathways to care and psychiatric and behavioral changes over time. Experts (N=30) working in FEP and CHR settings identified which of 27 early signs and symptoms constitute attenuated positive or subthreshold psychotic symptoms (APSPS) if they appear prior to a syndromal-level psychotic episode. RESULTS Nine early signs and symptoms were endorsed by the experts as representing APSPS. More than half of consenting patients, and two-thirds (68%) of those who completed all assessments, had experienced at least one such sign or symptom prior to their FEP. The groups with and without APSPS were similar in social, demographic, and clinical characteristics. CONCLUSIONS Most consenting patients with an FEP had experienced previous signs and symptoms consistent with a CHR state prior to the onset of threshold-level psychotic symptoms, although a substantial minority had not. This finding validates the viability of the CHR construct as a potential target for early case identification and preventive and therapeutic interventions.

The Clinic for Assessment of Youth at Risk (CAYR): 10 years of service delivery and research targeting the prevention of psychosis in Montreal, Canada

In the context of an increasing focus on indicated prevention of psychotic disorders, we describe the operation of the Clinic for Assessment of Youth at Risk (CAYR) over 10 years, a specialized service for identification, monitoring and treatment of young individuals who meet ultra‐high risk (UHR) criteria for psychosis, and its integration within the Prevention and Early Intervention Program for Psychosis (PEPP) in Montreal, Canada.