At-risk mental states

C H A P T E R

3 At-risk mental states Alison R. Yung1,2 1

Centre for Youth Mental Health and Orygen, The University of Melbourne, Parkville, Victoria, Australia; 2Division of Psychology and Mental Health, School of Health Sciences, The University of Manchester, Manchester, United Kingdom

Following the success of early intervention in the first episode of psychosis, in the late 1990s, consideration was given to whether even earlier intervention was possibledbefore the first episode of psychosis. That is, we aimed to intervene during the lead up to the first psychotic episode in what is called the “prodrome” or “prodromal phase”. The idea was that intervention in the prodromal phase of schizophrenia and related psychoses may result in attenuation, delay, or even prevention of the onset of psychosis in some individuals (Yung et al., 1996). (McGlashan et al., 2003; McGorry et al., 2002; Morrison et al., 2004).

Psychotic disorders such as schizophrenia have a lifetime prevalence of over 1% and are among the world’s leading causes of disability. They have potentially high personal, social, and economic impact (Saha et al., 2005; van Os and Kapur, 2009). Their onset is usually in adolescence and young adulthood (Abel et al., 2010), meaning that the most productive years of a person’s life are affected and could lead to living many years with the illness. Given this background, there has been an increasing emphasis on early intervention to detect illness early and minimize disability. Early intervention services that aim to provide timely and high quality multidisciplinary care have now been established worldwide. Such early intervention, during the first episode of psychosis, can significantly improve quality of life, reduce the rate of relapse, risk of suicide, and number of hospital admissions (Correll et al., 2018). They can improve employment and education outcomes and wellbeing, are cost effective (Craig et al., 2004; Petersen et al., 2005; Garety et al., 2006; McCrone et al., 2010) and well-liked by service-users and carers (Schizophrenia Commission, 2012).

Risk Factors for Psychosis https://doi.org/10.1016/B978-0-12-813201-2.00003-X

Identifying the prodrome of psychotic disorder There were several issues that we needed to deal with when considering the identification of the prodrome of psychotic disorder. The first was conceptual: the term prodrome is a retrospective concept and is used after the onset of fully fledged disorder. For example, once the characteristic rash of measles develops, it is

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possible to look back and say that the cough and coryza that preceded the rash was the “measles prodrome.” However, when only the cough and coryza are present, it is not be possible to label these symptoms as the measles prodrome as they may equally indicate a common cold, hay fever, or pneumonia. This example also highlights the second issue: that prodromal symptoms and signs are necessarily nonspecific, otherwise they would not be the prodrome of illness but would be the illness itself. The third issue was that we needed more information about characteristic features of the psychotic prodrome. Coining the term “At-Risk Mental State” was a way of dealing with the fact that “prodrome” is a retrospective concept. This term does not imply inevitable progression to full disorder, unlike the term “prodrome”. We then set about developing criteria for the “At-Risk Mental State” or “ARMS”. The criteria were determined following two pieces of work. The first was a comprehensive review of the literature describing the signs and symptoms leading up to a first episode of psychosis or schizophrenia (Yung and McGorry, 1996). The second was a qualitative study exploring the experiences of individuals who had recently recovered after a first episode of psychosis (Yung and McGorry, 1996). The synthesis of these two studies concluded that the first manifestations of a psychotic prodrome were likely to be nonspecific symptoms, such as sleep disturbance, anxiety, and low mood. More proximal to the onset of psychotic symptoms were subthreshold or attenuated versions of these symptoms. Examples include an overvalued idea that one might be being followed or watched which was held with some doubt, rather than a fully formed persecutory delusion, or hearing mumbling or whispering but not clear auditory hallucinations with the same quality as normal perceptions. This led to the ARMS category of attenuated psychotic

symptoms. The literature review and study of recovered patients also revealed that short and self-limited episodes of frank psychotic symptoms could also occur in the lead up to a more prolonged psychotic episode. This led to the ARMS category of brief limited intermittent psychotic symptoms. Also included as an ARMS category was a group with both trait and state risk factors for psychotic disorder. The thinking was that a young person with a trait risk factor, such as a family history of schizophrenia, was at higher risk for development of psychosis than an individual without such family history, and that marked and prolonged decline in functioning may indicate a developing psychotic disorder. This led to the ARMS category of the trait and state risk factor group. We also made an arbitrary definition of frank psychosis as the outcome variable. This was based on the presence of clear threshold level psychotic symptoms (delusions, hallucinations, and formal thought disorder) occurring several times per week for at least 1 week. This threshold is that at which antipsychotic medication would commonly be commenced in clinical practice (Yung et al., 2003). The criteria are summarized in Box 3.1. In developing the ARMS criteria (or Ultra High Risk Criteria (UHR)), we aimed to describe clinical features that would indicate high and imminent risk of psychotic disorder, such that identification and treatment of these individuals would reduce risk for psychotic disorder. The idea behind the criteria and the name “At-Risk Mental State” was that the syndrome indicated risk for psychosis at the time that the person was experiencing such symptoms. That is, it was considered a state risk factor for psychotic disorder. Risk is linked to the presence of symptoms. The converse is a trait risk factor, such as genetic risk, which places the individual at risk of psychotic disorder regardless of their current mental state.

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True positives, false positives, and false false positives

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BOX 3.1

CRITERIA FOR AN AT-RISK MENTAL STATE FOR PSYCHOSIS (A) Age between 15 and 30 years (B) Help-seeking at a mental health service, and (C) Belonging to at least one of the following three groups: (1) Trait and State Risk Factor Group having a trait risk factor of either a first-degree relative with a psychotic disorder and/ or schizotypal personality disorder plus a state risk factors of a significant decrease in functioning within the last year or chronic low functioning.

True positives, false positives, and false false positives ARMS individuals who transition to a psychotic disorder are known as “true positives.” That is, the ARMS syndrome with which they presented was the prodrome to their first episode of psychosis. ARMS individuals who do not develop a psychotic disorder are known as “false positives.” This means that their ARMS syndrome was not indicative of a psychosis prodrome, but rather symptoms may have been transient or related to some other disorder or experience. However, we must also consider the concept of “false false positives.” These are individuals who would have developed a psychotic disorder, but did not during the period of monitoring. This may be due to an intervention that was provided, or some change in their circumstances (e.g., they stopped using cannabis). The problem we face is that it is difficult to differentiate “false positives” and “false

(2) Attenuated Psychotic Symptoms Groupdhaving attenuated positive psychotic symptoms, for at least 1 week, several times per week, within the last year (3) Brief Limited Intermittent Psychotic Symptoms Groupdhaving experienced short episodes of frank psychotic symptoms that have resolved without treatment within the last year

false positives.” Phenotypically they are the same. In theory, the “false false positives” should resemble the “true positives” in factors that predict transition to psychotic disorder (such as biomarkers). However, these groups should differ on factors that ultimately predicted development of psychotic disorder. For example, while both the “true positives” and the “false false positives” may have a high polygenic risk score for schizophrenia, the “true positives” may have high levels of perceived stress and substance use and low social support, while the “false false positives” may have lower levels of stress and substance use and strong social support, all of these factors being potentially relevant to development of a psychotic disorder. “False false positives” therefore continue to be at risk of psychotic disorder. In 1994, the first clinical service for individuals meeting the UHR criteria, the Personal Assessment and Crisis Evaluation (PACE) clinic was established in Melbourne, Australia. The

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service was designed to be low stigma and so was located at a general adolescent health service. Although it was able to receive referrals from a range of services, including young people themselves and their families, the majority of referrals were from the nearby Early Psychosis Prevention and Intervention Centre (EPPIC), a service for people in the first few years after psychosis onset. Referrals from EPPIC to PACE were individuals who were referred to EPPIC but who were found to have subthreshold rather than threshold psychotic symptoms. Early treatment at the PACE clinic consisted of management of presenting complaints, supportive therapy and monitoring of mental state.

Operationalization of the ARMS criteriadThe Comprehensive Assessment of At-Risk Mental States (CAARMS) A new instrument was needed to assess emerging subthreshold and brief psychotic symptoms. This was because existing instruments such as the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen, 1987) were adequate to assess symptom intensity, but they were unable to measure the more “finegrained” aspects of these symptoms such as their frequency, duration, and recency. The Comprehensive Assessment of At-Risk Mental States (CAARMS) was designed so that all relevant domains (intensity, frequency, duration, and recency) could be assessed with the one tool (Yung et al., 2005). Early publications referenced the BPRS and CASH, while the CAARMS instrument was being validated. The CAARMS consists of a semistructured interview and rating system and was designed to be used by trained interviewers (Yung et al., 2005). It is able to detect change in symptoms

over time and should be used as a repeated measure. No strict frequency of use is in place. Ideally an individual meeting ARMS criteria should be assessed every 3e4 months to monitor symptom progression or reduction and determine if a first episode of psychosis has developed. There are three main aims of the CAARMS: 1. To determine if an individual meets the criteria for an “At-Risk Mental State,” 2. To rule out, or confirm, criteria for first episode psychosis, 3. To map a range of psychopathology and functioning factors over time. For Aims 1 and 2, the positive symptoms scales are needed. For Aim 3, the CAARMS measures other symptoms thought to be indicative of imminent psychotic disorder. A literature review found that these experiences are present in the period leading up to a first episode of psychosis (Yung and McGorry, 1996). These include negative symptoms, depression, anxiety, obsessive-compulsive symptoms, dissociative symptoms, concentration and attention difficulties, and “basic” symptoms (Gross, 1989). Basic symptoms were first defined in the German psychiatric literature (Huber et al., 1980), and are subjective deficit features, the experiential equivalents of the behaviorally defined negative symptoms. They have been shown to occur in the prodromal phase of schizophrenia, as well as in the schizophrenia deficit state. Some basic symptoms, particularly cognitive, language, and perceptual disturbances, have been shown to predict first episode of psychosis (Klosterkoetter et al., 1996; Schultze-Lutter et al., 2007) (see Chapter 4). Instruments have been designed to measure basic symptoms in individuals considered at risk of psychotic disorder (SchultzeLutter et al., 2012). Table 3.1 shows the CAARMS subscales and items.

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Operationalization of the ARMS criteriadThe Comprehensive Assessment of At-Risk Mental States (CAARMS)

TABLE 3.1

Full CAARMS subscales.

Subscale

Items

Positive symptoms

Unusual thought content Non-bizarre ideas Perceptual abnormalities Disorganized speech

Cognitive change, attention, concentration

Subjective experience

Emotional disturbance

Subjective emotional disturbance

Observed cognitive change

Observed blunted affect Observed inappropriate affect

Negative symptoms

Alogia Avolition/apathy Anhedonia

Behavioral change

Social isolation Impaired role function Disorganizing/odd/stigmatizing behavior Aggression/dangerous behavior

Motor/physical changes

Subjective complaints of impaired motor functioning Informant reported or observed changes in motor functioning Subjective complaints of impaired bodily sensation Subjective complaints of impaired autonomic functioning

General psychopathology

Mania Depression Suicidality and self harm Mood swings/lability Anxiety Obsessive compulsive symptoms Dissociative symptoms Impaired tolerance to normal stress

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The original version of the CAARMS included three types of positive symptoms, disorders of thought content (e.g., delusional mood, overvalued ideas, and delusions), perceptual abnormalities (e.g., distortions, illusions, and hallucinations), and conceptual disorganization (e.g., subjectively experienced difficulties with forming thoughts and objective assessment of formal thought disorder). However, several factor analyses of psychotic symptoms suggested that this three-factor model did not adequately describe the different forms of positive symptoms. For example, there are three four-factor models (paranoia, first rank symptoms, hallucinations, and grandiosity (Stefanis et al., 2002)), (bizarre experiences, persecutory ideation, perceptual abnormalities, and magical thinking (Yung et al., 2009)), (bizarre experiences, persecutory ideation, perceptual abnormalities, and grandiosity (Armando et al., 2010)) and a five-factor model (hallucinations, delusions, paranoia, grandiosity, and paranormal beliefs (Dominguez et al., 2011)). These studies have all been conducted in nonclinical populations, and the factors are similar. Persecution, persecutory ideas, paranoia are all likely to be describing the same phenomena, as are first rank symptoms and bizarre experiences, and hallucinations and perceptual abnormalities. Paranormal beliefs and grandiosity may be equivalent to the dimension of magical thinking. In the light of these findings, the CAARMS disorders of thought content scale was split into two: unusual thought content (UTC) and non-bizarre ideas (NBI), with UTC describing clearly implausible symptoms, including the first rank symptoms of thought insertion, withdrawal, and broadcasting, and NBI including symptoms that could be plausible, such as persecutory and jealous ideas. An abbreviated version of the CAARMS is also available which includes only the positive symptom subscales as these are the ones needed

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to confirm or rule out an At-Risk Mental State. This version is frequently used in clinical services. Each CAARMS item is scored according to its intensity and frequency (from 0 (absent/no frequency) to 6 (severe and psychotic/continuous)). In addition, the positive symptom items include a distress scale, which is scored from 0 (no distress) to 100 (extremely distressing). The intensity, frequency, and distress scales of the positive symptoms have been shown to measure distinct aspects of the CAARMS (Wilson et al., under submission). The CAARMS has been translated into 18 languages and is widely used worldwide. An alternative instrument, the Structured Interview for Prodromal Syndromes (SIPS) (Miller et al., 2003) is based on the CAARMS and similar in structure. It is widely used in the United States. The CAARMS and the ARMS criteria have fairly good validity and reliability, meaning that the ARMS can be differentiated from psychotic disorder and from mental states below the ARMS threshold and that there tends to be agreement between clinicians about into which of these groups an individual falls (Woods et al., 2009). Further, the ARMS criteria are relatively specific for psychotic disorders, given their low incidence in the general population (Woods et al., 2009; Lin et al., 2015).

The predictive validity of the ARMS criteria Early studies found that the ARMS criteria had high predictive ability for development of psychosis. The original study from the PACE clinic found that over 40% of ARMS individuals (20 out of 49) developed a psychotic disorder within 1 year, a rate several hundred-fold over expected rates for that age group in the general population (Yung et al., 2003). Similarly, in the United States, a high risk was found in the

earliest study using the SIPS to define ARMS criteria, with 7 of 14 patients (50%) developing a psychotic disorder within 1 year (Miller et al., 2003). Subsequently, the criteria have shown predictive validity for psychotic disorders across different countries and service settings. A metaanalysis found that ARMS individuals have a risk of developing a full psychotic disorder of 15%e30% within 12 months, and over 36% after 3 years (Fusar-Poli et al., 2012). Most individuals who develop a psychotic disorder have a diagnosis of schizophrenia or a schizophrenia spectrum disorder. However, several more recent studies have found that the risk of developing a psychotic disorder has decreased in the ARMS population. We explored reasons for this in a 2007 paper (Yung et al., 2007). This paper examined the reduction in transition rate in the PACE clinic over time between 1993 and 2000 and found that the decline was associated with a shorter duration of symptoms prior to being referred to the PACE clinic (Yung et al., 2007). That is, people were referred to PACE earlier. Thus, the relationship between early detection and decreased transition rate could have been due to a “lead time bias”. This means that, due to earlier identification, a group will experience the event in question after a longer period following detection. It is a term frequently used in relation to cancer and survival times, and describes the situation in which a person diagnosed earlier may appear to survive longer, but in fact, early detection has no real effect on the time course of events. In ARMS studies, this means that there is no genuine reduction in transition rate, rather a longer time designated as being at ARMS before psychosis onset. That is, that there is an apparent decline in the transition rate but this is due to earlier detection and the rate will increase if longer follow up is provided. Alternatively, the reduction in transition rate may be a reflection of more effective treatment,

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Broadening the outcomes of interest

especially if that treatment is applied earlier in the course of illness. Several interventions have been used in the ARMS population (see below). It may be that if they are applied very early in the ARMS phase, perhaps before brain changes have occurred, then treatment may be more effective and perhaps preventive than if applied later. The reduction in transition rate would then be due to more “false false positives”dthose who would have developed psychosis but were prevented from doing so by the intervention. Another possibility that may explain the reduced transition rate is a “dilution effect”. That is, as the work of the PACE clinic has become more well-known, potential referrers may be more likely to ask about psychotic like symptoms. For example, a young person may seek help from a general practitioner or counseling service due to depressive symptoms. He or she may then be questioned about psychotic like experiences, as the well-meaning clinician is keen to detect any hint of risk for psychosis. As transient psychotic like experiences are not uncommon in adolescents and young adults (Van Os et al., 2009), these may be detected and lead to referral. In other words, the number truly at risk may be “diluted” with false positives: those not at risk of psychotic disorder.

Intervention studies to prevent transition to psychotic disorder Treatment of ARMS individuals has two aims: to manage current symptoms and problems and to reduce the risk of developing a psychotic disorder (Yung et al., 1996). Intervention trials have tended to have “transition to psychosis” as the primary outcome, with symptoms, level of functioning, and distress sometimes included as secondary outcome measures. A recent meta-analysis studied 10 randomized trials that reported effects on transition rates of low-dose antipsychotic medication, cognitive behavioral therapy (CBT), omega 3 fatty acid,

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and integrated treatment that included family therapy, cognitive remediation, social skills training, and CBT (van der Gaag et al., 2013). This study found that receipt of any specific intervention significantly reduced the risk of developing a first episode of psychosis both at 12 months and over the longer term (2e4 years), albeit with diminished effects over time. The reduced effect at long-term follow-up suggests that at least some ARMS individuals remain at risk and that interventions might delay, rather than prevent, onset of psychosis. Even so, such a delay could be of benefit, enabling people to, for example, finish education and develop supportive networks outside the family of origin. Since publication of this meta-analysis, several negative trials have been published, including of omega 3 fatty acids (McGorry et al., 2017) and CBT (Addington et al., 2011a). Additionally, a network meta-analysis examining trials with transition to psychosis as the outcome found that no specific treatment was effective. However, this claim was based on a comparison of specific treatments to a combination of several different “needs-based interventions,” many of which included active components. Additionally individuals who develop a first episode of psychosis after having been treated in the prodromal phase have improved outcomes compared to their counterparts who did not receive such very early intervention (Valmaggia et al., 2015). Interventions for ARMS individuals are further discussed in detail in Chapters 18 and 19.

Broadening the outcomes of interest As noted above, transition to psychosis has traditionally been the main outcome of interest in this ARMS group (Yung et al., 2003; Ruhrmann et al., 2010; Cannon et al., 2008). However, the majority of ARMS patients do not develop psychotic disorder even up to 10 years post

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identification (Nelson et al., 2013). Nonetheless, many remain symptomatic and disabled (Schlosser et al., 2012; Addington et al., 2011b; Lin et al., 2014; Cotter et al., 2014; Yung et al., 2010). This functional disability appears to be independent of positive symptoms (Cotter et al., 2014; Carri
on et al., 2013; Meyer et al., 2014), although its relationship to transition and diagnosis of psychotic disorder is unclear. It is important, therefore, to study psychosocial functioning as an outcome in at-risk research. Other outcomes of interest are persistent subthreshold positive symptoms, persistent negative symptoms (Yung et al., 2018), and nonpsychotic disorders such as anxiety and depression (Lin et al., 2015). Reflecting the need to include different outcomes in ARMS trials, recently some novel treatments have also been piloted in this group. These have had more targeted outcomes, based on hypothesized mechanisms of action of the intervention rather than global aims of reducing transition risk. For example, a small study of lithium hypothesized that it may have a neuroprotective effect and examined hippocampal MRI T2 relaxation time and proton magnetic resonance spectroscopy as outcomes testing this hypothesis (Berger et al., 2012). Glycine has been tested in two small pilot trials with outcomes of symptoms and neurocognitive functioning (Woods et al., 2013), a study of biofeedback measured anxiety and distress as outcomes (McAusland and Addington, 2016), and a trial of processing speed training examined improvement in processing speed and its correlation with social functioning (Choi et al., 2016). A trial of a family intervention measured caregiver warmth, family communication, and social functioning as outcomes (O’Brien et al., 2006). All studies showed feasibility and either significant results or trends to significance, indicating future avenues of research. A recent systematic review and network meta-analysis examined treatments for negative

symptoms in the ARMS group (Devoe et al., 2018). Psychosocial treatments and pharmacological treatments were examined. While N-methyl-D-aspartate-receptor (NMDAR) modulators (such as D-serine and glycine) ranked higher than all other treatments, no intervention significantly reduced negative symptoms. However, interpretation of this meta-analysis should take into account the relative paucity of studies in this area, small sample sizes and that the primary outcome for the majority of interventions was development of a psychotic disorder and not reduction in negative symptoms (Devoe et al., 2018). This meant that the psychosocial treatments did not include specific elements targeting negative symptoms. Further, as negative symptoms were not the focus of the studies, many ARMS participants had low levels of negative symptoms (e.g., (Nordentoft et al., 2006; Amminger et al., 2010)).

The attenuated psychosis syndrome More recently, the psychotic disorders working group of the Diagnostic and Statistical Manual of Mental Disorders (DSM V) in the United States considered the possibility of introducing a “psychosis risk syndrome” or “attenuated psychosis syndrome” into the psychiatric classification system (Tsuang et al., 2013). The syndrome described is roughly equivalent to the category of attenuated psychotic symptoms described in the ARMS criteria. There were a number of arguments for and against including it in the main document (Woods et al., 2010; Yung et al., 2010), but the eventual decision was to introduce the clinical term “Attenuated Psychosis Syndrome” (APS) in to the Appendix section (Section 3) as a condition for further systematic study (Yung et al., 2012). Further research in the field in the next few years will also concentrate on individuals meeting this specific set of criteria for an attenuated psychosis syndrome.

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References

The next wave of researchdrefining prediction One problem in ARMS research is that we lack understanding of the factors that predict different outcomes, including underlying biological mechanisms. This means that some ARMS individuals are having unnecessary treatment, and others are having ineffective interventions that potentially delay initiation of effective treatment. There is a need for investigation into factors that predict different outcomes. The aim would be to stratify the ARMS group according to their underlying pathological processes and target treatment accordingly, moving the field toward personalized management. Several “risk prediction tools” have now been published, but validation studies of them are lacking. One difficulty is that most studies of ARMS individuals have small sample sizes and low numbers of individuals developing psychotic disorder. Variables predictive of transition in one study may not be predictive in another and may not be generalizable to the whole population of ARMS individuals (not just those who consent to research studies). The field would benefit from pooled resources enabling analysis of large sample sizes, multiple factors, and interaction between factors. This would allow predictors with even small effects to be examined.

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I. Risk paradigms