Asian Journal of Psychiatry 5 (2012) 98–105

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Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp

Review

Early intervention in psychosis: Insights from Korea Jun Soo Kwon a,d,*, Min Soo Byun a, Tae Young Lee b, Suk Kyoon An c a

Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea c Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea d Department of Brain & Cognitive Sciences-WCU Program, Seoul National University College of Natural Sciences, Seoul, Republic of Korea b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 7 December 2011 Received in revised form 8 February 2012 Accepted 10 February 2012

Subjects at clinical high risk (CHR) for psychosis have been the focus of clinical attention in psychiatry for the last 15 years, leading to the development of valid and reliable diagnostic instruments to detect these individuals early in the course of their illness. These efforts have resulted in research into optimal preventive measures. Our experiences at and data from the Seoul Youth Clinic support the validity of the CHR concept and its underlying neurobiological basis and provide valuable information related to the determination of appropriate clinical interventions. The limitations of the current criteria for CHR, such as the relatively low transition rates to psychosis and the ‘‘false-positive’’ problem, are also common critical issues in Korea. Additionally, concerns about social stigmatization and the potential side effects of pharmacotherapy render individuals at CHR reluctant to visit clinical settings. Therefore, further investigations using a combination of predictive markers based on clinical and neurobiological studies of those at CHR are needed to refine the diagnostic criteria, overcome their current limitations including ethical issues, and develop phase-specific and individualized therapeutic interventions. ß 2012 Elsevier B.V. All rights reserved.

Keywords: Schizophrenia Clinical high risk Prodrome Prevention Korea

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and neurobiological characteristics of a high-risk cohort in Korea: experience from the Seoul Youth Clinic 2.1. Introduction to the Seoul Youth Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Clinical characteristics of the high-risk cohort in the Seoul Youth Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Demographic and clinical characteristics of the CHR cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Social and neurocognitive functioning of the CHR cohort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Neurobiological characteristics of the high-risk cohort in the Seoul Youth Clinic. . . . . . . . . . . . . . . . . . . . . . . Challenges and future directions for the CHR cohort in the Seoul Youth Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Common characteristics of CHR cohorts throughout the world . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Limitations and challenges of the current CHR criteria in Korea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Future directions: the role of biological markers and the clinical staging model . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Schizophrenia, one of the most debilitating psychiatric illnesses, is characterized by significant disruptions in daily life and social functioning over time. Because return to a pre-morbid state * Corresponding author at: Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-no, Chongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82 2 2072 2972; fax: +82 2 747 9063. E-mail address: [email protected] (J.S. Kwon). 1876-2018/$ – see front matter ß 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.ajp.2012.02.007

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after the onset of schizophrenia is difficult, many researchers have attempted to identify a vulnerability marker or early indicator of this disease in the service of early detection and intervention (Cannon et al., 2007). Previous studies on early recognition and treatment of first-episode psychosis have suggested that early detection and intervention in the disease may affect long-term prognosis (Hafner and Maurer, 2006; Miller et al., 1999). This has further motivated researchers to investigate whether the onset of the disease can be predicted. One of these efforts attempted to clarify the clinical characteristics of the prodromal phase of

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schizophrenia, including sub-threshold psychotic symptoms and such other clinical signs as cognitive deficits, difficulties in interpersonal relationships, mood changes, and decreased functioning (Cornblatt et al., 1999). As the term ‘‘prodromal’’ can be applied only after the onset of schizophrenia, the concepts of ‘‘atrisk mental state’’ (ARMS), ‘‘ultra-high risk (UHR) for psychosis,’’ ‘‘clinical high risk (CHR) for psychosis,’’ and ‘‘psychosis risk syndrome’’ have served as the foci of research conducted by the early psychosis movement during the last decade (McGorry et al., 2009; Woods et al., 2009). The notion that certain young individuals are at risk for later suffering from psychosis is not new. Indeed, it can be traced to as early as the 1960s, when Gerd Huber and colleagues observed that disturbances in cognition, emotion, and social functioning existed before patients experienced their first psychotic episode (Yung et al., 2005). Nevertheless, the application of the concept heralded by these German psychiatrists was pioneered by Australian psychiatrists at the Personal Assessment and Crisis Evaluation (PACE) clinic in the 1990s (Bell, 1992). Their approach to those at CHR, a term used almost interchangeably with UHR, focused on youths aged 16–30 years (Hafner et al., 1994). CHR is defined by the presence of at least one of the following three risk factors: (1) attenuated psychotic symptoms (APS); (2) brief, limited, intermittent psychotic symptoms (BLIPS); and (3) vulnerability, or trait and state risk factors (TS) such as recent functional decline in addition to trait-like factors such as schizotypal personality or family history of psychosis (Yung and McGorry, 1996). To identify these group in a reliable and valid manner via diagnostic criteria for CHR subjects, the ‘‘Comprehensive Assessment of At-Risk Mental States (CAARMS)’’ was developed (Yung et al., 2005); this instrument has been very useful in clinics worldwide, including in East Asia (Kwon et al., 2010; Lam et al., 2006; Miyakoshi et al., 2009). Independently of the PACE group, another team of researchers at Yale University, the Prevention through Risk Identification, Management, and Education (PRIME) group, constructed another valid tool to assess the prodromal phase of psychosis. Their ‘‘Structured Interview for Prodromal States (SIPS)’’ is useful for identifying individuals who meet a narrower definition of prodrome (Miller et al., 1999, 2002) and thus complements the CAARMS criteria. Propelled in part by the increasing concerns of the general public and health-care professionals about the seriousness and social burden of schizophrenia, the notion of CHR has drawn the attention of many psychiatrists around the world. The multiple aforementioned assessment tools have enabled us to apply a combination of approaches drawn from multiple theoretical stances (Hafner et al., 2004; Klosterkotter et al., 2005; Simon et al., 2006), which has become more common in attempts to detect psychosis in a nascent stage to implement timely preventive measures. The purpose of this article is to describe our clinical and neurobiological studies of CHR subjects in Korea and to discuss the critical issues that require consideration in clinical practice and research. 2. Clinical and neurobiological characteristics of a high-risk cohort in Korea: experience from the Seoul Youth Clinic 2.1. Introduction to the Seoul Youth Clinic The Seoul Youth Clinic was established in Seoul, Korea in November 2004 to provide early-detection and management services for individuals at high risk for psychosis and to identify the vulnerability markers associated with the transition to psychosis. Subjects at high risk for psychosis were divided into two groups for monitoring: (1) the CHR group and (2) the genetic high-risk (GHR) group. The CHR group was composed of individuals who had sought psychiatric help for symptoms such as suspiciousness, mood

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changes, sleep disturbances, emotional instability, social withdrawal, and cognitive disturbances such as reduced concentration and attention. On the other hand, the GHR group was composed of nonpsychotic subjects with a genetic loading for schizophrenia (i.e., non-psychotic subjects who have at least one first-degree relative and at least one second- to fourth-degree relative with schizophrenia). The sample was restricted to subjects 15–35 years of age to include individuals with increased vulnerability for the development of psychosis. Subjects were recruited from Seoul National University Hospital and other psychiatric clinics and a public mental health center. Subjects were able to contact the Clinic by telephone or an Internet homepage (http://www.youthclinic.org). After an initial screening via a telephone interview, candidates’ eligibility for participation in the CHR group was assessed with an intensive clinical intake interview. CHR status was determined with CAARMS and the Korean version of the SIPS (Jung et al., 2010a), and subjects who met the criteria identified by either of these two instruments were enrolled in the clinic’s CHR cohort after providing written informed consent. The Structured Clinical Interview for DSM-IV (SCID-IV) was used to assess comorbid axis I or II disorders. Clinician-rated scales for the evaluation of psychiatric symptoms including the Positive and Negative Syndrome Scale (PANSS), self-report questionnaires, blood tests with genetic samplings, neuropsychological tests including socialcognitive tasks, electrophysiological tests, and structural/functional neuroimaging were conducted at baseline and follow-up visits. CHR subjects initially received follow-up assessments every 6 months for 2 years and were subsequently assessed annually. Subjects who progressed to psychosis were withdrawn from the CHR-related assessments and treated as typical patients in the Seoul Youth Clinic. Following the clinical interview, all CHR subjects were informed that they met criteria for being at high risk for the development of psychosis; they were told that previous studies had found that about 40% of those at high risk converted to psychosis by the end of 1 year in the absence of therapeutic interventions (Schultze-Lutter, 2004; Yung et al., 2003). They were also informed that pharmacological treatment, such as the use of antipsychotics or antidepressants, and non-pharmacological treatment, such as cognitive-behavioral therapy (CBT), could help to alleviate their clinical symptoms and functional decline. Most CHR subjects at the Seoul Youth Clinic were treated with pharmacotherapy or CBT and monitored carefully on a weekly to monthly basis after they provided informed consent on treatment. CHR subjects were permitted to withdraw from the CHR assessments at any time. Upon withdrawal from the study, they could decide to continue the treatment. Individual CBT, supportive psychotherapy, crisis intervention, and psychoeducation were provided to CHR subjects at the Clinic. The Clinic also provided four sessions of a family education program containing information about the characteristics of the illness, treatment approaches including medication and CBT, and strategies for symptom management. Given that several studies have indicated the effectiveness of CBT for psychosis (Drury et al., 1996; Morrison et al., 2002; Sensky et al., 2000) and given that this therapeutic modality can be effective in reducing psychological disturbances, an individual CBT program, based on cognitive therapy for CHR subject developed by An and his colleagues (Kim et al., 2011a), was provided to each subject along with a workbook customized for CHR subjects. 2.2. Clinical characteristics of the high-risk cohort in the Seoul Youth Clinic 2.2.1. Demographic and clinical characteristics of the CHR cohort We had recruited 104 CHR subjects by mid-October 2011. Of these, 84 met the criterion of APS; one met the criterion of BLIPS;

100

[(Fig._1)TD$IG]

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and eight met the criterion for TS; 11 met criteria APS and TS at the same time. The criteria for these subgroups were based on the CAARMS and SIPS (McGlashan et al., 2003; Yung et al., 2005). Twelve CHR subjects were lost to follow-up (Fig. 1). The mean age of CHR subjects (71 males, 33 females) was 20.6  3.9 years. During the mean follow-up period of 39.0 months, 15 CHR subjects were identified as having converted to psychosis after participating in the study. Of these ‘‘converters,’’ seven were diagnosed with schizophrenia, paranoid type; three were diagnosed with schizophrenia, undifferentiated type; one was diagnosed with psychotic disorder NOS; and four were diagnosed with bipolar I disorder with psychotic features according to DSM-IV criteria. The mean prodromal period for converters (1.43  0.32 years) was significantly shorter than it was for those who did not convert to psychosis (2.56  0.23 years) (p = 0.04). This finding suggests that converters sought psychiatric help earlier than did non-converters due to the rapid aggravation of their symptoms. The mean CAARMS, SIPS, and total PANSS scores of CHR subjects were 35.03  1.28, 45.25  1.68, and 59.24  1.46, respectively (Table 1). We found no significant differences between converters and nonconverters in the clinical scales, suggesting that the two subgroups did not differ with respect to the severity of the clinical symptoms at baseline. Most of the CHR subjects in our cohort met criteria for the following comorbid axis I or II psychiatric disorders at baseline: mood disorder (64.1%), anxiety disorder (46.7%), personality disorder (21.7%), and other (7.6%). In some cases, CHR subjects had more than one comorbid diagnosis (Fig. 2). With regard to pharmacotherapy, 59 of the 92 CHR subjects were treated with psychotropic medications. The remaining subjects received psychotherapy or CBT with regular follow-up assessments. Antipsychotics were the most commonly prescribed medication, followed by benzodiazepines, antidepressants, and mood stabilizers (Fig. 3). The mean doses of amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone prescribed for the CHR patients were 150  40.82 mg, 9.11  8.72 mg, 10  6.05 mg, 238.60  248.81 mg, 2.05  1.23 mg, and 49.23  29.00 mg, respectively. We had previously investigated the effectiveness of antipsychotics in CHR subjects and found that low-dose antipsychotics were effective and safe in reducing prodromal symptoms (Shim et al., 2008a). Another recent naturalistic observational study in our CHR cohort (Kim et al., 2012) revealed that converters were treated with antipsychotics for longer periods and at higher doses than were non-converters, although the doses of antipsychotics prescribed for CHR subjects were usually lower than those prescribed for patients with full-blown psychosis. This finding may be attributable to clinicians’ reluctance to increase the dosage of antipsychotics that are used for off-label purposes for subjects with

Fig. 1. The recruitment of subjects at clinical high-risk for psychosis in the Seoul Youth Clinic. Abbreviations: CHR, clinical high risk; APS, attenuated psychotic symptoms criteria; BLIPS, brief limited intermittent psychotic symptoms criteria; TS, trait and state risk factors criteria.

no definite diagnosis of psychotic disorder. However, given that converters were exposed to a higher dosage of antipsychotics than were non-converters, it is possible that antipsychotics may not be as effective as expected (Kim et al., 2012). 2.2.2. Social and neurocognitive functioning of the CHR cohort Social and cognitive deficits are core features of schizophrenia (Pinkham et al., 2003), and impaired social-cognitive functioning has been recently implicated as a potential marker of vulnerability for the development of psychosis (Niendam et al., 2009). In our experience, CHR subjects demonstrated impaired social and affective functioning as well as cognitive deficits in various domains. At baseline, CHR subjects exhibited impaired social and affective functioning, and the duration of the prodromal symptoms was associated with impairments in interpersonal behavior (Jang et al., 2011a; Lee et al., 2008; Shim et al., 2008b). Furthermore, a 1year longitudinal follow-up assessment showed that the social functioning of converters was impaired before the onset of psychosis and further declined during the follow-up period.

Table 1 The demographic and clinical characteristics of subjects at clinical high-risk for psychosis in the Seoul Youth Clinic.

Age (years  SD) Sex (male, %) Duration of symptoms (years  SD) Intake criteria (n) APS BLIPS TS Both APS and TS Clinical scales (SD) CAARMS (total) SIPS (total) PANSS (total)

Total (n = 92)

Converter (n = 15)

Non-converter (n = 77)

p-Value

20.63  0.40 67.3 2.37  0.20

20.72  0.42 60.0 1.43  0.32

20.13  1.24 68.8 2.56  0.23

0.592a 0.980b 0.043a

73 1 7 11

12 1 0 2

61 0 7 9

45.25  1.68 35.03  1.28 59.24  1.46

38.06  18.41 32  14.35 54.21  12.58

46.67  15.33 35.59  11.73 60.17  14.05

0.106a 0.389a 0.126a

APS, attenuated psychotic symptoms criteria; BLIPS, brief limited intermittent psychotic symptoms criteria; TS, trait and state risk factors criteria; CAARMS, Comprehensive Assessment of At-Risk Mental States; SIPS, Structured Interview for Prodromal Syndromes; PANSS, Positive and Negative Syndrome Scale; SD, standard deviation. a Independent t-test. b Pearson’s Chi-square test.

[(Fig._2)TD$IG]

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2.3. Neurobiological characteristics of the high-risk cohort in the Seoul Youth Clinic

Fig. 2. Comorbid axis I and II diagnosis of subjects at clinical high-risk for psychosis at the baseline assessment in the Seoul Youth Clinic. yMajor depressive disorder, dysthymic disorder, depressive disorder not otherwise specified (NOS), bipolar II disorder, bipolar disorder NOS, mood disorder NOS. zSocial phobia, obsessive– compulsive disorder, panic disorder, specific phobia, generalized anxiety disorder, anxiety disorder NOS. §Schizotypal personality disorder, antisocial personality disorder, avoidant personality disorder, obsessive–compulsive personality disorder. ôAlcohol use disorder, somatoform disorder NOS, pain disorder, psychotic disorder NOS, adjustment disorder.

Additionally, pharmacological treatment was associated with increased scores on measures of prosocial activities, suggesting that appropriate pharmacotherapy may help to improve social functioning (Jang et al., 2011a). With respect to social functioning, findings from our previous studies suggest that neurocognitive and social-cognitive deficits may play important roles in the impaired social functioning of CHR subjects. CHR subjects showed not only general impairment in the cognitive domains (i.e., executive function, spatial working memory, and visuospatial memory) but also deficits in theory-of-mind (ToM) skills and face-recognition ability compared with healthy controls (HC) (Chung et al., 2008; Kim et al., 2010, 2011b). Compared with non-converters, converters exhibited more impaired ToM skills, executive function, and verbal/visual memory. Moreover, a model combining selective social-cognitive and neurocognitive variables significantly predicted conversion to psychosis. The results of our studies suggesting that the early deterioration in social and cognitive functioning occurs before the onset of psychosis support previous findings that impaired social and role functioning in CHR subjects can be predictive of the development of psychosis (Cornblatt et al., in press; Kim et al., 2011b). [(Fig._3)TD$IG]

Accumulated neurobiological studies provide considerable evidence for the view that neurodevelopmental changes occurring during the initial stage of psychosis contribute significantly to the pathophysiology of schizophrenia (Pantelis et al., 2007). We investigated whether CHR individuals have early brain vulnerability to psychosis and structural/functional brain changes during the transition to psychosis. Our first MRI study in CHR individuals examined abnormalities of the cavum septum pellucidum (CSP), which is one of putative markers of early disturbances in brain development. We found that CHR subjects exhibited a significantly higher prevalence of abnormalities in the CSP compared with controls; this is one of the consistent findings from studies on schizophrenia (Kwon et al., 1998). Additionally, we found regional cortical thinning in the superior temporal cortex, anterior cingulate cortex, prefrontal cortex, and inferior parietal cortex that varied as a function of the stage of the illness (i.e., in order, normal controls > CHR subjects > patients with schizophrenia). The intermediate levels of cortical thinning in regions vulnerable to psychosis observed in the CHR group suggests that features of the brain structure of the CHR group are likely to match those observed during the prodromal stage (Jung et al., 2011). With regard to functional brain abnormalities, we asked both CHR and GHR groups to perform a spatial working-memory task during fMRI scanning. In this study, both the CHR and the schizophrenia group showed functional deficits in the frontoparietal circuit, whereas the GHR group showed compensatory activation in this circuit (Choi et al., in press). Additionally, we found aberrant functional connectivity in CHR subjects during both performance of the task and the resting state. These findings indicate hyperconnectivity in the region of the default-mode network (DMN) and reduced anti-correlation between this region and task-related-network regions (Shim et al., 2010). GHR subjects also showed reduced DMN functional connectivity in the prefrontal cortex compared with HC, and the degree of this alteration was correlated with the severity of the psychopathology (Jang et al., 2011b). The neurophysiological characteristics of our CHR cohort also resembled the aforementioned pattern. Studies using the magnetoencephalography revealed abnormal mismatch negativity (MMN) and N1m adaption, findings consistently observed in patients with schizophrenia, in our CHR subjects, indicating that the CHR group would have deficits in the early stage of auditory processing (Shin et al., 2009, in press; Umbricht and Krljes, 2005). Additionally, decreased alpha event-related desynchronization was found in CHR subjects, whereas the value for the CHR group

Fig. 3. The percentage of subjects at clinical high-risk for psychosis who received medication more than once during the follow-up period in the Seoul Youth Clinic.

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was between those for HC and patients with schizophrenia (Koh et al., 2011). These findings suggest that abnormal top-down attentional control during auditory perception occurs before the onset of psychosis and that this phenomenon may be sensitive to the progression of illness (Shin et al., in press). 3. Challenges and future directions for the CHR cohort in the Seoul Youth Clinic 3.1. Common characteristics of CHR cohorts throughout the world In our experience, clinical and neurobiological studies of the CHR cohort at the Seoul Youth Clinic indicate that Korean subjects identified by current CHR criteria resemble participants in other study groups (Lam et al., 2006; Liu et al., 2011; McGlashan et al., 2006; McGorry et al., 2002; Miller et al., 2003; Ruhrmann et al., 2010; Yung et al., 2004). The baseline characteristics of our cohort including mean age, sex distribution, and mean score on clinical rating scales were similar to those of cohorts from the West (i.e., Australia, Europe, North America) and to those of cohorts from East Asian countries such as Taiwan and Hong Kong. The impaired social functioning and deficits in social cognition/neurocognition in our CHR cohort are also consistent with previous studies of other groups (Carrion et al., 2011; Cornblatt et al., in press; Jang et al., 2011a; Kim et al., 2011b; Shim et al., 2008b). Furthermore, the results of neurobiological studies on our CHR cohort are consistent with previous findings of structural and functional imaging abnormalities and aberrant auditory processing (Choi et al., in press; Jung et al., 2010b, 2011; Shin et al., 2009, in press). These findings suggest that although Korea’s racial, social, and cultural environments differ from those of Western countries, our CHR sample is comparable to those in other countries. In other words, subjects at CHR have common clinical and biological characteristics throughout the world, suggesting that the effect of environment on the onset of at-risk symptoms may be weaker than expected. However, more studies are necessary to confirm this hypothesis. 3.2. Limitations and challenges of the current CHR criteria in Korea Fifteen of the 92 subjects in our CHR cohort converted to psychosis during the mean 39-month follow-up period, which is lower than the 40% reported by previous studies (Yung et al., 2003). However, recent studies have revealed a clear trend toward a lower rate (around 15%) of transition to psychosis (Haroun et al., 2006; Yung et al., 2008). Another recent study found that individuals at CHR were actually four times more likely to fully remit than to develop psychosis within 1 year (Simon and Umbricht, 2010). Despite the argument that both earlier recognition and effective intervention could have influenced these findings (Yung et al., 2007), the lower conversion rates to psychosis suggest that the CHR group, defined according the current criteria, included heterogeneous subgroups: converters versus non-converters. Although the groups in our sample did not differ significantly in the baseline scores on the clinical rating scales, converters and non-converters seemed to experience different clinical courses. The mean prodromal period for converters was significantly shorter than it was for non-converters, and exposure to antipsychotics was more prevalent among converters than among non-converters. Additionally, converters demonstrated greater impairment in their social and cognitive functioning as well as more extensive structural brain changes than did non-converters (Jung et al., 2011; Sun et al., 2009). Our previous study also found that converters (n = 8) showed reduced cortical thickness in the right anterior cingulate cortex (ACC), left lingual cortex, right superior temporal cortex, and bilateral inferior temporal cortex compared with non-converters (n = 22), although these findings

should be considered preliminary due to the small sample size (Jung et al., 2011). However, the results of that study are consistent with a previous longitudinal follow-up study showing that converters showed more cortical volume loss than did nonconverters (Sun et al., 2009) and with a recent voxel-wise metaanalysis reporting that the onset of psychosis is associated with gray matter reductions in the temporoinsular, anterior cingulate, and cerebellar regions (Fusar-Poli et al., in press). These findings suggest that changes in regional brain structure are associated with the onset of psychosis and support the hypothesis that converters have their own discrete clinical and neurobiological characteristics compared with non-converters. However, the identification of subjects who will transition to psychosis based solely on clinical phenomenology is difficult due to the complexity of differentiating schizophrenia from bipolar disorder during the prodromal phase (Correll et al., 2007; Thompson et al., 2003). Consistent with this observation, our experiences at the Seoul Youth Clinic have also demonstrated that as many as one-fourth of converters were ultimately diagnosed with bipolar disorder instead of schizophrenia. This further dilution of the CHR group seems unavoidable as long as we are dependent on the current symptom-based operational criteria. The high false-positive rates resulting from current CHR criteria lead to ethical problems with over-diagnosis and the overprescription of antipsychotics, which are major concerns in current clinical practice and research (Francey et al., 2010; McGorry et al., 2009; Yung, 2010). For some portion of subjects in the current CHR group, the risk (i.e., the adverse effects of pharmacotherapy or social stigma) may be higher than the benefits. Metabolic syndrome related to exposure to atypical antipsychotic agents is not uncommon, and young individuals exposed to antipsychotics for the first time are considered to be at especially higher risk for this disorder (Pramyothin and Khaodhiar, 2010). The risk of tardive dyskinesia should also not be overlooked even though its incidence has decreased significantly in the current era of atypical antipsychotics (Weiden, 2007). Additionally, our previous study on the use of antipsychotics in CHR subjects showed that converters were exposed to higher dosages of antipsychotics than were non-converters. This finding suggests that antipsychotics may not be effective in preventing the onset of psychosis (Kim et al., 2012). However, other studies have demonstrated that low-dose antipsychotics can be beneficial to CHR subjects by reducing clinical symptoms and delaying the onset of psychosis (McGlashan et al., 2006; McGorry et al., 2002). Indeed, given the high rate of comorbid axis I or II disorders in CHR subjects observed in our cohort, some portion of CHR subjects may need pharmacotherapy to treat clinical symptoms. This explains, in part, why most of the subjects in our CHR cohort were treated with medication, although less than 20% of this group converted to psychosis. Additionally, the use of atypical antipsychotic agents in standard psychiatric practice is not limited to psychotic disorders, as many patients with mood, anxiety, or personality disorders benefit from taking this class of medication. Yet, we cannot completely rule out the possibility that pharmacological treatment during the prodromal period may prevent the transition to psychosis (Yung, 2010). Thus, evidence about whether to prescribe antipsychotics to subjects at CHR remains inconclusive, and this issue requires further investigation. Ongoing trials on a larger scale may resolve this issue (Bechdolf et al., 2010). Another significant obstacle resulting from the high falsepositive rates associated with the current CHR criteria involves the stigma attached to the possibility of developing psychosis in the future. Although patients and caregivers are reportedly less vulnerable to self-stigmatization during the early stages of the illness (Wong et al., 2009) and even accept their label in a generally

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adaptive way (Welsh and Tiffin, 2012), the stigmatizing attitudes of the general public remain significant (Jorm and Griffiths, 2008). Potential areas of discrimination experienced by patients may not be limited to emotional shunning, and discrimination often extends to disadvantages in more practical matters such as medical insurance (Dodds et al., 2011). This may present an additional obstacle to the willingness of subjects at CHR to seek appropriate and potentially beneficial treatment, and it is one of the reasons that even some clinicians are reluctant to make a formal diagnosis of ‘‘psychosis risk syndrome’’ (Corcoran et al., 2010). Korea is not exceptional with respect to the stigma associated with the term ‘‘psychosis’’ (Han et al., 2002; Park et al., 2004). However, recent efforts to ameliorate public prejudices about psychosis or psychiatric problems in general have been initiated in Korea. Changes in nomenclature have included the recent retranslation of schizophrenia as ‘‘attunement disorder’’ in Korean (Lee and Kwon, 2011). Although the effectiveness of this effort to combat the ignorance of the general population remains to be seen, a reported decrease in prejudice against schizophrenia that followed a similar renaming of schizophrenia as ‘‘integration disorder’’ in Japan several years ago (Takahashi et al., 2009) raises our hopes of achieving a similar positive outcome. 3.3. Future directions: the role of biological markers and the clinical staging model Further improvement in the diagnostic field of CHR constitutes the most central issue for future research on this issue. Many recent efforts to establish a diagnostic model that combines multiple clinical and neurobiological variables with current CHR criteria have been undertaken to overcome current limitations and develop measures that detect at-risk states more efficiently. Demographic variables (Choi et al., 2009) or constellations of symptoms (Kim et al., 2011b) may predict the future course of subjects at CHR. Cognitive deficits, especially in conjunction with clinical factors, may be valuable for refining the present notion of CHR. Deficits in working memory, executive function, and verbal memory have been suggested as candidate components of diagnostic criteria (Brewer et al., 2005, 2006). Verbal memory deficits combined with APS (Lencz et al., 2006) as well as reduced speed of information processing combined with suspiciousness and anhedonia/social withdrawal (Riecher-Rossler et al., 2009) have been reported to be more specific and sensitive for predicting conversion to psychosis. More recently, early impairment in social functioning in addition to APS has been suggested as a more accurate marker for CHR (Cornblatt et al., in press). Adding additional variables, whether clinical or cognitive, to the criteria would help to increase the diagnostic specificity, but the risk of decreased diagnostic sensitivity should always be taken into account. The incorporation of biological variables into diagnostic tools has also been suggested (Pantelis et al., 2009). Specifically, the neuroanatomical biomarkers identified by MRI studies would certainly lead to the increased positive predictive value of the CHR concept without significantly undermining diagnostic sensitivity. A few recent studies using multivariate machine-learning methods (i.e., a support-vector machine) have demonstrated the feasibility of predicting the conversion to psychosis in CHR subjects (Koutsouleris et al., in press), of differentiating those with firstepisode schizophrenia from HC (Takayanagi et al., 2011), and of predicting the course of the illness course at the first psychotic episode (Mourao-Miranda et al., in press). However, the increased cost may render utilization of this approach less acceptable in nonresearch clinical settings. Pharmacological treatment, although effective in the management of current symptoms, has produced contradictory results in terms of its efficacy in preventing conversion to psychosis

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(McGlashan et al., 2006). A balance between the risks and benefits of treating individuals at CHR with pharmacotherapy may be achieved by classifying these subjects according to their relative risk or the severity of their current symptoms; such an approach will assist in the selection of a subgroup for whom treatment with antipsychotics would be most beneficial. This effort is consistent with a recently proposed ‘‘clinical staging model’’ (McGorry et al., 2006). Following therapeutic guidelines for each clinical stage would provide safer interventions as the first line of treatment for subjects at CHR (McGorry et al., 2009). It should also be emphasized that the prescription of antipsychotics is not the only available option for CHR subjects. Indeed, non-antipsychotic medications (i.e., antidepressants (Fusar-Poli et al., 2007; Tadokoro et al., 2011), omega-3 fatty acids (Amminger et al., 2010), and psychosocial therapy such as CBT (Bechdolf et al., 2010) may also be of assistance. Furthermore, as one of the non-pharmacological interventions, our clinic is planning to develop mindfulness meditation program for stress management of subjects at CHR. Since the vulnerability of stress has been accepted as one of the core etiology of developing schizophrenia (Yuii et al., 2007) and individuals at CHR have been reported to have higher stress levels (Pruessner et al., 2011) and show greater negative emotions in response to stress (Palmier-Claus et al., in press) than HC, treatment strategies for reducing stress levels can be helpful for CHR subjects. As many recent studies showed that mindfulness meditation is effective to reduce stress (Chiesa and Serretti, 2010), we hope that mindfulness meditation can improve clinical outcome of CHR subjects and broaden our treatment strategies. 4. Conclusion Despite differences in racial and cultural environments, the current clinical and neurobiological characteristics used to identify CHR individuals seem to share common features throughout the world. This finding suggests that the current criteria represent considerable progress toward meeting the original goal of providing new strategies to manage the prodromal phase of psychosis. However, the high false-positive rates produced by current CHR criteria and the conflicting results of studies on the efficacy of antipsychotics for preventing the onset of psychosis raise concerns about ethical issues as well as require further research. Additionally, concerns about social stigmatization also render CHR subjects reluctant to visit clinical settings. Recent attempts to develop a prediction model that combines clinical variables and biological markers and to offer different therapeutic interventions according to the clinical stage of CHR subjects illuminate the future of clinical practice and research related to early intervention in psychosis. Further investigations are necessary to identify predictive markers in the service of more precise prediction of psychosis and to modify the criteria to increase their positive predictive value, which can be a solution to ethical issues of research as well. Role of funding source This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090096). The Ministry for Health, Welfare & Family Affairs had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Contributors Author Jun Soo Kwon developed the Seoul Youth Clinic, designed and supervised the overall studies that have been

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conducted at the Seoul Youth Clinic, and substantially contributed in drafting the manuscript. Authors Min Soo Byun and Tae Young Lee participated in writing the manuscript as well as analyzing the data. Author Suk Kyoon An contributed in reviewing and modifying the manuscript for revision. All authors contributed to and have approved the final manuscript. Conflict of interest None of the authors have any conflicts of interests. Acknowledgements We greatly acknowledge the contribution of Myong-Wuk Chon, MD, Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea, and Wi Hoon Jung, MS, Na Young Shin, MA, Kyung Soon Shin, PhD, Clinical Cognitive Neuroscience Center, Neuroscience Institute, SNU-MRC, Seoul, Republic of Korea, and Hyun Jung Han, MA, Department of Brain & Cognitive SciencesWCU Program, Seoul National University College of Natural Sciences, Seoul, Republic of Korea, for drafting the manuscript. References Amminger, G.P., Schafer, M.R., Papageorgiou, K., Klier, C.M., Cotton, S.M., Harrigan, S.M., Mackinnon, A., McGorry, P.D., Berger, G.E., 2010. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebocontrolled trial. Arch. Gen. Psychiatry 67 (2), 146–154. Bechdolf, A., Knost, B., Nelson, B., Schneider, N., Veith, V., Yung, A.R., Pukrop, R., 2010. Randomized comparison of group cognitive behaviour therapy and group psychoeducation in acute patients with schizophrenia: effects on subjective quality of life. Aust. N. Z. J. Psychiatry 44 (2), 144–150. Bell, R.Q., 1992. Multiple-risk cohorts and segmenting risk as solutions to the problem of false positives in risk for the major psychoses. Psychiatry 55 (4), 370–381. Brewer, W.J., Francey, S.M., Wood, S.J., Jackson, H.J., Pantelis, C., Phillips, L.J., Yung, A.R., Anderson, V.A., McGorry, P.D., 2005. Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis. Am. J. Psychiatry 162, 71–78. Brewer, W.J., Wood, S.J., Phillips, L.J., Francey, S.M., Pantelis, C., Yung, A.R., Cornblatt, B., McGorry, P.D., 2006. Generalized and specific cognitive performance in clinical high-risk cohorts: a review highlighting potential vulnerability markers for psychosis. Schizophr. Bull. 32, 538–555. Cannon, T.D., Cornblatt, B., McGorry, P., 2007. The empirical status of the ultra highrisk (prodromal) research paradigm. Schizophr. Bull. 33 (3), 661–664. Carrion, R.E., Goldberg, T.E., McLaughlin, D., Auther, A.M., Correll, C.U., Cornblatt, B.A., 2011. Impact of neurocognition on social and role functioning in individuals at clinical high risk for psychosis. Am. J. Psychiatry 168 (8), 806–813. Chiesa, A., Serretti, A., 2010. A systematic review of neurobiological and clinical features of mindfulness meditations. Psychol. Med. 40 (8), 1239–1252. Choi, J.S., Chon, M.W., Kang, D.H., Jung, M.H., Kwon, J.S., 2009. Gender difference in the prodromal symptoms of first-episode schizophrenia. J. Korean Med. Sci. 24 (6), 1083–1088. Choi, J.S., Park, J.Y., Jung, M.H., Jang, J.H., Kang, D.H., Jung, W.H., Han, J.Y., Choi, C.H., Hong, K.S., Kwon, J.S. Phase-specific brain change of spatial working memory processing in genetic and ultra-high risk groups of schizophrenia. Schizophr. Bull., in press. Chung, Y.S., Kang, D.-H., Shin, N.Y., Yoo, S.Y., Kwon, J.S., 2008. Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia. Schizophr. Res. 99 (1– 3), 111–118. Corcoran, C.M., First, M.B., Cornblatt, B., 2010. The psychosis risk syndrome and its proposed inclusion in the DSM-V: a risk-benefit analysis. Schizophr. Res. 120 (1–3), 16–22. Cornblatt, B., Obuchowski, M., Roberts, S., Pollack, S., Erlenmeyer-Kimling, L., 1999. Cognitive and behavioral precursors of schizophrenia. Dev. Psychopathol. 11 (3), 487–508. Cornblatt, B.A., Carrion, R.E., Addington, J., Seidman, L., Walker, E.F., Cannon, T.D., Cadenhead, K.S., McGlashan, T.H., Perkins, D.O., Tsuang, M.T., Woods, S.W., Heinssen, R., Lencz, T. Risk factors for psychosis: impaired social and role functioning. Schizophr. Bull., in press. Correll, C.U., Penzner, J.B., Frederickson, A.M., Richter, J.J., Auther, A.M., Smith, C.W., Kane, J.M., Cornblatt, B.A., 2007. Differentiation in the preonset phases of schizophrenia and mood disorders: evidence in support of a bipolar mania prodrome. Schizophr. Bull. 33 (3), 703–714. Dodds, T.J., Phutane, V.H., Stevens, B.J., Woods, S.W., Sernyak, M.J., Srihari, V.H., 2011. Who is paying the price? Loss of health insurance coverage early in psychosis. Psychiatr. Serv. 62 (8), 878–881. Drury, V., Birchwood, M., Cochrane, R., Macmillan, F., 1996. Cognitive therapy and recovery from acute psychosis: a controlled trial. I. Impact on psychotic symptoms. Br. J. Psychiatry 169 (5), 593–601.

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