Vulnerability to Psychosis

From Neurosciences to Psychopathology

Paolo Fusar-Poli, Stefan J. Borgwardt, Philip McGuire, Paolo Fusar-Poli, Stefan J. Borgwardt, Philip McGuire

• Publisher: Psychology Press
• Year: 2013
• Print ISBN: 9781848720879
• eBook ISBN: 9781136596384
• Topic: Psychology
• Subtopic: Clinical Psychology
• Index: Psychology

Early clinical intervention in psychosis is now a major objective of mental health services and the development of specialist intervention services has greatly facilitated research on the early phases of this disorder.

In this book, contributors provide a review of the neurobiological research in people at high risk of psychosis, focusing on the transition from being at a high risk state to their first episode. Contributors consider unaffected family members and twin studies as well as the individual's data before and after the onset of the illness. The environmental factors that contribute to a psychotic episode are also examined.

Vulnerability to Psychosis presents neurobiological findings in the context of what is now known about the psychopathology and cognitive impairments that are evident in people at high risk of psychosis. It will be essential reading for clinicians working with this client group, and will interest academics looking for state of the art information in this field.

1   Introduction

Stefan Borgwardt, Paolo Fusar-Poli and Philip McGuire

Early clinical intervention in psychosis has recently become a major objective of mental health services, and the development of specialist early intervention services has greatly facilitated research on the early phases of the disorder. Research at this stage is potentially a way of investigating the mechanisms underlying psychosis, as the same individuals can be studied before and after the onset of illness, often with minimal confounding effects of previous treatment. The identification of a clinical syndrome (an “at risk mental state”) that reflects an “ultra high risk” predisposition to psychosis is fundamental to both clinical and research work in this area.

Endorsing the genetic high-risk approach, putative endophenotypes can be evaluated for association with genetic risk for schizophrenia by comparing the unaffected co-twins or the unaffected relatives of patients with normal controls. Alternatively, “close in”, i.e., clinical high-risk, approaches are able to identify a group at high risk of psychosis with higher transition rates than those observed in studies purely based on genetic inclusion criteria. The latter approach, focusing on individuals who are considered to be at increased risk for psychotic disorders, is based primarily on the presence of clinical symptoms. This clinical strategy aims at identifying neural changes occurring prior to the onset of psychosis and may improve our ability to predict schizophrenia outcomes based on the combined perspectives of both neural and clinical characteristics observed at the baseline assessment.

The presence of individuals who are at high risk but not psychotic is consistent with evidence that schizophrenia results from the interaction of environmental with genetic and neurodevelopmental factors, with the latter associated with clinical, neurobiological and neuropsychological features before the onset of psychosis. Over the past years, neuroscience techniques such as: structural brain imaging—magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI); functional brain imaging—positron emission tomography (PET), single-photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI); neurochemical imaging—magnetic resonance spectroscopy (MRS); and computerized models (Virtual Reality), have rapidly developed as powerful tools to explore the neurophysiological basis of vulnerability to psychosis.

This monograph is indented to provide a state-of-the-art review of neurobiological research in people at high risk of psychosis, with a particular focus on the processes that may underlie the transition from a high-risk state to a first episode of frank psychosis. These neurobiological findings will be presented in the context of what is now known about the psychopathology and cognitive impairments that are evident in people at high risk of psychosis, and environmental factors that may influence the risk of the onset of illness. The monograph thus aims to bring together a diversity of new information from a range of different research modalities, which are sometimes studied separately.

2 Neuroscience, continua and the prodromal phase of psychosis

Matthew Broome, Jennifer Dale, Charlotte Marriott, Cristina Merino and Lisa Bortolotti

Introduction

Our focus in this chapter is to address some of the challenges that arise when a purely neuroscientific conception of the prodromal phase of psychosis is considered. Two clear challenges arise, both of which have been discussed in the wider literature on schizophrenia and psychopathology. The first is how models of a continuum of psychosis can be reconciled with a scientific understanding of the prodrome as a discrete constellation of signs and symptoms. The second issue is wider: psychopathology may not be able to be defined solely by reference to the brain (Broome & Bortolotti, 2009). Given the importance of psychopathology in the delineation of “prodromal” or “ultra-high-risk” states this difficulty may also limit our optimism in being able to characterize the prodrome by wholly biological variables. These challenges are by no means isolated to psychiatry and psychosis research but touch on mainstream and wide-ranging debates in cognitive neuroscience around the naturalization of meaning in the brain.

Schizophrenia, development and the prodrome

It has been apparent for almost two decades that there is a developmental component to schizophrenia. In its simple form, this model postulates that genes involved in neurodevelopment and/or environmental insults in early life lead to aberrant brain development, which in turn predisposes to the later onset of psychosis (Bullmore et al., 1998; McDonald, Fearon, & Murray, 1999; Murray & Lewis, 1987). However, more recent formulations incorporate the role of social factors such as urban upbringing, social isolation, and migration (Boydell, van Os, McKenzie, & Murray, 2004; Morgan et al., 2007), and point to an interaction between the biological and psychological in a cascade of increasingly deviant development (Howes et al., 2004).

Prospective studies show that children who later develop schizophrenia are more likely than peers to show subtle developmental delays and cognitive impairments, they also tend to be solitary and socially anxious (Cannon et al., 2002; Jones, Rodgers, Murray, & Marmot, 1994). Some evidence suggests that individuals destined to develop schizophrenia fail to learn new cognitive skills as they enter adolescence, thus appearing to show a relative decline compared with their peer group (Fuller et al., 2002; Jones et al., 1994). The combination of neurocognitive and emotional deviance increases the likelihood of developing minor quasi-psychotic symptoms: indeed a prospective study in Dunedin showed pre-schizophreniform individuals to be more likely to manifest such symptoms as early as age 11 years (Cannon et al., 2002; Poulton et al., 2000). It is postulated that in those destined to develop psychosis the strength, frequency, and associated distress of the odd ideas and experiences increases, and, at some ill-defined point, the individual crosses a threshold into the pre-psychotic or prodromal phase (Broome, Woolley, Tabraham et al., 2005).

The continuum and prodromal phase of psychosis

It is now clear that not only many children but also a proportion of the general adult population experience brief or isolated psychotic phenomena without coming into contact with psychiatric services (Johns & van Os, 2001). For example, in the Dunedin cohort, 25% of the entire population reported having experienced isolated or transient delusions or hallucinations at the age of 26 years though only 3.7% met criteria for a schizophreniform illness. Initially, there was considerable scepticism that such minor symptoms bore any relation to the frank and persistent hallucinations and delusions experienced by schizophrenic patients. However, van Os, Linscott, Myin-Germeys, Delespaul, and Krabbendam (2009) reported that the very same risk factors that are associated with clinical schizophrenia (single state, unemployment, urban living, etc.) are also associated with the occurrence of minor psychotic symptoms in the Dutch general population. Johns et al. (2004) confirmed these findings in a large sample (n = 8,580) of the British general population. Factors independently associated with psychotic symptoms were lower IQ, poorer educational qualifications, cannabis dependence, alcohol dependence, victimization, stressful life events, and neurotic symptoms. Such findings have suggested that psychosis is best considered as a dimension extending well into the general population (Verdoux & van Os, 2002).

To investigate this dimensional idea further, van Os and colleagues conducted a systematic review of the available evidence on the prevalence and incidence of psychotic symptoms and experiences in the general population (van Os et al., 2009). They found a median prevalence rate of around 5% and a median incidence rate of around 3%, demonstrating rates much higher than those recognized for clinically significant non-affective psychotic disorder. They also found, in their meta-analysis of demographic characteristics, that the prevalence of subclinical psychotic experiences or symptoms is associated with the same variables that are well recognized for schizophrenia, namely male gender, single marital status, unemployment and being from an ethnic minority or migrant group. They suggest that these findings support the notion of a continuum between subclinical and clinical psychosis, as does their finding that the risk factors for schizophrenia are also significant for subclinical psychosis, including urbanicity, traumatic life events and cannabis use.

Several research groups have identified characteristics of young people thought to be at “ultra high risk” of developing frank psychosis (Broome, Woolley, Johns et al., 2005; Klosterkötter, Hellmich, Steinmeyer, & Schultze-Lutter, 2001; McGlashan, Miller, & Woods, 2001; Morrison et al., 2004; Riecher-Rössler et al., 2006; Yung & McGorry, 1996; Yung et al., 1998, 2003). These individuals are described as experiencing cognitive dysfunction as the earliest detectable anomaly, followed by attenuated “negative” symptoms such as decreased motivation and socialization (Cornblatt, Lencz, & Obuchowski, 2002). Later, positive psychotic symptoms develop but are not sufficient in intensity or duration to meet formal criteria for frank psychotic illness. This constellation of symptoms has been combined with having: (i) a first-degree relative with psychosis; or (ii) a diagnosis of schizotypal personality disorder plus a decline in function, to create what is termed an “at risk mental state” or ARMS. Yung and colleagues reported that the presence of the “at risk” mental state in their clients predicted a 40% transition rate to frank psychosis within 12 months. If one accepts psychosis as a dimension, then the “at risk mental state” is likely to cover a segment of it, and the point of transition to frank psychosis is somewhat arbitrary. This relates to the first concern we outlined above: the ARMS could be viewed as being a segment of the continuum coupled with help seeking, decline of function and/or distress. A “Psychosis Proneness-Persistence-Impairment Model” has been suggested by van Os and colleagues, whereby transitory subclinical psychotic experiences can become persistent, and eventually of clinical significance, if “at-risk” individuals are exposed to additional environmental risk factors (van Os, 2009), such as those discussed above.

It has been pointed out by van Os and Delespaul (2005) that the highest transition rates occur in those “at-risk” populations that have been most highly selected, and that the process of screening and referral into these populations makes a major contribution to the success of researchers in identifying individuals at such high risk of transition. Thus, the application of ARMS criteria to the general population may have much less predictive power than in a clinic to which individuals suspected of being in a pre-psychotic phase have been specially referred. One reason for this loss of power is the evidence discussed above that psychosis exists as a continuous phenotype in the general population. A second reason is that the commonest outcome of subclinical psychotic symptoms in a general population is remission (Hanssen, Bak, Bijl, Vollebergh, & van Os, 2005). On this account, the clinical population is different from the general population not in the level of psychotic psychopathology, but rather in the prevalence of additional factors that lead to those symptoms being persistent and distressing.

The strategy of “sample enrichment” is utilized by most prodromal services to increase their ability to predict transition in an at-risk population. However, such enhanced predictive power may be falsely attributed to the psychopathological measure employed (van Os & Delespaul, 2005). Thus, the high predictive value may be consequent upon how the patients that make up a prodromal service are selected, rather than their psychopathology. Pathways may carry greater predictive power than mental-state abnormalities. This is not necessarily because those so detected are any less at risk, but rather that the greater proportion of those in the general population who would meet “at-risk” criteria for developing psychosis will never make it through the various selection procedures that account for the sample enrichment. However, such epidemiological criticisms may be more valid for some services than others, which have fewer “filters” between the person experiencing early psychotic symptoms and the clinician (Broome, Woolley, Johns et al., 2005). This is an obvious example of the more general problem that findings from cohort, epidemiological, and at-risk studies have not yet been fully integrated. Thus, neurodevelopmental theorists have struggled to explain what converts a developmentally impaired or socially isolated adolescent with odd ideas and experiences into a psychotic individual. Similarly, it is not yet clear what differentiates an individual in the community who experiences hallucinations and holds delusional beliefs but never sees a psychiatrist, from the individual who reaches a specialized clinic for those at risk of psychosis where he/she is considered as prodromal. The work of Hanssen et al. (2005) suggests that the intensity of the experiences is important but so too, they suggest, is depression. Escher et al. (Escher, Romme, Buiks, Delespaul, & van Os, 2002) also believe that the co-existence of affective disturbance is a major factor in determining whether young people who experience minor psychotic symptoms will progress to psychotic disorder that requires care. This shift away from a brain and symptom-based conception of clinical high risk, to one based around epidemiology and pathways through services has important theoretical ramifications in how we think of mental illness. Contrary to prevailing ideology in the DSM-IV (American Psychiatric Association, 1994), disorders are determined, at least in part, by a series of epidemiological factors and selection filters, by health behaviour of the individual and society, and by the beliefs and attitudes of health and legal professionals.

Normativity and delusions

Another argument for conceiving of psychosis as a continuum as opposed to a gradation of discrete stages comes from reflecting about the nature of psychopathology itself. Not only may the criteria of disorders themselves be not wholly dependent on neuroscientific or other biological variables, but the psychopathological symptoms used in the definitions of the disorders, or the items in the assessment tools we use to characterize the prodrome, are also contingent upon wider, normative, issues that are unlikely to be able to be reduced or correlated with brain function. A clear example, and one crucial in the prodrome, is that of delusions and disorders of thought content. In the case of delusions a merely neurobiological investigation becomes problematic early on. Unlike some other symptoms of psychosis, delus...

Table of contents

• Cover
• Title
• Copyright
• Contents
• List of plates
• List of Figures
• List of Tables
• List of contributors
• Acknowledgements
• 1. Introduction
• 2. Neuroscience, continua and the prodromal phase of psychosis
• 3. Defining the risk for psychosis: Can neuroscience help psychopathology?
• 4. Genetic determinants of the vulnerability to psychosis: Findings from twin studies
• 5. Stress and cortisol in the pre-psychotic phases
• 6. Neurocognitive indicators of high-risk states for psychosis
• 7. Grey matters: Mapping the transition to psychosis
• 8. Functional MRI in prodromal psychosis
• 9. Glutamate: Gateway to psychosis?
• 10. Does dopamine start the psychotic “fire”?
• 11. Neurophysiological alterations in the pre-psychotic phases
• 12. Stigma in early stages of psychotic illness: Connections with cognitive neuroscience
• 13. Conclusions
• Index