Volume Reduction of the Dorsal Lateral Prefrontal Cortex Prior to the Onset of Frank Psychosis in Individuals with an At-Risk Mental State.

Although some individuals with at-risk mental states (ARMS) develop overt psychosis, surrogate markers which can reliably predict a future onset of psychosis are not well established. The dorsal lateral prefrontal cortex (DLPFC) is thought to be involved in psychotic disorders such as schizophrenia. In this study, 73 ARMS patients and 74 healthy controls underwent 1.5-T 3D magnetic resonance imaging scans at three sites. Using labeled cortical distance mapping, cortical thickness, gray matter (GM) volume, and surface area of DLPFC were estimated. These measures were compared across the diagnostic groups. We also evaluated cognitive function among 36 ARMS subjects to clarify the relationships between the DLPFC morphology and cognitive performance. The GM volume of the right DLPFC was significantly reduced in ARMS subjects who later developed frank psychosis (ARMS-P) relative to those who did not (P = 0.042). There was a positive relationship between the right DLPFC volume and the duration prior to the onset of frank psychosis in ARMS-P subjects (r = 0.58, P = 0.018). Our data may suggest that GM reduction of the DLPFC might be a potential marker of future onset of psychosis in individuals with ARMS.

Longitudinal changes in personal recovery in individuals with psychotic disorders through hospitalisation in a psychiatric ward: preliminary findings.

BACKGROUND: This study aimed to investigate whether personal recovery indices in individuals with psychotic disorders would change through hospitalisation in a psychiatric ward and to identify factors associated with these changes. METHODS: Participants underwent assessments for personal recovery using the Questionnaire about the Process of Recovery, Recovery Assessment Scale, and Self-Identified Stage of Recovery Part A and B; clinical symptoms using the Positive And Negative Syndrome Scale; self-efficacy using the General Self-Efficacy Scale; and self-esteem using the Rosenberg Self-Esteem Scale at baseline and before hospital discharge. Wilcoxon signed-rank tests were administered for longitudinal comparisons between baseline and follow-up. Spearman's rank correlation tests were conducted to assess correlations of longitudinal changes in personal recovery with baseline values of personal recovery as well as baseline values or changes in the Positive And Negative Syndrome Scale, General Self-Efficacy Scale, and Rosenberg Self-Esteem Scale. RESULTS: Thirty-four individuals with psychotic disorders completed the assessments. The average duration of the current hospitalisation was 81.9 days (SD, 15.3; median, 85.0; range, 51-128 days). No significant changes were observed in personal recovery, self-efficacy, and self-esteem, although clinical symptoms significantly improved. Significant correlations were found between positive changes in the Recovery Assessment Scale and improvements in negative symptoms; between positive changes in the General Self-Efficacy Scale and those in personal recovery assessed with the Questionnaire about the Process of Recovery, Recovery Assessment Scale, and Self-Identified Stage of Recovery part A; and between positive changes in the Rosenberg Self-Esteem Scale and those in the Self-Identified Stage of Recovery part B. CONCLUSION: This study revealed longitudinal relationships between changes in personal recovery and amelioration of negative symptoms or enhancement of self-efficacy and self-esteem through moderate length of hospitalisation in individuals with psychotic disorders. Considering the small sample size in this study, further studies with a larger sample size are needed to confirm the present finding. TRIAL REGISTRATION: The protocol of this study is registered in the UMIN Clinical Trials Registry (UMIN-CTR; ID: UMIN000035131 ).

Emotional processing during speech communication and positive symptoms in schizophrenia.

AIMS: The recognition of emotion is often impaired in patients with schizophrenia. The relationship of this deficit with symptoms of psychosis remains unclear. In the current study, we investigated the relationship between emotional processing and positive psychotic symptoms in schizophrenia. METHODS: Twenty-eight patients with schizophrenia and 37 healthy participants were included in the study. They were instructed to listen to a set of sentences and judge whether the emotional valence expressed verbally and that expressed by affective prosody were congruous or incongruous. RESULTS: Overall, the patients with schizophrenia had more inaccurate responses than the healthy participants and the poor performance was prominent when the patients processed affectively negative scenarios. The percentage of accurate responses negatively correlated with the severity of positive symptoms when the scenarios and/or the affective prosody had a negative valence. CONCLUSION: Patients with schizophrenia appear to have impaired function in the processing of negative verbal information. Impaired processing of negative verbal and prosodic information seems to be associated with positive symptoms in schizophrenia.

[Application of cognitive behavioral therapy to early phase of psychosis].

Attempts to apply cognitive-behavioral therapy (CBT) to treat patients in the early stage of psychosis, including those with First-Episode Psychosis (FEP) and those with an At-Risk Mental State (ARMS), have recently attracted considerable attention. Such CBT for FEP focuses on promoting the recovery process and relapse prevention, although evidence on its efficacy is currently limited. Further, studies on CBT for ARMS have not consistently demonstrated its effectiveness. Some reports affirm the effectiveness of CBT in FEP prevention, while others claim that the treatment leads to no compelling difference in comparison to nonspecific treatment such as supportive therapy and treatment as usual. It is evident that psychosocial interventions play a fundamental role in the treatment of early stages of psychosis. Therapeutic approaches based on CBT have been applied to various cases: however, further research is necessary in order to produce more concrete results and obtain the evidence needed to approve this method.

Speech Illusions in People at Clinical High Risk for Psychosis Linked to Clinical Outcome.

BACKGROUND AND HYPOTHESIS: Around 20% of people at clinical high risk (CHR) for psychosis later develop a psychotic disorder, but it is difficult to predict who this will be. We assessed the incidence of hearing speech (termed speech illusions [SIs]) in noise in CHR participants and examined whether this was associated with adverse clinical outcomes. STUDY DESIGN: At baseline, 344 CHR participants and 67 healthy controls were presented with a computerized white noise task and asked whether they heard speech, and whether speech was neutral, affective, or whether they were uncertain about its valence. After 2 years, we assessed whether participants transitioned to psychosis, or remitted from the CHR state, and their functioning. STUDY RESULTS: CHR participants had a lower sensitivity to the task. Logistic regression revealed that a bias towards hearing targets in stimuli was associated with remission status (OR = 0.21, P = 042). Conversely, hearing SIs with uncertain valence at baseline was associated with reduced likelihood of remission (OR = 7.72. P = .007). When we assessed only participants who did not take antipsychotic medication at baseline, the association between hearing SIs with uncertain valence at baseline and remission likelihood remained (OR = 7.61, P = .043) and this variable was additionally associated with a greater likelihood of transition to psychosis (OR = 5.34, P = .029). CONCLUSIONS: In CHR individuals, a tendency to hear speech in noise, and uncertainty about the affective valence of this speech, is associated with adverse outcomes. This task could be used in a battery of cognitive markers to stratify CHR participants according to subsequent outcomes.

Reduced cortical thickness of the paracentral lobule in at-risk mental state individuals with poor 1-year functional outcomes.

Although widespread cortical thinning centered on the fronto-temporal regions in schizophrenia has been reported, the findings in at-risk mental state (ARMS) patients have been inconsistent. In addition, it remains unclear whether abnormalities of cortical thickness (CT) in ARMS individuals, if present, are related to their functional decline irrespective of future psychosis onset. In this multicenter study in Japan, T1-weighted magnetic resonance imaging was performed at baseline in 107 individuals with ARMS, who were subdivided into resilient (77, good functional outcome) and non-resilient (13, poor functional outcome) groups based on the change in Global Assessment of Functioning scores during 1-year follow-up, and 104 age- and sex-matched healthy controls recruited at four scanning sites. We measured the CT of the entire cortex and performed group comparisons using FreeSurfer software. The relationship between the CT and cognitive functioning was examined in an ARMS subsample (n = 70). ARMS individuals as a whole relative to healthy controls exhibited a significantly reduced CT, predominantly in the fronto-temporal regions, which was partly associated with cognitive impairments, and an increased CT in the left parietal and right occipital regions. Compared with resilient ARMS individuals, non-resilient ARMS individuals exhibited a significantly reduced CT of the right paracentral lobule. These findings suggest that ARMS individuals partly share CT abnormalities with patients with overt schizophrenia, potentially representing general vulnerability to psychopathology, and also support the role of cortical thinning in the paracentral lobule as a predictive biomarker for short-term functional decline in the ARMS population.

Structural MRI Study of the Planum Temporale in Individuals With an At-Risk Mental State Using Labeled Cortical Distance Mapping.

Background: Recent studies have demonstrated brain structural changes that predate or accompany the onset of frank psychosis, such as schizophrenia, among individuals with an at-risk mental state (ARMS). The planum temporale (PT) is a brain region involved in language processing. In schizophrenia patients, gray matter volume reduction and lack of normal asymmetry (left > right) of PT have repeatedly been reported. Some studies showed progressive gray matter reduction of PT in first-episode schizophrenia patients, and in ARMS subjects during their development of psychosis. Methods: MRI scans (1.5 T field strength) were obtained from 73 ARMS subjects and 74 gender- and age-matched healthy controls at three sites (University of Toyama, Toho University and Tohoku University). Participants with ARMS were clinically monitored for at least 2 years to confirm whether they subsequently developed frank psychosis. Cortical thickness, gray matter volume, and surface area of PT were estimated using FreeSurfer-initiated labeled cortical distance mapping (FSLCDM). PT measures were compared among healthy controls, ARMS subjects who later developed overt psychosis (ARMS-P), and those who did not (ARMS-NP). In each statistical model, age, sex, intracranial volume, and scanning sites were treated as nuisance covariates. Results: Of 73 ARMS subjects, 18 developed overt psychosis (12 schizophrenia and 6 other psychoses) within the follow-up period. There were no significant group differences of PT measures. In addition, significant asymmetries of PT volume and surface area (left > right) were found in all diagnostic groups. PT measures did not correlate with the neurocognitive performance of ARMS subjects. Discussion: Our results suggest that the previously-reported gray matter reduction and lack of normal anatomical asymmetry of PT in schizophrenia patients may not emerge during the prodromal stage of psychosis; taken together with previous longitudinal findings, such PT structural changes may occur just before or during the onset of psychosis.

Open-label study of cognitive behavioural therapy for individuals with at-risk mental state: Feasibility in the Japanese clinical setting.

AIM: To date, most cognitive behavioural therapy (CBT) trials for individuals with at-risk metal state (ARMS) have been conducted in few Western countries and its feasibility in other regions, including Japan, has not been established. METHODS: We designed an open-label pilot study. Fourteen ARMS participants received CBT over 6 months and were followed-up for 6 months. RESULTS: Thirteen individuals completed the CBT intervention and assessments. The mean total score on the Positive and Negative Syndrome Scale improved from 60.2 to 46.0 after the intervention (Cohen's d = 1.1). The effects were maintained at the follow-up assessment. One participant transitioned to psychosis after the CBT intervention, and was the only patient who received antipsychotics. CONCLUSIONS: We confirmed the feasibility of the provision of CBT for ARMS in Japan. Since overprescription of antipsychotics is a matter of great concern in Japan, CBT could be a valuable alternative treatment strategy.

Federated multi-site longitudinal study of at-risk mental state for psychosis in Japan.

There has been recent accumulation of evidence and clinical guidance regarding the at-risk mental state (ARMS) for psychosis. However, most studies have been observational cohort and intervention studies of Western populations. To assess the validity of the ARMS concept and the transition rate to psychosis in a non-Western nation, we retrospectively combined and analyzed clinical data of individuals diagnosed with ARMS who were prospectively followed-up at three specialized clinical services for ARMS in Japan. In total, we included 309 individuals with ARMS, of whom 43 developed overt psychosis. We estimated cumulative transition rates to psychosis with the Kaplan-Meier method, obtaining rates of 12% at 12, 16% at 24, 19% at 36, and 20% at 48 months. Only two individuals reported past cannabis use. Despite several differences among the three sites, transition rates did not differ among them. Furthermore, the transition rate of children aged between 14 and 17 years did not differ from that of individuals aged 18 years or older. Regression analysis revealed that meeting the brief limited intermittent psychotic symptoms (BLIPS) criterion was associated with an increased risk of transition to psychosis, whereas genetic risk factors were not. Although antipsychotic prescription was relatively frequent in this cohort, there was no evidence supporting frequent use of antipsychotics for this population. In conclusion, our findings support the assertion that the current concept of ARMS is applicable in Japan. Development of local clinical guidelines and training for clinicians is necessary to disseminate this concept to more clinical settings.

The relationship between cognitive insight and cognitive performance among individuals with at-risk mental state for developing psychosis.

Impairments in cognitive insight-the capacity to appraise and modify one's own distorted beliefs-are believed to be associated with the formation of psychosis. Nevertheless, the association between cognitive insight and cognitive function among people with at-risk mental state (ARMS) for developing psychotic illness has not been made clear. In this study, we used the Beck Cognitive Insight Scale (BCIS) to assess cognitive insight and the Brief Assessment of Cognition in Schizophrenia (BACS) and the Wisconsin Card Sorting Test (WCST) to assess cognitive functions. Fifty subjects with ARMS and 29 healthy volunteers were recruited as participants. The scores for the two groups on the BCIS, BACS, and WCST were compared and Spearman's rank correlations between the domains of the BCIS and cognitive performance were examined in each group. No significant differences were found in BCIS scores between these groups, whereas all of the cognitive function scores were poorer in the participants with ARMS. In the ARMS group, higher self-certainty on the BCIS was significantly correlated with lower performance in the mean number of categories achieved (ρ=-0.31, P=0.03) and perseverative errors of the Nelson type (ρ=0.29, P=0.04) on the WCST. This indicates that excessively high self-certainty might be linked with weaknesses in cognitive flexibility or set-shifting ability in people with ARMS.

No regional gray matter volume reduction observed in young Japanese people at ultra-high risk for psychosis: A voxel-based morphometry study.

OBJECTIVES: Structural brain magnetic resonance imaging studies of individuals at ultra-high risk (UHR) for psychosis have shown subtle but widespread reductions in baseline gray matter volume (GMV) in the frontal, temporal, and limbic regions compared with healthy controls (HC). These regions coincide with regions of reduced GMV in patients with established psychosis and have led to the consideration of structural changes in UHR as a potential biomarker for future transition to psychosis. However, most studies have been from Europe, North America, and Australia, with few reports from other regions, and two recent studies from Asian countries have failed to detect regional GMV reduction in UHR, suggesting the need for further analysis of an Asian sample. In this study, we investigated GMV reduction in Japanese UHR subjects. RESULTS: The study used voxel-based morphometry to compare magnetic resonance imaging brain scans between 45 UHR individuals recruited by a specialist and 33 HCs. This showed no significant GMV reduction in the UHR group compared with the healthy control group. This negative result may be attributable to characteristics of Asian samples, such as a low prevalence of illicit drug use, or to the heterogeneous nature of UHR subjects.

The associations between quality of life and clinical symptoms in individuals with an at-risk mental state and first-episode psychosis.

Quality of life (QOL) is strongly associated with severity of clinical symptoms and is often compromised in patients with chronic or first-episode psychosis (FEP). However, it remains unclear whether baseline QOL in individuals with an at-risk mental state (ARMS) for psychosis is higher or lower than that in patients with FEP, or what specific clinical symptoms relate to a decreased QOL in individuals with ARMS and FEP. The World Health Organization's WHOQOL-BREF, an instrument assessing QOL, was administered to 104 individuals with ARMS and 53 with FEP. Clinical symptoms were assessed by the Positive and Negative Syndrome Scale and the Beck Depression Inventory-II. We compared the four domain scores of the WHOQOL-BREF between the two groups, and calculated Pearson correlations between each WHOQOL-BREF domain score and the clinical symptoms and compared these correlations between the groups. We observed significant correlations between poor QOL and severity of depressive symptoms in both the FEP and ARMS group. No between-group differences were found in any correlation coefficients between WHOQOL-BREF domains and clinical symptoms. Thus, depressive symptoms should be investigated as a key factor relating to poor QOL in both individuals with ARMS and those with FEP.

Deficits of cognitive theory of mind and its relationship with functioning in individuals with an at-risk mental state and first-episode psychosis.

Disturbance of theory of mind (ToM) and its relationship with functioning in schizophrenia is well documented; however, this is unclear in spectrum disorders like at-risk mental state (ARMS) and first-episode psychosis (FEP). To assess mental state reasoning ability, the total score of the Theory of Mind Picture Stories Task questionnaire was compared among 36 Japanese individuals with ARMS, 40 with FEP, and 25 healthy controls (HC). Pearson's correlations between ToM performance and global and social functioning indices were examined. ToM performance for FEP and ARMS subjects was significantly lower than that for HC, though the significance of the difference between the ARMS and HC disappeared when controlling for premorbid IQ. ToM deficits in ARMS subjects were confirmed only in the comprehension of higher-order false belief. Only among FEP subjects were ToM performance and global functioning significantly correlated, though the significance disappeared when controlling for neurocognitive performance or dose of antipsychotics. No significant correlation between ToM performance and social functioning was observed in the FEP and ARMS groups. The current findings suggest that ToM deficits emerge in ARMS subjects confined within a higher-order domain, and that the relationship between ToM impairment and functional deterioration might be established after psychosis onset.

Correction: Criticism and Depression among the Caregivers of At-Risk Mental State and First-Episode Psychosis Patients.

[This corrects the article DOI: 10.1371/journal.pone.0149875.].

Criticism and Depression among the Caregivers of At-Risk Mental State and First-Episode Psychosis Patients.

Expressed emotion (EE), especially criticism, is an important predictor of outcomes for the patient for a wide range of mental health problems. To understand complex links between EE and various relevant variables in early phase psychosis, this study examined criticism, distress of caregivers, other patients', and caregivers' variables, and links between criticism and these variables in those with at-risk mental state (ARMS) for psychosis and first-episode psychosis (FEP). The participants were 56 patients (mean age 18.8 ± 4.2 years) with ARMS and their caregivers (49.4 ± 5.8 years) and 43 patients (21.7 ± 5.2 years) with FEP and their caregivers (49.3 ± 7.4 years). We investigated criticisms made by caregivers using the Japanese version of the Family Attitude Scale and caregiver depressive symptoms via the self-report Beck Depression Inventory. We also assessed psychiatric symptoms and functioning of the patients. Approximately one-third of caregivers of patients with ARMS or FEP had depressive symptoms, predominately with mild-to-moderate symptom levels, whereas only a small portion exhibited high criticism. The level of criticism and depression were comparable between ARMS and FEP caregivers. The link between criticism, caregivers' depression, and patients' symptoms were observed in FEP but not in ARMS caregivers. These findings imply that the interaction between criticism and caregivers' and patients' mental states may develop during or after the onset of established psychosis and interventions for the caregivers should be tailored to the patient's specific stage of illness. Interventions for FEP caregivers should target their emotional distress and include education about patient's general symptoms.

The association between cognitive deficits and depressive symptoms in at-risk mental state: a comparison with first-episode psychosis.

Cognitive deficits and a high prevalence of depressive symptoms have been reported in at-risk mental state (ARMS) for psychosis, but the relationships between these variables remain unclear. The Brief Assessment of Cognition in Schizophrenia (BACS) was administered to 50 individuals with ARMS, 50 with first-episode psychosis (FEP), and 30 healthy controls (HC). Clinical symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) and the Beck Depression Inventory-2nd edition (BDI-II). Composite z-scores in BACS were compared between the three groups. Pearson correlations between composite z-scores on the BACS and indices of clinical symptoms were compared in the ARMS and FEP groups. The mean composite z-scores on the BACS for the ARMS (-2.82) and FEP (-2.85) groups were significantly lower than the HC group (P<0.001); no differences between the ARMS and FEP groups emerged (P=0.995). Cognitive deficits and depressive symptoms were significantly correlated in the ARMS group (PANSS depression: r=-0.36, P=0.010; BDI-II: r=-0.34, P=0.02), while the correlation between cognitive deficits and negative symptoms was significant in the FEP group (r=-0.46, P=0.001) and approached significance in the ARMS group (r=-0.25, P=0.08). The correlation between cognitive deficits and depressive symptoms significantly differed between the ARMS and FEP groups (PANSS depression: Z=2.50, P=0.012; BDI-II: Z=1.96, P=0.0499). Thus, a relationship between cognitive deficits and depression appears to be specific to ARMS compared to FEP.

Relationship between cognitive insight and attenuated delusional symptoms in individuals with at-risk mental state.

Cognitive insight, defined as the ability to evaluate and correct one׳s own distorted beliefs and misinterpretations, is hypothesized to contribute to the development of psychotic symptoms. We investigated cognitive insight in individuals with at-risk mental state (ARMS), which is associated with a clinically high risk of psychosis. Sixty individuals with ARMS were compared with 200 healthy controls in terms of cognitive insight measured using the Beck Cognitive Insight Scale. We also investigated the relationship between cognitive insight and attenuated delusional symptoms. In addition, we examined differences in the cognitive insight of individuals with ARMS with or without near-threshold delusional symptoms and differences in the cognitive insight of individuals with ARMS with or without later transition to psychosis. The results showed that individuals with ARMS exhibited higher self-certainty than healthy controls, indicating impairments in cognitive insight in the former. More importantly, our results revealed that self-certainty was correlated with attenuated delusional symptoms and that individuals with ARMS who had near threshold delusional symptoms had higher self-certainty. These findings indicate that overconfidence in one׳s own beliefs or judgments might be related to the formation and maintenance of attenuated delusions in individuals with ARMS.

A naturalistic longitudinal study of at-risk mental state with a 2.4 year follow-up at a specialized clinic setting in Japan.

OBJECTIVE: The notion of at-risk mental state (ARMS) is valuable for identifying individuals in a putative prodromal state of psychosis and for reducing conversion risk by pharmacological and psychological interventions. However, further systematic study is required because 1) diagnostic reliability in various clinical settings is not yet established; 2) predictive ability is insufficient; 3) optimal interventions in diversified populations are elusive; and 4) little evidence from non-Western regions exists. METHODS: A naturalistic longitudinal study was conducted at a specialized clinic for early psychosis at a university hospital in Sendai, Japan. Individuals with ARMS (n=106) were recruited and followed up with case-by-case treatment. RESULTS: Two-thirds of the participants were psychiatrist referrals, and 83 were followed up for at-least 1 year (mean follow-up=2.4 years). Fourteen developed psychosis and the estimated (by Kaplan-Meier) cumulative transition rate was 11.1% at 12, 15.4% at 24, and 17.5% at 30 months. At the end-point, about 30% of the 83 followed-up participants including 11 converters received antipsychotic medication. Compared to non-converters, converters showed more severe attenuated psychotic symptoms, including ego-boundary disturbance, formal thought disorder, and emotional disturbance. CONCLUSIONS: The present study replicated previous major Western longitudinal studies, in terms of clinical characteristics, psychosis transition rate, and antipsychotic prescription rate. Our results emphasize the importance of phenomenological assessment of ARMS and intensive care in a clinical setting.

Application of the Comprehensive Assessment of At-Risk Mental States (CAARMS) to the Japanese population: reliability and validity of the Japanese version of the CAARMS.

AIM: The putative prodromal state of schizophrenia has been conceptualized as an at-risk mental state (ARMS), which is identified on the basis of ultra-high-risk (UHR) criteria, and the Comprehensive Assessment of At-Risk Mental States (CAARMS) has been developed as a specific instrument. However, the generalizability of CAARMS and the concept of ARMS have not been established. In this study, we tested the reliability and validity of the Japanese version of CAARMS (CAARMS-J). METHODS: The participants were recruited from a specialized clinic for ARMS. The inter-rater reliability of CAARMS-J was examined. The Positive and Negative Syndrome Scale (PANSS) subscale scores and the basic symptoms of the CAARMS-J-defined UHR-positive group were compared with those of first-episode psychosis (FEP) and UHR-negative groups. The predictive validity was examined by following up the UHR-positive individuals. The 12-month transition rate to psychosis and the antipsychotics prescription rate were calculated. RESULTS: The CAARMS-J showed good inter-rater reliability. The PANSS-positive symptoms subscale scores of the UHR-positive group were intermediate between the FEP and the UHR-negative groups, and the UHR-positive group scored higher than the UHR-negative group in some basic symptoms. The positive and negative symptoms scores of the CAARMS-J significantly correlated with the corresponding scores of the PANSS. After 12 months, 3 out of 28 (10.7%) UHR-positive cases had transitioned to psychosis and 11 (39.2%) individuals were prescribed antipsychotics. CONCLUSIONS: The CAARMS-J is a reliable and valid tool for assessing and detecting ARMS in Japanese clinical settings, suggesting that the concept of ARMS is applicable in Japan.