Characteristic association of symbol coding test score with occupational function in Japanese patients with schizophrenia.

AIM: Studies showed that cognitive function affects occupational function in patients with schizophrenia. This study aimed to determine the effects of cognitive function on occupational function in Japanese patients with schizophrenia using the Brief Assessment of Cognition in Schizophrenia (BACS). METHODS: Participants were 198 outpatients with schizophrenia or schizoaffective disorder (66 females; mean age 34.5 ± 6.8 years). Occupational function was assessed using the work subscale of the Life Assessment Scale for Mental Ill (LASMI-w). Multiple regression analysis was performed using the BACS as the independent variable and LASMI-w as the dependent variable. Furthermore, we divided the LASMI-w score into three groups, <11, 11-20, and >21, and performed a multinomial logistic regression analysis. RESULTS: Multiple regression analysis revealed that LASMI-w score was negatively associated with BACS composite score (ß = -0.20, p < 0.01). Among the sub-items of the BACS, only the symbol-coding score showed a significant negative association (ß = -0.19, p < 0.05). Multinomial logistic analysis showed that the better the composite and symbol coding scores, the smaller the impairment of the occupational function (composite score: ß = 2.39 between mild and moderate occupational impairments, p < 0.05; symbol coding score: ß = 2.44 between mild and severe impairments, p < 0.05). CONCLUSION: The occupational function of patients with schizophrenia was associated with overall cognitive function (composite score). In particular, the symbol coding score of the BACS was suggested to be related to work ability. These results might be useful in the assessment and training of cognitive rehabilitation aimed at employment support.

The association between clinical symptoms and later subjective quality of life in individuals with ultra-high risk for psychosis and recent-onset psychotic disorder: A longitudinal investigation.

AIM: Subjective quality of life is a clinically relevant outcome that is strongly associated with the severity of clinical symptoms in individuals with ultra-high risk for psychosis and patients with recent-onset psychotic disorder. Our objective was to examine whether longitudinal changes in clinical symptoms are associated with quality of life in ultra-high risk individuals and patients with recent-onset psychotic disorder. METHODS: Individuals with ultra-high risk and patients with recent-onset psychosis disorder were recruited in the same clinical settings at baseline and were followed up with more than 6 months and less than 5 years later. We assessed five factors of clinical symptoms using the positive and negative syndrome scale, and quality of life using the World Health Organization quality of life questionnaire-short form. We used multiple regression to examine the relationships between clinical symptoms and quality of life while controlling for diagnosis, follow-up period, age, and sex. RESULTS: Data were collected from 22 individuals with ultra-high risk and 27 patients with recent-onset psychosis disorder. The multiple regression analysis results indicated that the more severe anxiety/depression was at baseline, the poorer the quality of life at follow-up. Further, improvement of anxiety/depression and disorganized thoughts were associated with improvement in quality of life. The difference in diagnosis did not affect the association between clinical symptoms and quality of life. CONCLUSION: These findings suggest that the improvement of anxiety/depression and disorganized thoughts is important in the early stages of psychosis before it becomes severe, affecting the quality of life.

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.

Mismatch Negativity Predicts Remission and Neurocognitive Function in Individuals at Ultra-High Risk for Psychosis.

BACKGROUND: In the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR. MATERIALS AND METHODS: Individuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function. RESULTS: Compared with the HC group, the UHR group had a significantly attenuated dMMN amplitude (p = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, p = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) (p = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, p = 0.030; fMMN, p = 0.041). CONCLUSION: Our findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR.

Is Utena's Brief Objective Measures (UBOM) useful in real-world behavioral assessment of functioning? Validity and utility testing in patients with schizophrenia.

AIM: Utena's Brief Objective Measures (UBOM) was developed to assess psychophysiological functions proximal to real-world functioning in individuals with psychiatric disorders, including schizophrenia (SCZ), to facilitate shared decision-making. However, the validity of UBOM has not been fully examined. METHODS: We conducted a cross-sectional observational study to evaluate the validity of each of the three tests in UBOM: UBOM-Pulse, UBOM-Ruler, and UBOM-Random. We investigated associations: (i) between UBOM and existing cognitive- and autonomic-function tests; and (ii) between UBOM and daily social functioning. The participants included SCZ individuals and healthy controls. We evaluated the cognitive and autonomic function using UBOM, the heart rate variability test, the simple reaction time test, and the Brief Assessment of Cognition in Schizophrenia, Japanese version. We also assessed the daily social functioning using the WHO Disability Assessment Schedule 2.0 and the modified Global Assessment of Functioning, Japanese version. RESULTS: Thirty-one SCZ individuals and 35 healthy control individuals participated in this study. In the SCZ group, UBOM-Ruler was significantly associated with the Cognition and Getting Along domains of WHO Disability Assessment Schedule 2.0. UBOM-Random was significantly associated with the Brief Assessment of Cognition in Schizophrenia's Working Memory, Verbal Fluency and Attention domains, and the modified Global Assessment of Functioning in the SCZ group. CONCLUSION: The validity of the current version of UBOM is imperfect and further improvements will be necessary to attain the originally intended goal of developing a brief assessment tool for real-world functioning in SCZ.

Electrophysiological evidence for abnormal glutamate-GABA association following psychosis onset.

Previous studies have shown glutamatergic dysfunction and γ-aminobutyric acid (GABA)-ergic dysfunction in schizophrenia. Animal studies suggest that N-methyl-D-aspartate receptor (NMDAR) dysfunction and GABA-ergic dysfunction interact with each other and lead to alterations in excitatory/inhibitory balance. The NMDAR and GABAergic-interneuron functions may be indexed by mismatch negativity (MMN) and auditory steady-state gamma-band response (ASSR), respectively. However, no previous studies have tested the hypothesis of an abnormal association between MMN and gamma-band ASSR in the same patients to identify the in vivo evidence of NMDAR-GABA association during the early stages of psychosis. Participants were individuals with recent-onset schizophrenia (ROSZ; N = 21), ultra-high risk (UHR; N = 27), and healthy controls (HCs; N = 24). The MMN amplitude was significantly impaired in ROSZ (p = 0.001, d = 1.20) and UHR (p = 0.003, d = 1.01) compared with HCs. The intertrial phase coherence (ITC) index of gamma-band ASSR was significantly reduced in ROSZ compared with HCs (p < 0.001, d = -1.27) and UHR (p = 0.032, d = -0.75). The event-related spectral perturbation (ERSP) index of gamma-band ASSR was significantly smaller in ROSZ compared with HCs (p < 0.001, d = -1.21). The MMN amplitude was significantly correlated with the ITC in ROSZ (r = -0.69, p < 0.001). These findings provide the first in vivo evidence that an abnormal association of the electrophysiological indices of NMDAR and GABA dysfunctions may be present in recent-onset schizophrenia.

Auditory gamma oscillations predict global symptomatic outcome in the early stages of psychosis: A longitudinal investigation.

OBJECTIVES: The gamma-band auditory steady-state response (ASSR) is thought to reflect the function of parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and may be a candidate biomarker in early psychosis. Although previous cross-sectional studies have shown that gamma-band ASSR is reduced in early psychosis, whether reduced gamma-band ASSR could be a predictor of the long-term prognosis remains unknown. METHODS: In this longitudinal study, we investigated the association between gamma-band ASSR reduction and future global symptomatic or functional outcome in early psychosis. We measured 40-Hz ASSR in 34 patients with recent-onset schizophrenia (ROSZ), 28 ultra-high risk (UHR) individuals, and 30 healthy controls (HCs) at baseline. After 1-2 years, we evaluated the global assessment of functioning (GAF) in the ROSZ (N = 20) and UHR (N = 20) groups. RESULTS: The 40-Hz ASSR was significantly reduced in the ROSZ and UHR groups. The attenuated 40-Hz ASSR was correlated with the future global symptomatic outcome in the ROSZ, but not in the UHR groups. CONCLUSIONS: A reduction in the gamma-band ASSR after the onset of psychosis may predict symptomatic outcomes in early psychosis. SIGNIFICANCE: Gamma-band ASSR may be a potentially useful biomarker of the long-term prognosis in patients with recent-onset schizophrenia.

Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial.

BACKGROUND: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished. METHODS: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates. RESULTS: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects. CONCLUSIONS: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.

Lack of correlation between phonetic magnetic mismatch field and plasma d-serine levels in humans.

OBJECTIVE: Uncovering molecular bases for auditory language processing in the human brain is a fundamental scientific challenge. The power and latency of the magnetic mismatch field (MMF) elicited by phoneme change, which are magnetoencephalographic indices of language function in its early stage of information processing, are theoretically thought to be modulated by N-methyl-d-aspartate-type glutamate receptor (NMDAR) function, but no study has yet assessed this possibility. We have thus sought to demonstrate an association between phonetic MMF power/latency and levels of plasma d-serine, an intrinsic co-agonist of glycine binding sites on NMDAR, in adults. METHODS: The MMF response to phoneme changes was recorded using 204-channel magnetoencephalography in 61 healthy, right-handed, Japanese adults. Plasma levels of d- and l-serine were measured for each participant. RESULTS: We did not find a significant correlation between MMF power/latency and plasma serine levels. CONCLUSIONS: Despite a sufficient sample size, we failed to find an association between the physiological markers of the early stage of information processing of language in the auditory cortex and biomarkers indexing glutamatergic function. SIGNIFICANCE: Our study did not indicate that a molecular index of glutamatergic function could be a surrogate marker for the early stage of information processing of language in humans.

Association between mismatch negativity and global functioning is specific to duration deviance in early stages of psychosis.

BACKGROUND: Mismatch negativity (MMN) is a candidate biomarker for early stages of psychosis. Although an association among duration MMN (dMMN), cognitive deficits, and functional outcome in chronic schizophrenia has been shown by a large-scale study, the effects of deviant type and clinical stages have not been investigated. METHODS: We investigated the relationships among dMMN, frequency MMN (fMMN), global functioning, and cognitive function in early stages of psychosis. The participants included 26 individuals with recent-onset schizophrenia (ROSZ), 30 individuals with ultra-high risk (UHR), and 20 healthy controls. RESULTS: The correlational analyses revealed that dMMN amplitude, which was impaired in the ROSZ group compared to the healthy controls, correlated with global functioning (Global Assessment of Functioning-Functioning scale) in the ROSZ (r=-0.45) and UHR (r=-0.37) groups. The amplitude of fMMN, which did not differ among the groups, correlated with working memory (r=-0.57) only in the ROSZ group. The path analyses indicated that dMMN had a direct effect on global functioning in the ROSZ and UHR groups while fMMN had a direct effect on working memory only in the ROSZ group. CONCLUSIONS: Our findings suggested that the association between MMN and global functioning was specific to the duration deviant and was already present in early stages of psychosis. These findings confirm the usefulness of dMMN as a biological marker of early psychosis to guide treatment interventions.

Associations between daily living skills, cognition, and real-world functioning across stages of schizophrenia; a study with the Schizophrenia Cognition Rating Scale Japanese version.

Cognitive function is impaired in patients with schizophrenia-spectrum disorders, even in their prodromal stages. Specifically, the assessment of cognitive abilities related to daily-living functioning, or functional capacity, is important to predict long-term outcome. In this study, we sought to determine the validity of the Schizophrenia Cognition Rating Scale (SCoRS) Japanese version, an interview-based measure of cognition relevant to functional capacity (i.e. co-primary measure). For this purpose, we examined the relationship of SCoRS scores with performance on the Brief Assessment of Cognition in Schizophrenia (BACS) Japanese version, a standard neuropsychological test battery, and the Social and Occupational Functioning Assessment Scale (SOFAS), an interview-based social function scale. Subjects for this study (n = 294) included 38 patients with first episode schizophrenia (FES), 135 with chronic schizophrenia (CS), 102 with at-risk mental state (ARMS) and 19 with other psychiatric disorders with psychosis. SCoRS scores showed a significant relationship with SOFAS scores for the entire subjects. Also, performance on the BACS was significantly correlated with SCoRS scores. These associations were also noted within each diagnosis (FES, CS, ARMS). These results indicate the utility of SCoRS as a measure of functional capacity that is associated both with cognitive function and real-world functional outcome in subjects with schizophrenia-spectrum disorders.

Reduced Mismatch Negativity is Associated with Increased Plasma Level of Glutamate in First-episode Psychosis.

Reduced amplitude of mismatch negativity (MMN) is one of the more promising biological markers of schizophrenia. This finding holds true in both early and chronic phases of the disorder, and is compatible with the glutamatergic dysfunction hypothesis. To further establish MMN as a biomarker of aberrant glutamatergic neurotransmission, an exploration for an association with blood levels of glutamatergic amino acids is an important next step. Despite a large body of work investigating MMN in schizophrenia, no previous studies have undertaken this endeavor. Nineteen patients with first-episode psychosis (FEP), 21 ultra-high risk individuals (UHR), and 16 healthy controls (HC) participated in the study. The MMNs in response to duration change (dMMN) and frequency change (fMMN) were measured. The fasting plasma levels of glutamate, glutamine, glycine, D-serine, and L-serine were measured. dMMN amplitudes were significantly reduced in FEP and UHR, compared to HC. The plasma levels of glutamate of FEP were significantly higher than those of HC. Higher plasma levels of glutamate were associated with smaller dMMN amplitudes in the FEP and HC groups. These findings are compatible with the hypothesis that MMN is a useful biological marker of aberrant glutamatergic neurotransmission in the early stages of schizophrenia.

Identifying neurocognitive markers for outcome prediction of global functioning in individuals with first-episode and ultra-high-risk for psychosis.

AIM: There is an increasing need for identifying neurocognitive predictors of global functional outcome in early psychosis toward optimizing an early intervention strategy. METHODS: We conducted a longitudinal observational study to investigate an association between neurocognitive assessments at baseline and global functional outcome at an average of 1-year follow up. Participants included ultra-high-risk for psychosis (UHR) individuals who had not converted to psychosis during the follow-up period (UHR-NP) and those with first-episode psychosis (FEP). We evaluated neurocognition at baseline using the Brief Assessment of Cognition in Schizophrenia Japanese version, including Verbal Memory, Working Memory, Motor Speed, Verbal Fluency, Attention/Processing Speed, and Executive Function. We also assessed global functional outcome using the modified Global Assessment of Functioning (mGAF) scale both at baseline and after the follow-up period. RESULTS: Thirty-four UHR-NP individuals (34/47, 72%) and 29 FEP individuals (29/36, 81%) completed assessment of neurocognitive function at baseline and functional outcome at follow up. In the UHR-NP group, Attention/Processing Speed was significantly associated with the mGAF score at follow up. In the FEP group, Executive Function was significantly associated with the average mGAF score during follow up. CONCLUSION: Attention/Processing Speed and Executive Function at baseline may predict global functional outcome of early psychosis. These neurocognitive tests are easy to incorporate in clinical settings and, if replicated in independent samples, may be included in routine clinical assessments for prediction of functional outcome in early psychosis.

Duration and frequency mismatch negativity shows no progressive reduction in early stages of psychosis.

The auditory mismatch negativity (MMN) is a component of event-related potentials, which is being increasingly recognized as a candidate biomarker for early stages of psychosis. Although previous cross-sectional studies have demonstrated small MMN amplitude in early stages of psychosis, it remains unknown whether small MMN amplitude is due to progressive reduction during the early course. In this study, we investigated longitudinal changes of MMN in early stages of psychosis. Participant included 14 patients with first-episode psychosis (FEP), 16 individuals with ultra-high risk (UHR), and 16 healthy control subjects (HC). We measured MMN in response to duration deviants (dMMN) and that in response to frequency deviants (fMMN), respectively. The amplitudes of dMMN in FEP and UHR were significantly smaller in comparison to those in HC, which did not show a progressive decrease over time. The amplitude of fMMN did not differ among groups, which again did not show progression. There was no significant correlation between the length of the follow-up period and the longitudinal change of either deviant-type MMN in the FEP or UHR. These results suggest that dMMN is a trait marker in the early stages of psychosis, and that small dMMN amplitude in early stages of psychosis may reflect altered developmental process rather than progressive brain pathology. The amplitude of fMMN may not alter in early stages of psychosis. These findings may contribute to the future establishment of MMN as a biomarker in early stages of psychosis.

Familial Influences on Mismatch Negativity and Its Association with Plasma Glutamate Level: A Magnetoencephalographic Study in Twins.

Mismatch negativity (MMN) or its magnetic counterpart (magnetic mismatch negativity; MMNm) is regarded as a promising biomarker for schizophrenia. Previous electroencephalographic studies of MMN have demonstrated a moderate-to-high heritability for MMN amplitudes. N-methyl-D-aspartate receptor-dependent glutamatergic neurotransmission is implicated in MMN generation. We hypothesized that the differences between identical twins in MMNm variables might be associated with differences in plasma levels of amino acids involved in glutamatergic neurotransmission. Thirty-three pairs of monozygotic (MZ) and 10 pairs of dizygotic (DZ) twins underwent MMNm recording. The MMNm in response to tone duration changes, tone frequency changes, and phonemic changes was recorded using 204-channel magnetoencephalography. Of these, 26 MZ and 7 DZ twin pairs underwent blood sampling for determination of plasma amino acid levels. MMNm peak strength showed relatively high correlations in both MZ and DZ twin pairs. The differences in MMNm latencies tended to correlate with the differences in plasma amino acid levels within MZ pairs, while no significant correlation was observed after the Bonferroni correction. We observed a familial trait in MMNm strength. The differences in MMN latency in MZ twins might be influenced by changes in glutamate levels and glutamate-glutamine cycling; however, the results need to be replicated.

Magnetoencephalographic recording of auditory mismatch negativity in response to duration and frequency deviants in a single session in patients with schizophrenia.

AIM: Auditory mismatch negativity (MMN) and its magnetoencephalographic (MEG) counterpart (MMNm) are an established biological index in schizophrenia research. MMN in response to duration and frequency deviants may have differential relevance to the pathophysiology and clinical stages of schizophrenia. MEG has advantage in that it almost purely detects MMNm arising from the auditory cortex. However, few previous MEG studies on schizophrenia have simultaneously assessed MMNm in response to duration and frequency deviants or examined the effect of chronicity on the group difference. METHODS: Forty-two patients with chronic schizophrenia and 74 matched control subjects participated in the study. Using a whole-head MEG, MMNm in response to duration and frequency deviants of tones was recorded while participants passively listened to an auditory sequence. RESULTS: Compared to healthy subjects, patients with schizophrenia exhibited significantly reduced powers of MMNm in response to duration deviant in both hemispheres, whereas MMNm in response to frequency deviant did not differ between the two groups. These results did not change according to the chronicity of the illness. CONCLUSION: These results, obtained by using a sequence-enabling simultaneous assessment of both types of MMNm, suggest that MEG recording of MMN in response to duration deviant may be a more sensitive biological marker of schizophrenia than MMN in response to frequency deviant. Our findings represent an important first step towards establishment of MMN as a biomarker for schizophrenia in real-world clinical psychiatry settings.