Evidence of a dimensional relationship between ...

Neuroscience and Biobehavioral Reviews 37 (2013) 317–327

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Review

Evidence of a dimensional relationship between schizotypy and schizophrenia: A systematic review M.T. Nelson a,b,c,∗ , M.L. Seal b,d , C. Pantelis c , L.J. Phillips a a

Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Victoria, Australia Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, Victoria, Australia d Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia b c

a r t i c l e

i n f o

Article history: Received 20 June 2012 Received in revised form 26 December 2012 Accepted 3 January 2013 Keywords: Schizotypy Psychosis Schizophrenia Schizoaffective disorder Schizophreniform disorder Schizotypal personality traits Fully dimensional model

a b s t r a c t The personality dimension of schizotypy is well established, and schizotypal traits can be taken to represent a proneness toward developing psychosis. Yet, there are competing theories about the latent structure of schizotypy. More specifically, there is controversy over the extent to which this propensity toward psychosis is present only in a small proportion of the population, or whether it is spread dimensionally throughout the general community. On the basis of accumulating research findings the present article argues for a fully dimensional model of schizotypy. It describes recent neurobiological, neuropsychological, social and environmental evidence supporting the idea that schizotypy in healthy populations, and disorders on the schizophrenia spectrum are fundamentally linked. Directions for further research are also considered. © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The quasi-dimensional approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The fully dimensional approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic research: family, twin and adoption studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic research: molecular genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropsychological research: cognitive deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental and social research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological research: neuroanatomical abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Schizophrenia is a psychiatric disorder characterised by experiences such as hallucinations, delusions, personality changes, thought disorder, bizarre behaviour, impaired social interaction, and difficulties in carrying out daily activities (Compton

∗ Corresponding author at: The Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, VIC, Australia. Tel.: +61 421812989. E-mail address: [email protected] (M.T. Nelson). 0149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2013.01.004

and Broussard, 2009). These symptoms are usually subsumed under three main categories. They are; positive symptoms including hallucinations and delusions, disorganised symptoms including thought disorder and bizarre behaviour; and negative symptoms including alogia, apathy, and amotivation. Although these psychotic symptoms are most commonly associated with schizophrenia, they are also characteristic of other psychotic disorders like schizophreniform disorder, schizoaffective disorder, and delusional disorder. Symptoms of psychosis can also be seen in neurological disorders such as dementia, and in psychiatric disorders

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M.T. Nelson et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 317–327

that are not generally considered under the rubric of psychotic disorders, for example severe depression. Categorical diagnostic categories for mental health difficulties like schizophrenia are described in current nosological systems, such as the Diagnostic System of Mental Disorders (DSM-IV-TR; APA, 2000). They are useful in that they help to ensure disorders are easily identifiable; they serve as a basis for treatment decisionmaking; and they aid communication between clinicians (Livesley and Jackson, 1992; Kraemer et al., 2004). However, there are also a number of criticisms of the assumption that psychotic disorders are truly categorical phenomena. For example, there is considerable hetereogenity within diagnostic categories (Wing and Agrawal, 2003; Beck et al., 2009), and homogeneity between them. Furthermore, diagnoses do not necessarily remain stable across individuals’ lifetimes, and it is often not until a person has experienced multiple episodes and chronic disability that a psychotic diagnosis becomes stable and clear-cut (McGorry et al., 2009). Also, despite numerous studies into the physiological correlates of schizophrenia and related disorders, no biological markers, or endophenotypes have yet been discovered (Beck et al., 2009). There is no test (biological or otherwise) that will unequivocally distinguish someone with psychosis, from someone who is psychologically healthy (Wing and Agrawal, 2003; Wong and van Tol, 2003; Beck et al., 2009). This is reflected in Heinrichs’ (2005) review of biological studies, which describes a substantial overlap between samples of people with schizophrenia, and samples of people who are psychologically healthy. This overlap between clinical and non-clinical samples indicates that categorical diagnoses such as that of schizophrenia, decided upon by expert committee consensus rather than by nature, may obscure the true psychosis phenotype. This could reflect a misrepresentation of latent constructs, and may lead to erroneous diagnoses, inappropriate treatment, and conflicting research findings. Indeed, there is a growing consensus that dimensional views of schizophrenia and other psychotic disorders may be a more valid representation of the population distribution (van Os et al., 2009; Neuvo et al., 2012). For similar reasons, traditional (categorical) understandings of schizotypy have also met with theoretical criticism. Schizotypy describes a cluster of personality traits that include odd or bizarre behaviour, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. There is some disagreement regarding the underlying factor structure of schizotypy (Stefanis et al., 2004; Mason and Claridge, 2006; Fonseca-Pedrero et al., 2011). However, the prevailing understanding is that it is comprised of three identifiable factors, which broadly correspond to the positive, negative and disorganised dimensions of schizophrenia (Wuthrich and Bates, 2006; Fonseca-Pedrero et al., 2011). The first factor is the ‘cognitive-perceptual factor’, which includes magical thinking, unusual perceptual experiences, ideas of reference and paranoia (Raine, 1991, 2006). The second is the ‘interpersonal factor’, which includes constricted affect, social anxiety, lack of close personal relationships, and suspiciousness (Raine, 1991, 2006). The final ‘disorganised factor’ includes odd behaviour and odd speech (Raine, 1991, 2006). Recent reviews summarising research into schizotypy have examined a range of topics associated with the construct. Examples include unusual speech associated with schizotypy (Kiang, 2010); the assessment of schizotypy (Fonseca-Pedrero et al., 2008); affective traits in schizophrenia and schizotypy (Horan et al., 2008); schizotypal personality disorder and schizophrenia (Siever and Davis, 2004); as well as cannabis use, psychosis and schizotypy (Compton et al., 2007). Much of this research is based on theoretical assumptions arising from two competing models of the distribution of schizotypy in the general population–called the quasi-dimensional and fully dimensional approaches respectively.

However, these models are often taken at face value, and evidence for them has not recently been critically scrutinised. The present review sought to resolve this by examining recent empirical taxometric, neuropsychological, environmental and biological evidence pertaining to a potential dimensional relationship between schizophrenia and schizotypy in otherwise psychologically healthy populations. Some methodological issues prevalent in the area will also be considered, as well as directions for future research. For the sake of brevity, the present review includes findings pertaining to schizophrenia and schizotypal personality traits. However reflecting the aforementioned difficulties, controversies and complexities inherent in conducting research into categorical psychiatric constructs, we do acknowledge that the findings herein can be also be common to other clinical phenomena; such as schizoaffective disorder (e.g. Cheniaux et al., 2008), first-episode psychosis (e.g. Mesholm-Gately et al., 2009), bipolar disorder and mania (e.g. Berrettini, 2000; Bramon and Sham, 2001); and other personality constructs such as psychoticism (e.g. Mason and Claridge, 2006). It is for this reason, we prefer to use the terms ‘schizotypy’ and ‘schizophrenia’ in a relatively broad sense.

2. The quasi-dimensional approach The quasi-dimensional approach to schizotypy is based on a disease model of mental illness. It posits that schizotypy is a personality organisation specific to a small group of individuals within the population (approximately 10%), who are labelled ‘schizotypes’ (Rado, 1953; Meehl, 1990; Lenzenweger, 1994; Beauchaine et al., 2008). They are compared to a larger group (approximately 90%) who are not at risk. As reviewed by Lenzenweger (2006), the model can be attributed to Meehl’s (1962) theory; which described a specific genetic vulnerability towards developing psychosis. This vulnerability was said to exist in the form of a genetic predisposition, manifesting as a neurointegrative defect called schizotaxia. According to Meehl (1962), schizotaxia is necessary but not sufficient to cause schizophrenia. Rather than causing schizophrenia directly, it interacts with environmental influences throughout a person’s lifetime to determine the degree of decompensation they experience (Lenzenweger, 2006). From this perspective, genetic vulnerability towards developing psychotic symptoms is considered to be ‘taxonic’ (Korfine and Lenzenweger, 1995; Waller et al., 2006). The approach is quasi-dimensional only because it refers to levels of expression of a proposed disease process. Otherwise it is a discontinuous, categorical theory wherein any one individual is considered to either possess a genetic vulnerability, or they do not. Support for the quasi-dimensional approach can be found in studies that employ taxometric analyses (Waller and Meehl, 1998; Rawlings et al., 2008b). Taxometric analyses are a group of statistical procedures that are used to determine the underlying structure of latent constructs. They are able to determine whether a given construct is categorical (taxonic), or dimensional. In 2008, a review of 19 published taxometric studies pertaining to schizotypy reported that fifteen supported a categorical model (Rawlings et al., 2008b). Furthermore the taxonic base rate estimates in these studies, ranging between 0.03 and 0.13, appeared to support Meehl’s (1990) postulation that 10% of the population are schizotypes (Rawlings et al., 2008b). Yet there are criticisms of the quasi-dimensional model, and some of these focus particularly on the sampling methods used when conducting taxometric analyses (Rawlings et al., 2008b). For instance, taxometric studies have often used either clinical samples with insufficient power for the purposes of taxometrics, or they have used large student samples, which may not be representative of the general population (Rawlings et al., 2008b). Additionally, studies often investigate only one aspect of schizotypy, using only


one taxometric procedure (Rawlings et al., 2008b). Lastly and most importantly, Rawlings et al. (2008b) have argued that evidence from taxometric analyses which support both a categorical viewpoint and a base rate in the range of 10%, may actually arise as an artefact of positively skewed sample distributions (Rawlings et al., 2008b). Their own taxometric study attempted to address these criticisms by using more than one taxometric procedure, a large diverse adult sample, multiple measures of schizotypy, and by taking skew into account. Its findings supported a dimensional rather than a categorical latent structure (Rawlings et al., 2008b). Another criticism of the quasi-dimensional approach has been highlighted by research showing that the anomalous perceptual experiences associated with schizotypy are much more prevalent in the general population than the 10% estimate proposed by Meehl (1990). For example, Verdoux et al. (1998) asked 790 individuals from primary care services to fill in a self-report measure comprising items assessing experiences that resembled hallucinations and delusions. Examples include: “Do you ever feel as if there is a conspiracy against you?”, “Do you ever feel as if people are looking oddly at you?”, and “Do you ever think that people can communicate telepathically?”. For participants with no history of psychiatric disorder (n = 462), individual item endorsement varied from between 5% and 70%, with 46.9% of people believing they could communicate telepathically, 25.5% believing they had been persecuted in some way, and 4.8% believing that they could hear voices conversing (Verdoux et al., 1998). Another study investigated the prevalence of psychotic-like experiences in 2441 young people (aged 18–23) in Australia (Scott et al., 2008). Individual item endorsement in this study ranged from between 5.5.% (‘do you ever feel as if you are a robot or zombie without a will of your own?’) and 77% (‘do you ever feel as if some people are not what they seem to be?). Indeed, one estimate from a longitudinal study looking at mental health in the Dutch adult general population indicated that the incidence of positive subclinical psychotic experiences in otherwise healthy cohorts is up to 100 times greater than traditional estimates such as Meehl’s would suggest (Hanssen et al., 2005). This high prevalence of anomalous experiences in the general population blurs the line between what may be considered ‘normal’ and ‘abnormal.’ It indicates that schizotypy may not be a discrete, bounded entity affecting only a small proportion of the population, as would be consistent with a quasi-dimensional model.

3. The fully dimensional approach A more recent model of the potential relationship between schizotypal personality and schizophrenia is the fully dimensional approach, which is outlined by Claridge and colleagues (Claridge and Beech, 1995; Claridge and Davis, 2003; Rawlings et al., 2008a). The fully dimensional approach posits that schizotypy represents ‘natural central nervous system variations’, which in their extreme, manifest as vulnerability to mental illness (Rawlings et al., 2008a, p. 1669). The main contention advocated by the fully dimensional approach is that the latent structure of schizotypy is on a continuum applying to all members of the population. It is considered to range from low schizotypy and psychological health, to extremely high schizotypy and potential dysfunction in the form of psychosis (Fig. 1). As the fully dimensional approach describes schizotypy as continuous throughout the general population, it can account for the high prevalence of anomalous experiences reported by researchers such as van Os and his colleagues (Verdoux et al., 1998; Johns and van Os, 2001; van Os et al., 2009). In this way, the fully dimensional approach appears superior to the quasi-dimensional approach. It is also consistent with the majority of current theories pertaining to schizophrenia, which tend to describe continuity between

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Fig. 1. A diagrammatic representation of the proposed model of schizotypy (Claridge and Beech, 1995).

clinical and non-clinical psychosis populations (Linscott and van Os, 2010). Further evidence for the dimensional approach is based on analyses supporting the three factor structure of schizotypy (cognitive-perceptual, interpersonal and disorganised), which is analogous to the three factor structure of psychosis (positive, negative and disorganised; Liddle, 1987; Rossi and Daneluzzo, 2002; Wuthrich and Bates, 2006). There is also evidence that individuals with psychotic disorders tend to score highly on measures of schizotypy (Lenzenweger, 1994; Camisa et al., 2005). However, it should be remembered that not all people with high levels of schizotypy are necessarily dysfunctional. For example, it has been shown that individuals scoring highly on measures of schizotypy can (and do) function well in terms of subjective wellbeing (Goulding, 2004). Here, subjective wellbeing can be defined as a self-rated sense that a person has control over their own life, can balance and cope with both positive and negative life events, and can maintain stability (Goulding, 2004). Many people who score highly on measures of schizotypy also exhibit adaptive strengths such as creativity, as evidenced by increased involvement in creative activities including painting and drawing, writing, music, gardening and web design (Batey and Furnham, 2008; Rawlings and Locarnini, 2008; Nelson and Rawlings, 2010). Therefore, similar to the quasi-dimensional approach, the fully dimensional approach does not assume schizotypal traits are sufficient in and of themselves, to indicate risk for psychopathology (Rawlings et al., 2008a). Rather, it is only when high levels of schizotypy are combined with other aetiological risk factors that an individual may be considered at risk for schizophrenia and other psychotic disorders. According to this perspective, unless high schizotypy is combined with other risk factors, it is considered neutral in regards to psychopathology (Rawlings et al., 2008a). The fully dimensional approach is also consistent with what is termed the ‘continuum hypothesis’ of psychosis (Allardyce et al., 2007). This is the current predominant view, that psychosis is similar to chronic physical problems like diabetes and heart disease. It is considered to have multifactorial aetiology, wherein multiple genes interact both with each other and with the environment to determine outcome (Allardyce et al., 2007; The International Schizophrenia Consortium, 2009). These different combinations of genes and environmental risk factors result in a range of different phenotypic expressions lying on a continuum from normal through to clinical psychosis. Consequently by adopting the fully dimensional theory, research into schizotypy becomes important because it directly aids investigation into the aetiology of schizophrenia and other psychotic disorders. Furthermore, it does so whilst avoiding confounds often associated with psychosis research, such as illness chronicity, medication, and hospitalization. From this perspective,

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it is important to assess not only similarities between various levels of schizotypy and schizophrenia, but also dissimilarities (Fanous and Kendler, 2004). For example, it has been proposed that possible biological endophenotypes common to the two constructs may represent underlying genetic factors, while findings specific to schizophrenia may represent environmental factors (Cannon et al., 2002; Fanous and Kendler, 2004). Further empirical evidence that psychotic symptoms and schizotypal personality features in psychologically healthy people lie on a common continuum can be gleaned from genetic, neuropsychological, environmental, and biological research.

4. Genetic research: family, twin and adoption studies A first line of convincing evidence that schizotypy lies on a continuum with schizophrenia comes from genetic research. Both Kraeplin (1919/1971) and Bleuler (1911/1950) first observed that relatives of individuals with schizophrenia appeared notably more odd and eccentric than people in the general population. Since then, much behavioural genetic research throughout the 20th and early 21st centuries has indicated that schizotypal traits and psychosis show some level of genetic inheritance (Kety et al., 1975; Baron et al., 1983; Kendler et al., 1996; Mata et al., 2003). For example, it has been clearly established from family, twin, and adoption studies that schizophrenia is heritable (McCue et al., 1983; Cannon et al., 1998; McClellan et al., 2007). Similarly, there is growing evidence that heightened schizotypy can also be experienced by multiple generations of the one family. For instance, Hanssen et al. (2006) gave three measures of schizotypy to 272 individuals from 82 families. All three measures showed familyspecific variation for both positive and negative traits. However, only one measure showed family-specific variation for the negative trait once variation due to the positive trait was controlled for, indicating that the positive dimension of schizotypy (anomalous experiences) specifically varied with family membership. Interestingly, these results were obtained in families that were not selected on the basis of a pre-existing diagnosis of any psychiatric disorder, providing evidence for dimensional variation within the general population as well as heritability (Hanssen et al., 2006). Further evidence of the dimensional and heritable nature of schizotypy within psychologically healthy populations comes from Kendler et al. (1991) who administered four measures of schizotypy (including self-report and interview) to 29 monozygotic and dizygotic twin pairs. Distributions of schizotypy in this sample were normal, indicating dimensionality rather than taxonicity, which would have been represented by a bimodal distribution (Kendler et al., 1991). Comparison of correlations between monozygotic and dizygotic pairs in this sample also indicated that both positive and negative schizotypal traits showed family-specific variation (Kendler et al., 1991). It is acknowledged, of course, that evidence showing schizotypy runs in families, and separate evidence showing that schzophrenia runs in families does not mean that the two phenomena are necessarily associated. Yet, there is also research indicating that both schizotypy and schizophrenia occur in the same families, which suggests they may be heritable together (Kety et al., 1975; Baron et al., 1983; Kendler et al., 1989, 1996; Mata et al., 2003). One example is a study by Kremen et al. (1998) wherein 44 controls and 40 biological relatives of people with schizophrenia completed the Schizotypal Personality Questionnaire (SPQ; Raine, 1991). Relatives had higher scores on the Cognitive-Perceptual (positive) Factor than controls. Similar results using the same measure were reported in a smaller study of 13 participants with a family history of psychosis, 38 participants with a family history of substance use disorder, and 51 control participants (Yaralian

et al., 2000). Also in a more recent study, 263 relatives of people with psychosis completed three measures of schizotypy – including two self-report measures and a semi-structured interview (Mata et al., 2003). In this investigation, it was the positive symptoms of psychosis, as reported by the patients, which were related to schizotypy in their relatives. A cluster of symptoms reported by the patients (delusions, hallucinations and thought disturbance) was positively correlated with outcomes from all three measures of schizotypy in relatives, including both positive and negative traits. Two other family studies have reported mixed findings as to heritability between schizotypy and schizophrenia. Kendler et al. (1996) found no differences in levels of schizotypy between relatives of patients with psychotic illnesses, and relatives of controls. Furthermore, Appels et al. (2004) reported that parents of schizophrenia patients actually had lower scores on the SPQ Cognitive-Perceptual Factor than control participants. However, the authors of both of these studies account for their somewhat anomalous findings by highlighting the problems of conducting research into schizotypy using self-report measures (Kendler et al., 1996; Appels et al., 2004). Appels et al. (2004) also reasoned that including both parents (mothers and fathers) of schizophrenia patients in their analysis may have resulted in a loss of power. It is more likely that only one parent passes on a genetic risk of psychosis, not necessarily both parents (Appels et al., 2004). Indeed, Appels et al. (2004) then conducted an alternative investigation, wherein parents of an individual with schizophrenia who reported a family history of schizophrenia spectrum disorder in earlier generations (i.e. their own parents or earlier) reported higher levels of both positive and negative schizotypal traits than parents with no family history. Further to the above family-based research, there have been some investigations that have used a twin design to assess a possible genetic relationship between schizotypy and schizophrenia. Self-reported experiences of perceptual aberration and social anhedonia in particular were found to be at least partly inherited in a study of 98 monozygotic and 59 same sex dizygotic twin pairs (MacDonald et al., 2001). Another study with 105 monzygotic and 90 dizygotic twins described common family specific variation between psychosis and schizotypy as measured by the OxfordLiverpool Inventory of Feelings and Experiences (O-LIFE; Mason et al., 1995; Jang et al., 2005).

5. Genetic research: molecular genetics In summary, considerable evidence from family, adoption, and twin studies indicates that psychotic disorders and schizotypy in healthy populations share common genetic underpinnings. Yet although these family, twin and adoption studies are informative in terms of describing heritability, they cannot identify specific chromosomal regions giving rise to any one phenotype (Fanous et al., 2007). Around 25 years ago, Gottesman, McGuffin and Farmer (1987) remarked that the results of behavioural genetic studies gave only clues to the genetic basis of schizophrenia, and that molecular genetics would provide clear answers. However despite years of molecular genetic research, no single gene, or even a clear number of possible genes have been identified for schizophrenia, nor for psychosis more broadly (Allardyce et al., 2007; Tandon et al., 2008), despite large samples in recent studies (Ripke et al., 2011). Indeed, there are no genes proposed to be related to schizophrenia that are not controversial or subject to conflicting findings. For instance, in a recent review and meta-analysis of the genetic research into schizophrenia, it was estimated that there have been in excess of 1000 genetic association studies exhibiting largely inconsistent results (Allen et al., 2008). This review found that across 118 different meta-analyses, there were nominally


significant effects in 24 variants of 16 different genes – namely, APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53, and TPH1 (Allen et al., 2008). To date there has been limited molecular genetic research into a potential relationship between schizotypy and schizophrenia specifically. In a linkage study, Fanous et al. (2007) demonstrated that a number of genes thought to be related to schizophrenia in patients, were also associated with levels of schizotypy in non-psychotic relatives. Two other studies have indicated a significant level of association between schizotypy and the COMT gene (Avramopoulos et al., 2002), and between schizotypy and the DTMBP1, NRG1 and DAAO genes (Stefanis et al., 2007). However, reflecting the conflictual findings in regards to molecular genetic research and psychosis, another investigation found no clear relationship between schizotypy and the COMT gene (Ma et al., 2007). As reviewed by Fanous and Kendler (2004), the following conclusions can be drawn from the genetic research on schizotypy and schizophrenia. First, behavioural genetic research has shown that both schizophrenia and schizotypy are heritable, and that schizotypy and psychotic disorders aggregate in families together. Furthermore, heritability can be broken down into specific traits, whereby negative psychotic symptoms tend to predict negative schizotypal traits in relatives, and in particular, positive psychotic symptoms tend to predict positive schizotypal traits (Fanous et al., 2001; Fanous and Kendler, 2004). Yet despite the optimism surrounding early molecular genetic research into the genetic causes of both schizotypy and schizophrenia (Gottesman et al., 1987; Tandon et al., 2008), findings in this area are still unclear. Further research is needed before it can be confidently established that there are shared genetic abnormalities between schizotypy and schizophrenia, and even more before we can break these down into specific traits. This is reflective of the state of genetic research into psychiatric disorders more broadly (Meyer-Lindenberg and Weinberger, 2006; Psychiatric GWAS Consortium Coordinating Committee et al., 2009), and particularly the difficulties of finding genetic commonalities in inherently heterogeneous populations.

6. Neuropsychological research: cognitive deficits In another relevant vein of research, it has been consistently shown that schizophrenia is associated with cognitive deficits (Tandon et al., 2009). These include generalised cognitive dysfunction (Heinrichs and Zakzanis, 1998; Fioravanti et al., 2005; Reichenberg and Harvey, 2007; Simonsen et al., 2011), as well as deficits in verbal IQ (Heinrichs and Zakzanis, 1998; Reichenberg and Harvey, 2007), working memory (Wood et al., 2003; Haenschel and Linden, 2011; Simonsen et al., 2011), episodic memory (Reichenberg and Harvey, 2007), executive functioning (Heinrichs and Zakzanis, 1998; Fioravanti et al., 2005; Reichenberg and Harvey, 2007), verbal fluency (Simonsen et al., 2011), processing speed (Simonsen et al., 2011), and attention (Heinrichs and Zakzanis, 1998; Fioravanti et al., 2005), amongst others (Heinrichs and Zakzanis, 1998; Fioravanti et al., 2005; Reichenberg, 2010). These neurocognitive deficits are more often correlated with negative and disorganised symptoms than with positive symptoms (Basso et al., 1998; Pantelis et al., 2001; Galderisi et al., 2009; Lindsberg et al., 2009). Heightened schizotypy has also been associated with subtle cognitive deficits in psychologically healthy people (Moritz et al., 1999; Noguchi et al., 2008). Specifically, inverse associations have been found between schizotypy and verbal IQ (Noguchi et al., 2008), attention (Chen et al., 1997), and working memory (Park and McTigue, 1997; Schmidt-Hansen and Honey, 2009). Furthermore, at least one paper has explicitly evaluated neurocognitive

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functioning in both schizotypy and schizophrenia together, on the basis of a fully dimensional model (Cochrane et al., 2012). Cochrane et al. (2012) conducted two separate studies. In the first, it was reported that in 99 psychologically healthy people, the Interpersonal (negative) Factor of the SPQ was related to reduced verbal fluency, and the Disorganised Factor was related to reduced negative priming. In the second study, corresponding symptom measures from the Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS; Andreasen, 1983, 1984) showed similar relationships with verbal fluency and negative priming in 20 participants with a diagnosis of schizophrenia. Again, similar to outcomes of research focused on psychosis, relative cognitive deficits associated with schizotypy appear to relate to negative (interpersonal) and disorganised traits rather than positive (cognitive-perceptual) traits (Chen et al., 1997; Park and McTigue, 1997; Moritz et al., 1999). One point of departure in neurocognitive findings between schizotypy and schizophrenia is that effect sizes appear to be larger in schizophrenia research compared to schizotypy research. Specifically, significant reductions in cognitive variables in people with schizophrenia are often reported alongside medium to large effect sizes (e.g. Reichenberg and Harvey, 2007; Simonsen et al., 2011); whilst effect sizes in studies of schizotypy are often small (e.g. Chen et al., 1997; Noguchi et al., 2008). This may indicate that cognitive decline is more prominent for people with schizophrenia, and indeed may be a significant defining feature of clinical psychosis (Bora et al., 2010).

7. Environmental and social research Further support for a continuum model of schizotypy and schizophrenia can be gleaned from research examining environmental and social correlates of the two constructs. Identified environmental and social risk factors for schizophrenia are wideranging. They include antenatal and birth complications such as maternal infections (Stober et al., 1997; Brown, 2006; Xiao et al., 2009), nutritional deficiency (St Clair et al., 2005; Markham and Koenig, 2011), maternal stress during pregnancy (Markham and Koenig, 2011), foetal hypoxia (Cannon et al., 2000) and older parental age at conception (Malaspina et al., 2001; Petersen et al., 2011). They also include childhood trauma (Lardinois et al., 2011), migration and minority group membership (Morgan et al., 2010), urbanicity (Kelly et al., 2010), cannabis use (Richardson, 2010), parental separation (including death; Morgan et al., 2007), adverse child rearing (Willinger et al., 2002), and childhood infection (Rantakallio et al., 1997). Similar environmental and social risk factors have been implicated in the development of anomalous experiences associated with schizotypy. Zammit et al. (2009) report in their longitudinal study of 6356 children, that ‘PLIKS’ (‘psychotic-like experiences’) were positively associated with pregnancy and birth complications. These included maternal infection, maternal diabetes, and need for resuscitation following birth (Zammit et al., 2009). Additionally, positive anomalous experiences have been associated with childhood trauma (Steel et al., 2009; Lovatt et al., 2010), urbanicity (Scott et al., 2009), and ethnicity and minority group membership (Sharpley and Peters, 1999; Johns et al., 2002; Morgan et al., 2009). Parental separation has been associated with symptoms of schizotypal personality disorder (SPD), which is said to lie on the continuum between schizotypy in healthy populations and full blown psychotic disorders (see Fig. 1; Anglin et al., 2008). However there does not appear to be any research to date addressing parental separation and schizotypy in healthy populations.

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With respect to cannabis use, a large study involving 1049 students showed that high levels of cannabis use were associated with both positive and negative ‘non-clinical psychotic experiences’, as measured by the Community Assessment of Psychic Experiences (CAPE) questionnaire (Skinner et al., 2011). Furthermore, the earlier students began their cannabis use, the more likely they were to report positive experiences (Stefanis et al., 2002; Skinner et al., 2011). This study along with numerous others, echoes psychosis research and demonstrates a positive association between schizotypy and cannabis use (Barkus and Lewis, 2008; Compton et al., 2009; Esterberg et al., 2009; Cohen et al., 2011). In addition, unlike the neurocognitive findings reported above, it is worth noting that effect sizes for these environmental findings appear on the whole to be of similar magnitude for both schizotypy (Morgan et al., 2010) and psychosis (Morgan et al., 2009). This may be because most studies investigating environmental variables in relation to schizotypy have used measurement tools that assess for positive traits specifically (such as the PsychoticLike Experiences Structured Interview and Psychosis Screening Questionnaire; Bebbington and Nayani, 1995; Horwood et al., 2008; Morgan et al., 2009; Zammit et al., 2009), rather than all aspects of schizotypy (as is assessed via the SPQ and O-LIFE). This might have increased power, as effects did not get ‘washed out’ when averaging across qualitatively different aspects of schizotypy.

8. Biological research: neuroanatomical abnormalities Research has indicated that both schizophrenia and schizotypy have been associated with a number of similar neuroanatomical abnormalities. Importantly, several of the key neuroanatomical findings relating to schizophrenia have also been replicated in schizotypy research. For instance, neurological soft signs are subtle deficits in areas such as motor coordination, laterality and sensory-perceptual performance (Obiols et al., 1999). Unlike hard neurological signs, they do not indicate any specific neurological disease (Obiols et al., 1999). Higher rates of neurological soft signs have been identified in people with psychotic disorders compared to controls (Leask et al., 2002), and they have also been shown to correlate with schizotypy in non-clinical samples (Bollini et al., 2007; Kaczorowski et al., 2009; Chan et al., 2010). In two studies, this relationship with schizotypy appeared to be driven by associations with interpersonal (negative) and disorganised factors rather than by associations with the cognitive-perceptual (positive) factor (Bollini et al., 2007; Kaczorowski et al., 2009). However, two studies have also found associations between neurological soft signs and positive aspects of schizotypy (Barkus et al., 2006; Chan et al., 2010). Furthermore, people with schizophrenia also have higher levels of the subtle variations in bone structure, cartilage and soft tissue known as minor physical anomalies (McGrath et al., 2002). These minor physical anomalies have also been significantly associated with levels of overall schizotypy, as well as cognitiveperceptual and interpersonal factors specifically (Bollini et al., 2007). In addition, there are wide reports of eye tracking dysfunctions in relation to schizophrenia (Levy et al., 2010), such as impairments in smooth pursuit and antisaccade eye movements (Lipton et al., 1983). Like neurological soft signs and minor physical anomalies, findings of occulomotor deficits have also been replicated in high schizotypy groups (O’Driscoll et al., 1998). More recently, developments in neuroimaging technologies have identified brain structural, metabolic and functional abnormalities in relation to schizophrenia. These technologies include magnetic resonance imaging (MRI), functional magnetic resonance

imaging (fMRI), diffusion weighted imaging (DWI), magnetic resonance spectroscopy (MRS), single-photon computed emission tomography (SPECT), and positron emission tomography (PET). There are a multitude of reviews and meta-analyses summarising the field of neuroimaging and schizophrenia (Ward et al., 1996; Shenton et al., 2001; Pantelis et al., 2005; Gur et al., 2007; Keshavan et al., 2008; Fornito et al., 2009; Wood et al., 2011), therefore only main findings are reported here. Briefly, structural MRI studies have shown reduced whole-brain volume and complimentary enlargement of lateral ventricles and increases in cerebrospinal fluid (Gur et al., 2007; Keshavan et al., 2008). Affected cortical regions include but are not limited to, medial temporal lobe areas, most notably the hippocampus and amygdala (Velakoulis et al., 2006; Gur et al., 2007; Keshavan et al., 2008). DWI studies report deficits in white matter connectivity across the whole brain, corpus callosum, cingulum bundle, and superior longitudinal fasciculus, amongst others (Kubicki et al., 2007; Kyriakopoulos et al., 2008; Seal et al., 2008; Zalesky et al., 2011). MRS research seems to have focused on findings of reductions in N-acetyl aspartate metabolites (Gur et al., 2007). PET and SPECT research has examined the role of over activation of dopamine receptors (particularly D2 receptors) in schizophrenia (Gur et al., 2007; Keshavan et al., 2008). Lastly, fMRI research has explored decreases in activation of the dorsolateral prefrontal cortex, especially when participants are presented with challenging cognitive tasks (Berman and Meyer-Lindenberg, 2004; Keshavan et al., 2008). This tendency is reinforced by outcomes of PET and SPECT research focusing on the same area (Keshavan et al., 2008). Although there is much neuroimaging research into schizotypal personality disorder (Dickey et al., 2002; Hazlett et al., 2012), a very limited number of neuroimaging studies have investigated neuroanatomical correlates of schizotypy in psychologically healthy people. One MRI study reported that schizotypy was associated with reduced brain volume in prefrontal areas (Raine et al., 1992). In another investigation, Modinos et al. (2010) gave a self-report measure of schizotypy to six hundred university students. Thirtyeight of the highest and lowest scorers subsequently underwent MRI scans. Differences between groups included significantly larger volumes in the whole brain, medial posterior congulate cortex and precuneus for the high schizotypy group (Modinos et al., 2010). This was the reverse of what is normally seen in psychosis research, in which there are reductions in volume (Keshavan et al., 2008). However, the authors concluded that the alterations were consistent with a continuum model. They cite previous research findings of increases in volume in SPD and first-episode psychosis samples (Modinos et al., 2010), as opposed to reductions in volume in chronic schizophrenia samples (Keshavan et al., 2008). Increases in grey matter in the middle, superior temporal, angular, and orbitofrontal gyri have also been associated with PLEs (‘psychoticlike experiences’) in a young adolescent sample (Jacobson et al., 2010). In another adolescent sample (aged 12–20), Lagioia et al. (2010) examined brain networks relating to schizotypy using fMRI. They report a discontinuity between their findings and those investigating psychosis. However, their study was limited by its small sample size of only 39 across a relatively large developmental age range. Then, in our recent DWI study we identified negative correlations between measures of white matter structure and positive schizotypal traits in seven white matter tracts within frontal and temporal areas (Nelson et al., 2011). This supports the findings of Volpe et al. (2008), which showed that ‘psychotic personality traits’ as measured by the Schizophrenia, Paranoia and Psychopathic Deviate subscales of the Minnesota Multiphasic Personality Inventory (Greene, 2000), were associated with changes in white matter structure in the corpus callosum, right arcuate fasciculus,


and frontoparietal fibres (Volpe et al., 2008). Currently, there are no known investigations of the neurobiological basis of schizotypy using MRS, PET, or SPECT imaging modalities. In summary, despite the relative lack of research into a relationship between schizotypy and schizophrenia using neuroimaging modalities, other biological findings such as those of oculomotor deficits, MPAs and neurological soft signs indicate there may be some biological similarity between people who score highly on measures of schizotypy and people with schizophrenia.

9. Methodological considerations The above paucity in neuroimaging research is a case in point, in that further investigation into the relationship between schizotypy and schizophrenia is still needed to resolve mixed findings, particularly in relation to neurobiology and molecular genetics. Large scale longitudinal and cross-sectional designs are required that apply the same measures to people in the general population, to people with SPD, people at high risk for psychosis, first episode psychosis and to people with schizophrenia. Again reflecting the complexity of the field, and reflecting the burgeoning unitary psychosis view, which posits that schizophrenia and bipolar disorder as two representations of a single construct, these investigations could be extended to other psychotic disorders and affective psychoses. Indeed, as was pointed out by one reviewer, there is some evidence (to be built upon) that the unitary psychosis view is also reflected in dimensional schizotypy research; for example via the four factor overlapping scales of the O-LIFE (Mason et al., 1995; Mason and Claridge, 2006). Continuum research of this type is difficult currently, with many measures designed only for one level of severity on a proposed schizotypy and psychosis dimension. For example, there are measures designed to assess the positive symptoms of psychosis, but not the anomalous experiences associated with schizotypy, and vice versa. Problems of floor and ceiling effects could be avoided by designing measurement tools that can account for variation across the entire continuum. One example of this is the Appraisals of Anomalous Experiences Interview (AANEX; Brett et al., 2007). Although lengthy, the AANEX is able to measure experiences ranging from the anomalous, psychotic-like experiences of schizotypy, to the florid hallucinations and delusions of psychosis. Another important methodological issue is that thus far, schizotypy research has predominantly relied on self-report measures such as the SPQ and O-LIFE. These questionnaires are short and easy to administer, however they can be subject to the various confounds associated with self-report measures, such as social desirability bias (Moritz et al., 1999; Shean et al., 2007). Therefore there is a need for wider use of psychometrically sound measurements such as structured and semi-structured interviews. In this way, the AANEX also meets another need in relation to future research on schizotypy. A related issue is the widespread use of statistical techniques imposing artificial categorical boundaries on what are otherwise dimensional scales. We refer here to the use of median splits and similar techniques that dichotomize, or trichotomize samples that have been administered self-report measures such as the SPQ. They are used to extract, for example, ‘high schizotypy’ and ‘low schizotypy’ groups to be compared in subsequent statistical analyses. However, they result in a substantial loss of statistical power, and can therefore lead to mixed and contradictory findings. Interview measures such as the AANEX, that allow wide variability across the continuum will avoid floor and ceiling effects, increase power, and allow investigators to compare ‘apples with apples’ when looking at similarities and differences between schizotypy and schizophrenia.

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Another reason that it is difficult to compare studies in this area, is that although there has been much investigation into underlying structure of schizotypy itself (Stefanis et al., 2004; Mason and Claridge, 2006; Wuthrich and Bates, 2006); further research is needed to determine the concurrent, discriminant and construct validity of schizotypy and psychosis-related phenomena together. For instance, terms such as positive and negative schizotypy, schizotypal personality, ‘PLIKS’ and ‘PLEs’ (’psychotic-like experiences’; e.g. Zammit et al., 2009; Kelleher and Cannon, 2011), subclinical psychotic experiences (e.g. van Os et al., 2009), anomalous experiences (e.g. Brett et al., 2007), cognitive-perceptual, interpersonal and disorganised personality traits (e.g. Raine, 1991, 2006), SPD-proneness (Chan et al., 2010), and non-clinical dimensions of psychosis (Skinner et al., 2011) are used interchangeably. It is not clear whether they are measuring the same experiences, or how they relate to one another. We have assumed that terms like ‘PLEs’, ‘positive schizotypy,’ and ‘subclinical psychotic experiences’ all refer to the same phenomena. That is, the anomalous experiences of positive schizotypy which are represented on the cognitive-perceptual factor of the SPQ. We have similarly assumed that ‘negative schizotypy’, and the interpersonal factor of the SPQ are the same construct. Furthermore, we have assumed that the terms ‘schizotypy’, schizotypal personality’, ‘SPD-proneness’, and ‘non-clinical dimensions of psychosis’ are all subsumed under the umbrella of schizotypy. There is certainly evidence that ‘psychotic’ traits and ‘schizotypal’ traits are convergent constructs (Bentall et al., 1989; Claridge et al., 1996; Stefanis et al., 2002; Kwapil et al., 2008). For instance, Claridge et al. (1996) assessed the convergence of schizotypal traits and subclinical hallucinations and delusions in a community sample of 1095 participants. Factor analysis from this study suggested that subclinical hallucinations and delusions do map onto the cognitive-perceptual factor of schizotypy. However, more upto-date investigation exploring and comparing the psychometric properties of a range of measures pertaining to schizotypy, anomalous experiences and psychotic symptoms would greatly assist in further development of the field. If the above terms are found to be referring the same constructs, in our own research and in future research we prefer to use the following terminology. The term ‘anomalous experiences’ is preferred when referring to PLEs, PLIKs and so forth. The term ‘anomalous experiences’ distances these types of phenomena from psychotic symptoms, thus avoiding the risk of pathologizing experiences that are considered to lie within the range of normal human experience. ‘Positive schizotypy’ is preferred when referring to the tendency to have anomalous experiences, ‘negative schizotypy’ is preferred when referring to non-clinical experiences similar to negative symptoms of psychosis, and ‘disorganised schizotypy’ is preferred when referring to non-clinical experiences similar to disorganised symptoms of psychosis. We prefer ‘schizotypy’ as the umbrella term subsuming all of the above. Use of the term ‘schizotypy’ rather than terms such as ‘non-clinical dimensions of psychosis’ and ‘SPD-proneness’ avoids the loss of its status as a personality trait, and again avoids pathologizing normal experiences. Finally, it could well be that all of these methodological issues mentioned above are contributing to small effect sizes and type II error in categorical research comparing groups. As has been seen, some investigations into schizotypy and anomalous experiences often report much smaller effects sizes than those seen relation to psychosis. While others – for example those environmental investigations focusing specifically on anomalous experiences rather than schizotypy as a whole – report findings of similar magnitude to psychosis research. It is not yet possible to conclude whether or not smaller effects sizes are reflective of low power and extraneous variables, or whether they reflects a ‘true’ reduction in magnitude of effect.

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10. Conclusions As has been demonstrated, in the last five years there has been an explosion of research consistently demonstrating similarities between schizotypy and schizophrenia. Indeed, it would seem that for many findings in relation to schizophrenia, there is a corresponding finding in relation to schizotypy – although not always of the same magnitude of effect. This is especially true for environmental and neurocognitive findings, but is somewhat less true for biological and molecular genetic findings – where there is a relative paucity of research. The investigations reviewed in the present article that report parallel, albeit attenuated, results between schizotypy and schizophrenia are consistent with a fully dimensional model, wherein varying levels of schizotypal personality traits throughout the general population lie on a continuum with schizophrenia spectrum disorders. It would appear that it is no longer a question of whether or not the two constructs are related. A more pertinent question would be what determines whether or not an individual makes the hypothetical transition from high schizotypy to full-blown psychosis? This transition could happen in a number of different ways. One possible mechanism might be that as an individual moves along the continuum, their symptoms become linearly more severe. For example, in relation to cognitive deficits, it might be that impairments become more numerous, pervasive and severe along an increasing schizotypy and psychosis scale. However, as a fully dimensional model of schizotypy would suggest, it is more likely that the effects of various genetic, biological and environmental risk factors combine with high schizotypy in various cumulative, nonlinear and perhaps even idiopathic ways to determine outcome. Although outside the scope of this article, valuable intersections could be made here with the burgeoning literature on ultra high-risk for psychosis groups, which identify the anomalous psychotic experiences associated with schizotypy as a risk factor for the development of full-blown psychosis along with a number of other risk factors such as depression, reduced attention, and family history of psychosis (Yung et al., 2004). We propose that the relationship between schizotypy and psychosis can be viewed as similar to the relationship between neuroticism and anxiety disorders. High levels of neuroticism are often found in people with anxiety disorders, however high neuroticism is not sufficient in and of itself to indicate the presence of an anxiety disorder. The same can be said of schizotypy and psychosis in that high levels of schizotypy may be associated with psychosis, and they may be associated with similar variables to psychosis, but they do not necessarily indicate dysfunction. Just as neuroticism on its own is insufficient to indicate a specific anxiety disorder, the value of schizotypy is not found in its use as a screening measure for specific psychotic disorders. Rather, the value of schizotypy lies in what it can tell us about normal human experience, and the possible pathways from psychological health to psychological dysfunction.

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