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Objective More attempts have been made recently to improve psychosocial functioning and quality of life in patients with schizophrenia, due to their crucial role in long-term outcomes. Previous studies on the effects of clozapine on psychosocial functioning have been limited in terms of generalizability and application to clinical practice. This study examined the relationship of clozapine use with psychosocial functioning and quality of life in patients with schizophrenia in a real-world setting.Methods Data were obtained from a survey targeting community-dwelling patients with schizophrenia. The Behavior and Symptom Identification Scale (BASIS) and Satisfaction with Life Scale (SWLS) were administered to evaluate psychosocial functioning and quality of life, and patients were classified into Clozapine and Non-clozapine groups. Group differences were assessed using ANCOVA, with additional sensitivity analyses for participants on atypical antipsychotic medications only.Results Of 292 patients, the Clozapine group (n=34) had significantly better psychosocial functioning and quality of life than the Nonclozapine group (n=258), as demonstrated by their low BASIS score (F=4.651, df=1, 290, p=0.032) and high SWLS score (F=14.637, df=1, 290, p

Objective Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC).Methods Twenty-four patients with schizophrenia and twelve HC underwent [18F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients.Results Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384).Conclusion Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

Objective Metabolic side effects of antipsychotics significantly affect adherence to medication. We aimed to identify factors associated with the occurrence of metabolic diseases among Korean patients with schizophrenia (SCZ) from the national health insurance system database. We evaluated the frequency of antidiabetic and antihyperlipidemic use after diagnosis of SCZ according to typical or atypical antipsychotic use. Materials and methods Among the 43,800 patients diagnosed with SCZ between 2008 and 2012, 29,591 patients who had no metabolic diseases before the diagnosis were included in the analysis to investigate the occurrence of metabolic diseases associated with antipsychotic use. The associations between the development of metabolic diseases and patient characteristics were evaluated using logistic regression analysis. Results Use of both typical and atypical antipsychotics (multivariate-adjusted odds ratio (OR), 1.2513; 95% confidence interval (CI), 1.0953 - 1.4294) was associated with higher incidence of metabolic diseases than without their use. Among the atypical antipsychotics, use of clozapine (multivariate-adjusted OR, 1.1959; 95% CI, 1.0086 - 1.4179) and quetiapine (multivariate-adjusted OR, 1.1284; 95% CI, 1.0446 - 1.2189) showed higher incidence of metabolic diseases compared to that without their use. Among the patients using ≥ 1 type of antidiabetic or antihyperlipidemic agents within 6 years after diagnosis of SCZ, the proportion of patients using only atypical antipsychotics was greater than those using only typical antipsychotics. Conclusion The use of both typical and atypical antipsychotics, and clozapine and quetiapine treatment, may be associated with the occurrence of metabolic diseases in patients with SCZ. Additional prospective studies with accurate dosage information are needed to validate our findings.

The classic subtype classification of schizophrenia has been removed, and DSM-5 now includes the Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). In the present study, a factor analysis of the CRDPSS was performed, and we assessed whether patient classification using the derived factor structure helps predict the clinical course. The participants were 390 patients with recent-onset psychosis enrolled in the Korean Early Psychosis Cohort Study (KEPS). Two factors were identified: psychotic (including delusions, hallucinations, disorganization, and abnormal psychomotor behavior) and negative-cognitive (including negative symptoms and impaired cognition). Patients were grouped based on the factor structure and changes in clinical course were monitored over 1 year. The negative-cognitive group demonstrated longer duration of untreated psychosis, earlier onset, and a higher rate of psychiatric comorbidities. Baseline Positive and Negative Syndrome Scale (PANSS) total and Clinical Global Impression-Severity (CGI-S) scores were higher in psychotic group, but group differences were not observed after 2 months. Conversely, the PANSS negative scale score was significantly higher in negative-cognitive group throughout follow-up, and CGI-S score was reversed at 12 months. The findings indicate that the factor structure derived herein for the CRDPSS could be helpful for predicting the clinical course of recent-onset psychosis patients.

Objectives Whilst reduced signalling and gene expression related to gamma-aminobutyric acid (GABA) play a role in the presumed pathophysiology of schizophrenia, its origin is unclear. Studying asymptomatic individuals with high genetic liability to schizophrenia (AIs) would provide insights. Therefore, this study aimed to investigate the role of genetic liability in GABAergic dysfunction of schizophrenia by exploring in vivo GABA-A/benzodiazepine receptor (GABAR) availability in AIs. Methods A total of 10 AIs with multiple relatives diagnosed as schizophrenia and 11 healthy controls underwent [11C]flumazenil positron emission tomography and neurocognitive function tests. Results There was no significant difference in [11C]flumazenil availability based on the groups. GABAR availability in caudate nuclei had positive correlations with genetic liability of AIs. GABAR availability in caudate nuclei and verbal memory measures of AIs revealed positive correlations. Only the correlation between right caudate and short-term verbal memory survived multiple-comparison correction (p = 0.030). Conclusions This study, for the first time, reports correlations between the genetic liability of schizophrenia and GABAR availability. Correlations between [11C]flumazenil binding in caudate of individuals with high genetic liability to schizophrenia suggests that the GABAergic dysfunction may arise from shared genetic factors and also that it may be responsible for cognitive impairment of AIs.

Introduction A psychotic relapse of schizophrenia is commonly preceded by nonpsychotic behavioral symptoms and signs, and detection of these early signs may enable prevention of relapse of schizophrenia. This study aimed to test the predictive validity of a Korean version of Early Signs Scale (K-ESS) for psychotic relapse for detecting the early signs. Materials and methods In this multicenter noninterventional 52-week prospective study, outpatients diagnosed as having schizophrenia within 5 years were recruited. The K-ESS and Clinical Global Impression-Severity (CGI-S) scale were administered monthly until the end of the study or the relapse. The primary objective was to determine an optimal cutoff point of K-ESS score for prediction of psychotic relapse. The secondary objective was to assess the concurrent validity of the K-ESS using CGI-S scale. Results Among the 162 included patients, 14 (8.6%) relapsed during the 52-week study period. The optimal cutoff score of K-ESS was 15 with a sensitivity of 71.43% and a specificity of 52.70%, indicating poor predictive accuracy of K-ESS. A lower cutoff K-ESS score of 3 and a higher cutoff score of 28 were found in the subgroups with milder (CGI-S = 1-2) and severer (CGI-S = 3-4) symptom severity, respectively, with fair to good predictive accuracy. The K-ESS showed acceptable concurrent validity with CGI-S and concordance rate between self-rated and informant-rated scores. Discussion The predictive accuracy of K-ESS was limited by evaluation interval of a month. At least fortnightly follow-up would be needed for detection of early signs to prevent a psychotic relapse in schizophrenia.

OBJECTIVE This study aimed to examine the degree of clinical and functional improvement after paliperidone long-acting injectable (LAI) administration according to the duration of illness. METHODS Patients with schizophrenia diagnosed by ICD-10 criteria who were planned to start once-monthly paliperidone LAI were recruited from 2010 to 2017. Clinical and functional changes were measured every 4 weeks using the Clinical Global Impressions-Severity of Illness scale (CGI-S) and Personal and Social Performance scale (PSP), respectively, for 6 months after paliperidone LAI initiation. Improvements after starting paliperidone LAI were compared among patients with duration of illness < 3 years, ≥ 3 and < 10 years, and ≥ 10 years. RESULTS A total of 1,166 participants (duration of illness < 3 years, n = 240; 3 ≤ duration of illness < 10 years, n = 442; duration of illness ≥ 10 years, n = 484) were enrolled. The total olanzapine-equivalent doses of antipsychotics and the LAI monotherapy proportion at the final visit were significantly different among the 3 duration of illness groups (dose: F₂,₁₁₆₃ = 18.41, P < .001; monotherapy: χ²₂ = 11.73, P = .003). The changes in CGI-S score were significantly different according to the duration of illness, and those with duration of illness < 3 years showed the best improvement (group × week: χ²₁₂ = 25.33, P = .013). All 3 groups showed significantly improved PSP scores (week: χ²₆ = 294.2, P < .001). CONCLUSIONS Starting paliperidone LAI significantly improved clinical and functional outcomes in patients with schizophrenia, especially those with shorter duration of illness. These findings suggest that LAI antipsychotic administration may be considered in early-stage schizophrenia for improved outcomes.

Background The Seoul Pluripotent Risk for Mental Illness (SPRIM) study was designed to identify predictors leading to mental illness in help-seeking individuals by securing sufficient statistical power through transdiagnostic approaches. The SPRIM study aims to examine the clinical characteristics of high-risk individuals for mental illness and to identify proteomic biomarkers that can predict the onset of mental illness. Methods This paper describes the study protocol of the SPRIM study. We aim to recruit 150 participants who meet the criteria for high risk for major mental illness, 150 patients with major psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder), and 50 matched healthy control subjects for 2 years. Clinical evaluations, self-report measures, and proteomic analyses will be implemented. The assessment points are at baseline, 6, 12, 18, and 24 months. Conclusions In the present study, we introduced the study protocol of the SPRIM study, which is the first prospective cohort study of transdiagnostic high-risk concepts using proteomic biomarkers. This study has a paradigm that encompasses various diseases without aiming at predicting and preventing the development of a specific mental illness in help-seeking individuals. The transdiagnostic high-risk concept could be extended to provide a perspective for people with various psychopathological tendencies below a threshold, such that they do not meet the existing diagnostic criteria of mental illnesses, to determine what may lead them to a specific disease and help identify appropriate preventative interventions.

BackgroundObsession and delusion are theoretically distinct from each other in terms of reality testing. Despite such phenomenological distinction, no extant studies have examined the identification of common and distinct neural correlates of obsession and delusion by employing biologically grounded methods. Here, we investigated dimensional effects of obsession and delusion spanning across the traditional diagnostic boundaries reflected upon the resting-state functional connectivity (RSFC) using connectome-wide association studies (CWAS).MethodsOur study sample comprised of 96 patients with obsessive–compulsive disorder, 75 patients with schizophrenia, and 65 healthy controls. A connectome-wide analysis was conducted to examine the relationship between obsession and delusion severity and RFSC using multivariate distance-based matrix regression.ResultsObsession was associated with the supplementary motor area, precentral gyrus, and superior parietal lobule, while delusion was associated with the precuneus. Follow-up seed-based RSFC and modularity analyses revealed that obsession was related to aberrant inter-network connectivity strength. Additional inter-network analyses demonstrated the association between obsession severity and inter-network connectivity between the frontoparietal control network and the dorsal attention network.ConclusionsOur CWAS study based on the Research Domain Criteria (RDoC) provides novel evidence for the circuit-level functional dysconnectivity associated with obsession and delusion severity across diagnostic boundaries. Further refinement and accumulation of biomarkers from studies embedded within the RDoC framework would provide useful information in treating individuals who have some obsession or delusion symptoms but cannot be identified by the category of clinical symptoms alone.

BackgroundGiven that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.MethodsTwenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.ResultsNo significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.ConclusionsThe relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

Aripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.

Background Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia pathophysiology, which underlies in majority of treatment-responsive patients. Although supported by findings that prefrontal cortical lesions lead to striatal dopamine dysregulation and that recently, prefrontal structural volume is negatively correlated with striatal dopamine synthesis, the relationship between corticostriatal connectivity and striatal dopamine synthesis has not been tested in patients with schizophrenia. We therefore investigated the relationship between corticostriatal connectivity and striatal dopamine synthesis capacity in treatment-responsive patients with schizophrenia, and compared them to treatment-resistant patients and healthy control subjects. Methods Twenty-four patients with schizophrenia and twelve matched healthy control subjects underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer), structural and diffusion 3T MRI. Connectivity(indexed as Fractional anisotropy, FA) were assessed in 3 major corticostriatal tracts (dorsolateral prefrontal cortex-associative striatum, ventromedial prefrontal cortex-limbic striatum, and pre/primary motor cortex-sensorimotor striatum). Furthermore, these measures were tested whether they were correlated with a measure of Wisconsin Card Sorting Test (WCST). Results Treatment responsive patients showed a negative correlation between connectivity of dorsolateral prefrontal cortex-associative striatum and striatal dopamine synthesis capacity of associative striatum, but this was not evident in treatment-resistant patients. Furthermore, WCST negatively correlated with Kicer in associative striatum and positively correlated with FA in dorsolateral prefrontal cortex-associative striatum in whole subjects and treatment responsive patients but not in treatment-resistant patients. Discussion These findings demonstrate that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia and especially, connectivity of dorsolateral prefrontal cortex-associative striatum is a core part for the different pathophysiology.

The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations.MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019).The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations.The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated.Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner.The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

Patients with schizophrenia are characterized by deficits in their ability to identify facial expressions of emotion, which are associated with impaired social and occupational function. An understanding of the deficits of facial affect recognition (FAR) early in the course of the illness can improve early intervention efforts to ameliorate potential functional deterioration. This study aimed to investigate the characteristics and correlations between psychotic symptoms and FAR deficits in patients with early-stage schizophrenia using data from the Korean Early Psychosis Cohort Study. Patients with schizophrenia were divided into three groups: 1) severely and markedly ill (n = 112), 2) moderately ill (n = 96), and 3) mildly ill (n = 115). These groups were compared with age- and sex-matched healthy controls. The FAR test was developed using Korean emotional faces from the Korean Facial Expressions of Emotion database. Error rates, correct response times, and nonresponse rates of each subset were calculated. Several psychopathology assessments were also performed. There were significantly more deficits associated with the recognition of anger (p < 0.01), fear (p < 0.01), and contempt (p < 0.01) in the three patient groups than in the healthy control group. In the severely and markedly ill states, all emotions apart from surprise had impaired error rates (p < 0.01 for all analyses). The error rates for happiness, sadness, disgust, surprise, and neutral faces were not significantly different between mildly ill patients and healthy controls. All emotions, except for sadness, had significantly more delayed correct response times in all patient groups than in the healthy controls (p < 0.01 for all analyses). The severity of psychotic symptoms was positively correlated with the happiness and neutral error rates, and depression was positively correlated with the happiness error rates. General social function was negatively correlated with the error rates for happiness, sadness, fear, disgust, and surprise. Overall, our results show that the severity of psychosis and clinical symptoms leads to distinct differences in certain emotions of patients with early-stage schizophrenia. It is considered that these specific emotional characteristics will help deepen our understanding of schizophrenia and contribute to early intervention and recovery of social function in patients with schizophrenia.

Objective High rates of childhood trauma and adult suicidality have been reported in patients who have schizophrenia. This study sought to explore mediators between childhood trauma and suicidality in adulthood to help determine therapeutic approaches. Methods This study included 314 adult patients with early psychosis who were participants in the Korean Early Psychosis Cohort Study, which was a prospective naturalistic observational cohort study started in December 2014. DSM-5 criteria were used to assign the diagnosis of schizophrenia spectrum and other psychotic disorders. Cross-sectional data obtained at baseline were used for analysis. The Early Trauma Inventory Self Report-Short Form and the Columbia Suicide Severity Rating Scale were employed to collect data on childhood trauma and suicidal ideation and attempts. Other measures were used to evaluate depression, empathy, psychopathology, and rumination. Results A total of 90.1% of the participants experienced at least 1 childhood traumatic event. The rates of significant` physical punishment, emotional abuse, and sexual events were 37.3%, 35.6%, and 6.4%, respectively. The rates of recent suicidal ideation and attempts were 32.0% and 10.0%, respectively. Independent predictors of recent suicidal ideation included depression, negative schema, and rumination. Furthermore, negative schema and rumination played partial or full mediating roles in the relationship between childhood trauma and recent suicidal ideation. Conclusions These findings highlight the importance of performing careful evaluations of childhood trauma and suicidality and of developing effective strategies to reduce mediating factors that may be amenable to psychosocial approaches.

Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment resistant schizophrenia. The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment resistant schizophrenia. However, in this study, the treatment resistant patients were highly symptomatic whilst the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls(n=12), patients treated with clozapine(n=12) who had not responded to first-line antipsychotics and patients who had responded to first-line antipsychotics(n=12) were recruited. Participants were matched for age and sex, and symptomatic severity level in patient groups. Participants' dopamine synthesis capacity was measured by using [(18)F]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment(Cohen's d=0.9191(whole striatum), 0.7781(Associative striatum), 1.0344(Limbic striatum), 1.0189(Sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.Neuropsychopharmacology accepted article preview online, 18 November 2016. doi:10.1038/npp.2016.258.

Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

Aim This study investigated the clinical characteristics and psychosocial factors associated with depression in patients with early psychosis according to stage of illness. Methods The present study includes patients who fulfil the DSM-5 criteria for schizophrenia spectrum and other psychotic disorders. Patients were divided into two groups according to illness stage (the acute stage of first-episode psychosis and stabilization phase of recent-onset psychosis). Clinically meaningful depression was defined as moderate or severe on the depression dimension of the Clinician-Rated Dimensions of Psychosis Symptom Severity scale in the DSM-5. Results In total, 340 (207 first-episode and 133 recent-onset) patients were recruited in this study. Patients with comorbid depression were characterized by frequent suicidal ideation, a past suicide attempt, and lower scores on the Subjective Well-being Under Neuroleptics and Brief Resilience Scale in both groups. Long duration of untreated psychosis and higher scores on the Early Trauma Inventory Self Report were associated with depression in the acute stage of first-episode psychosis. In the stabilization phase of recent-onset psychosis group, a monthly income and scores for sexual desire and on the Family Adaptability and Cohesion Evaluation Scale-III were significantly lower in patients with depression than in those without depression. Conclusion Comorbid depression was associated with high suicidality, lower quality of life and poor resilience in patients with first-episode and recent-onset psychosis. Depression was associated with factors that had been present before the initiation of treatment in patients with first-episode psychosis and with environmental factors in those in the stabilization phase.

Aripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.

Aim: To explore the differences in pharmacotherapy and clinical characteristics of individuals at ultra-high-risk (UHR) for psychosis according to the conversion status, we analyzed the data for UHR patients seen at the Seoul Youth Clinic. Methods: This was a naturalistic observational study. We obtained clinical data, including demographic data, presenting complaint, duration of psychiatric symptoms, diagnosis and scores on clinical rating scales from individual records in the Seoul Youth Clinic. Prescription data were obtained from electronic medical records. Results: As of April 1, 2010, a total of 78 people were registered as being UHR for psychosis in the Seoul Youth Clinic. Patients commonly presented with paranoid ideas and anxiety. On entry to the Seoul Youth Clinic, 81% of the UHR group were diagnosed as having psychiatric disorders according to DSM-IV criteria. Of the 67 individuals who did not drop out of the Seoul Youth Clinic, 14 converted to psychosis. The mean time to conversion was 412 days post baseline examination. The mean duration of psychiatric symptoms before clinic presentation was shorter in the converter group than in the non-converter group. There were no differences in baseline scores on clinical rating scales between the two groups. Antipsychotics were commonly prescribed for UHR patients in the Seoul Youth Clinic, with the converter group exposed to antipsychotics for a longer period and at higher doses than the non-converter group. Conclusions: In a naturalistic setting, the different pattern of exposure to antipsychotics between the converter and non-converter groups calls attention to the effects of antipsychotics on conversion to psychosis.

Background While deficits in cognitive functions are frequently reported in psychotic disorders, further longitudinal research is needed to confirm the specific risk factors for the development of psychosis. We examined longitudinally the social–cognitive and neurocognitive function of individuals at ultra-high risk for schizophrenia who developed psychosis later as predictive markers. Method The investigators studied 49 subjects at ultra-high risk (UHR) for psychosis and 45 healthy controls. The UHR subjects were followed for up 5.2 years (mean:2.8 years) and 13 of these subjects developed psychosis. Theory of mind (ToM) tasks and neuropsychological tests were administered at baseline. Analyses compared the UHR patients who later developed psychosis, those who did not develop, and healthy controls. To examine the cognitive variables to predict transition to psychosis, Cox regression analyses were conducted. Results At baseline, we found significant differences among the three groups in social cognition according to the False Belief and cartoon tasks and in neurocognition according to tasks measuring executive function, working memory, verbal memory, and visual memory. Our study showed that a model combining working memory, visual memory, executive function, and ToM tasks was significantly predictive of time to conversion to psychosis. Conclusion This study indicated that UHR patients who later converted to psychosis performed more poorly on tasks involving social cognition and neurocognition than did those who did not convert. We suggest that these deficits can serve as specific markers to predict the development of psychosis.

Dopamine D2 receptor occupancy of antipsychotic drugs is calculated relative to the subject's D2 receptor binding potential (BP) in the drug-free state (baseline BP). Because baseline BP is seldom known in patients with schizophrenia, population means from unrelated control samples are often used to estimate it. However, this is likely to introduce bias and error into the occupancy measure. There is thus a need for a method to reliably estimate baseline BP for patient populations in whom it may be impractical or unethical to get baseline measurements. It has been previously found that the relationship between plasma concentration and dopamine receptor occupancy by antipsychotic drugs follows a sigmoid Emax model. Based on this, we developed a method for calculating dopamine D2 receptor occupancy by antipsychotic drugs using an inhibitory Emax model ( Imax method) that estimates individual baseline BPs. To validate this, we compared the result from the Imax method with actual occupancy and estimated occupancy calculated from the average baseline BP (substitution method). The data for validation were obtained from two different receptor occupancy studies with the antipsychotic medications YKP1358 and aripiprazole. We estimated the reliability between the true measured occupancy and the predicted occupancy using the intraclass correlation coefficient (ICC), and the variability of occupancy was also compared between the Imax and substitution methods. In YKP1358 study, all the ICCs of the Imax method were above 0.8, but those of the substitution method showed values lower than 0.8. In aripiprazole study, the ICCs of the Imax method were higher than those of the substitution method, but all the ICCs showed higher values than 0.8. The variability of Imax method was significantly smaller than that of substitution method in both studies. The Imax method shows better reliability and less variability than the substitution method. The Imax method can be applied for receptor occupancy study, and bring more reliability and accuracy to the occupancy study in patients with schizophrenia.

Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate. To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration–occupancy relationship in terms of EC50 between patients and healthy volunteers. Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [11C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D2 receptor occupancy using E max model and calculated EC50. The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC50 was 7.6 ng/ml (95% confidence interval (CI) 6.2–9.0) in healthy volunteers and 8.6 (95% CI 7.4–9.9) in patients. The antipsychotic concentration–occupancy relationship in patients can be estimated from the EC50 data of healthy volunteers.

Background Schizophrenia is thought to be a heterogeneous disorder and evidences reflect categorically distinct subtypes according to the antipsychotic treatment response. Altered frontostriatal functional connectivity (FC) in schizophrenia and its correlation with antipsychotic treatment response also suggests divergence of underlying pathophysiologic mechanism. Meanwhile, the observations that prefrontal activity correlates with striatal dopaminergic function, leads to the hypothesis that the disrupted frontostriatal FC would be related with altered dopaminergic pathway in schizophrenia. The aim of this study was to investigate the relationship between frontostriatal FC and striatal dopaminergic activity in patients with schizophrenia according to the responsiveness to first-line antipsychotic drug. Methods 24 symptomatically stable schizophrenia patients were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 stable under clozapine (clozapine group), along with 12 matched health controls. All participants underwent resting-state functional MRI and [F18]DOPA positron emission tomography. Results There were no significant difference in the total PANSS score between the first-line AP group and the clozapine group (mean difference=0.67, s.e.=3.21, df=33, p=1.000). Voxel-based analysis found significant negative correlation between frontal FC to the left associative striatum and the kicer in the corresponding region was found in first-line AP group but not in clozapine group or healthy control. Additional region of interest analysis confirmed the result (control group: R2=0.032, p=0.572; first-line AP group: R2=0.551, p=0.005; clozapine group: R2=0.108, p=0.297). Discussion Different patterns of relationship between striatal dopamine capacity and frontostriatal FC observed in this study indicates different pathophysiology underlying schizophrenia according to antipsychotics treatment-responsiveness. Results should be reconfirmed in prospective manner with larger sample size in future studies.

Context: Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D-2 receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia.Objective: To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.Data Sources: The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.Study Selection: A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.Data Extraction: Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.Data Synthesis: There was a highly significant elevation (P < .001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D-2/3 receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.Conclusions: The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D-2/3 receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.

Background: The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations. Methods: We compared dopamine synthesis capacity (using 6-[18F]fluoro-L-DOPA [[18F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls. Results: There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group. Conclusions: Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.

Objective: Impaired social functioning is one of the defining features of patients with schizophrenia and subjects at ultra-high risk (UHR) for psychosis. This prospective study aimed to investigate the course of social dysfunction in UHR subjects and to examine its relationship with later conversion to psychosis. The effect of pharmacotherapy on the course of social dysfunction was also examined. Method: A total of 57 UHR subjects and 58 healthy controls participated in this study. The Social Functioning Scale (SFS) was used to assess social functioning of UHR subjects at baseline and at the 1 year follow up. The changes in social functioning of UHR subjects have been examined to compare the social functioning of those who later converted to psychosis (‘converters’) with those who did not (‘non-converters’). The effect of pharmacotherapy on longitudinal change in social functioning was also evaluated. Results: Subjects at UHR for psychosis showed more impaired social functioning at baseline than did healthy controls. Moreover, the course of social dysfunction of the converter and non-converter groups differed during the 1 year follow up period. The converters showed decreases in SFS average (F (1,32) = 7.85, p = 0.009) and interpersonal behaviour (F (1,32) = 10.43, p = 0.003) scores over time, whereas the non-converters showed increased scores. Additionally, we found that pharmacological treatment was associated with increased prosocial activities score (F (1,32) = 4.66, p = 0.038). Conclusions: We found that the social functioning of converters was impaired before the onset of the psychosis and further declined during the at-risk phase. A series of social functioning indices in the longitudinal course may be helpful in predicting conversion to psychosis in subjects at UHR. Appropriate pharmacotherapy can offer clinical benefits by improving social functioning in UHR individuals.

Receptor occupancy study has been performed to evaluate pharmacokinetic profiles in new antipsychotic drug development. While these findings highlight the value of positron emission tomography (PET) for dose-finding study, what is unclear is if it is necessary to conduct these studies in patients with schizophrenia or whether studies in healthy volunteers are adequate.To determine if it is necessary to conduct dopamine receptor occupancy studies in patients with schizophrenia or whether studies in healthy volunteers are adequate for dose-finding study, we compared the concentration-occupancy relationship in terms of EC(50) between patients and healthy volunteers.Ten healthy volunteers and eight patients with schizophrenia participated in the study. We measured dopamine receptor occupancy using [(11)C]raclopride PET and plasma concentration of YKP1358, a novel antipsychotic drug under clinical development, at a number of time points after the administration of YKP1358. Pharmacokinetic data including area under the plasma concentration versus time curve, elimination half-life, maximum observed plasma concentration, and the time to reach the maximum observed plasma concentration were obtained. We explored the relationship between plasma concentration and dopamine D(2) receptor occupancy using E (max) model and calculated EC(50).The elimination half-life was longer in healthy volunteers than in patients. Other pharmacokinetic parameters were not significantly different between two groups. The EC(50) was 7.6 ng/ml (95% confidence interval (CI) 6.2-9.0) in healthy volunteers and 8.6 (95% CI 7.4-9.9) in patients.The antipsychotic concentration-occupancy relationship in patients can be estimated from the EC(50) data of healthy volunteers.

We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene. In this 26-week, prospective, open-label, double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n=14; A1A2+A2A2, n=76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured. Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups. The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole.

Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders. This review considers the application of molecular imaging to CNS disorders focusing on its potential to inform the development and evaluation of treatments. We focus on schizophrenia, Parkinson's disease, depression, and dementia as major CNS disorders. We also review the potential of molecular imaging to guide new drug development for CNS disorders.Las técnicas de imaginología molecular tienen numerosas ventajas para la investigación acerca de la fisiopatología y el tratamiento de los trastornos del sistema nervioso central (SNC). Primero, porque ellas aportan formas no invasoras para la caracierización de procesos fisiológicos en el cerebro vivo, permitiendo que las alteraciones moleculares se relacionen con cambios clínicos. Segundo, porque el blanco fisiopatológico de un determinado trastorno del SNC puede ser medido de la misma forma en modelos animales y en modelos humanos experimentales, lo que permite la investigación translacional. Sin embargo, como la imaginología molecular facilita la detección del cambio funcional que precede a la patología grave, resulta especialmente útil para el diagnóstico y tratamiento precoces de los trastornos del SNC. Esta revisión examina la aplicación de la imaginología molecular en los trastornos del SNC y se enfoca en su potencial para informar sobre el desarrollo y evaluación de los tratamientos.Este artículo centra la atención en esquizofrenia, Enfermedad de Parkinson, depresión y demencia como los principales trastornos del SNC. También se revisa el potencial de la imaginología molecular como guía para el desarrollo de nuevos fármacos para trastornos del SNC.Les avantages des techniques d'imagerie moléculaire sont nombreux pour la recherche physiopathologique et le traitement des troubles du SNC (système nerveux central). Elles permettent tout d'abord d'explorer de façon non invasive les processus physiologiques du cerveau vivant en liant les changements moléculaires aux modifications cliniques. Deuxièmement, une recherche translationnelle est rendue possible mesurant de la même façon dans un trouble donné du SNC, la cible physiopathologique dans des modèles animaux et dans des modèles humains expérimentaux. De plus, l'imagerie moléculaire permet la détection de modifications fonctionnelles précédant la pathologie manifeste, ce qui est particulièrement utile pour le diagnostic précoce et le traitement des troubles du SNC.Dans cet article, nous nous intéressons à la capacité de l'imagerie moléculaire d'informer sur le développement et l'évaluation des traitements dans son application aux troubles du SNC, en particulier pour la schizophrénie, la maladie de Parkinson, la dépression et la démence, troubles majeurs du SNC. Nous analysons également la possibilité de piloter le développement de nouveaux médicaments des troubles du SNC par l'imagerie moléculaire.