Clozapine Treatment Is Associated With Higher Prescription Rate of Antipsychotic Monotherapy and Lower Prescription Rate of Other Concomitant Psychotropics: A Real-World Nationwide Study.

BACKGROUND: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine. METHODS: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary. RESULTS: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P < 2.0 × 10-16) and the ND-TRS without clozapine group (54.7%; P < 2.0 × 10-16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; P = 1.1 × 10-6) and the ND-TRS without clozapine group (17.0%; P = 5.9 × 10-6). CONCLUSIONS: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription.

Improvement of psychiatrists' clinical knowledge of the treatment guidelines for schizophrenia and major depressive disorders using the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' project: A nationwide dissemination, education, and evaluation study.

AIM: Although treatment guidelines for pharmacological therapy for schizophrenia and major depressive disorder have been issued by the Japanese Societies of Neuropsychopharmacology and Mood Disorders, these guidelines have not been well applied by psychiatrists throughout the nation. To address this issue, we developed the 'Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE)' integrated education programs for psychiatrists to disseminate the clinical guidelines. Additionally, we conducted a systematic efficacy evaluation of the programs. METHODS: Four hundred thirteen out of 461 psychiatrists attended two 1-day educational programs based on the treatment guidelines for schizophrenia and major depressive disorder from October 2016 to March 2018. We measured the participants' clinical knowledge of the treatment guidelines using self-completed questionnaires administered before and after the program to assess the effectiveness of the programs for improving knowledge. We also examined the relation between the participants' demographics and their clinical knowledge scores. RESULTS: The clinical knowledge scores for both guidelines were significantly improved after the program. There was no correlation between clinical knowledge and participant demographics for the program on schizophrenia; however, a weak positive correlation was found between clinical knowledge and the years of professional experience for the program on major depressive disorder. CONCLUSION: Our results provide evidence that educational programs on the clinical practices recommended in guidelines for schizophrenia and major depressive disorder might effectively improve participants' clinical knowledge of the guidelines. These data are encouraging to facilitate the standardization of clinical practices for psychiatric disorders.

Survey of recognition and treatment of at-risk mental state by Japanese psychiatrists.

AIM: The importance of early intervention in psychiatry is widely recognized among psychiatrists. However, it is unknown whether precise knowledge of at-risk mental state has been disseminated. With this survey, we aimed to reveal how Japanese psychiatrists diagnose patients with at-risk mental state and prescribe treatment strategies for them. METHODS: Using fictional case vignettes, we conducted a questionnaire survey of psychiatrists (n = 1399) who worked in Tokyo. We mailed study documents to all eligible participants in November 2015 with a requested return date in December. RESULTS: Two hundred and sixty (19.3%) psychiatrists responded to the survey. Their correct diagnosis rates for the patients in the at-risk mental state vignettes were low (14.6% for the vignette describing at-risk mental state with attenuated positive symptom syndrome; 13.1% for the vignette describing at-risk mental state with brief intermittent psychotic syndrome). Many psychiatrists selected pharmacotherapy and antipsychotics to treat patients in the at-risk mental state vignettes. The psychiatrists who correctly diagnosed patients in the at-risk mental state vignettes had significantly fewer years of clinical psychiatric experience than did those who diagnosed them as having a non-at-risk mental state (12.5 years vs 22.7 years for the vignette describing at-risk mental state with attenuated positive symptom syndrome, P < 0.01; 14.3 years vs 22.2 years for the vignette describing at-risk mental state with brief intermittent psychotic syndrome, P < 0.01). CONCLUSION: This study suggests that precise knowledge of at-risk mental state has not been disseminated among Japanese psychiatrists.

Associations between Verbal Fluency and Asymmetry of White Matter Integrity in the Superior Longitudinal Fasciculus in At-Risk Mental States for Psychosis.

Verbal fluency is one of the most severely impaired components of cognitive function in schizophrenia and is also impaired in at-risk mental states (ARMSs) for psychosis. The aim of this study was to explore the markers of disease progression in subjects with ARMSs by comparing the association between the white matter integrity of the superior longitudinal fasciculus (SLF) and verbal fluency in subjects with ARMSs and healthy control (HC) subjects. The correlations of the fractional anisotropy (FA) values on diffusion tensor imaging (DTI) and the laterality index (LI) values of SLF branches I, II, and III with the verbal fluency performance were analyzed in right-handed subjects with ARMSs (ARMS group; n = 18) and HC subjects (HC group; n = 34) aged 18 to 40 years old. In the HC group compared with the ARMS group, the LI values suggested right lateralization of the SLF II and III. Letter fluency was significantly correlated with the LI of the SLF III in both the ARMS and HC groups. The regression coefficient (ß) of this correlation was calculated using the least squares method and yielded a positive number (73.857) in the ARMS group and a negative number (-125.304) in the HC group. The association of the rightward asymmetry of the SLF III with the verbal fluency performance observed in the HC group appeared to be lost in the ARMS group, and this could serve as one of the markers of the pathological progression to psychosis in patients with schizophrenia.

Exploring the impact of biological alterations in the superior thalamic radiations on exploratory eye movements in attenuated psychosis syndrome.

Introduction: Aberrant fixation and scan paths in visual searches have been repeatedly reported in schizophrenia. The frontal eye fields (FEF) and thalamus may be responsible for fixation and scan paths. These two regions are connected by superior thalamic radiation (STR) in humans. Studies have reported reduced fixation numbers and shortened scan path lengths in individuals with attenuated psychosis syndrome (APS) and schizophrenia. In this study, we hypothesized that STRs in the white matter fiber bundles of impairments underlie abnormalities in fixation and scan path length in individuals with APS. Methods: Twenty-one individuals with APS and 30 healthy controls participated in this study. All participants underwent diffusion tensor imaging, and fractional anisotropy (FA) values of the left and right STR were analyzed using the novel method TractSeg. The number of eye fixations (NEF), total eye scanning length (TESL), and mean eye scanning length (MESL), derived using the exploratory eye movement (EEM) test, were adopted to evaluate the fixation and scan path length. We compared the FA values of the bilateral STR and EEM parameters between the APS and healthy control groups. We investigated the correlation between bilateral STR and EEM parameters in the APS and healthy control groups. Results: NEF, TESL, MESL, and the FA values of the left STR were significantly reduced in individuals with APS compared to healthy controls. The left STR FA value in the APS group was significantly positively correlated with the MESL (r = 0.567, p = 0.007). In addition, the right STR FA value of the APS group was significantly correlated with the TESL (r = 0.587, p = 0.005) and MESL (r = 0.756, p = 0.7×10-4). Discussion: These results demonstrate that biological changes in the STR, which connects the thalamus and FEF, underlie abnormalities in fixation and scanning. Recently, aberrations in the thalamus-frontal connection have been shown to underlie the emergence of psychotic symptoms. STR impairment may be a part of the biological basis of APS in individuals with subthreshold psychotic symptoms.

Nomenclature for psychosis risk in Japan: Survey results from high-risk individuals, caregivers, and mental health professionals.

BACKGROUND: Labeling terms for high-risk state for psychosis, such as 'ultra-high risk' (UHR), 'attenuated psychosis syndrome' (APS), and 'at-risk mental state' (ARMS), have been criticized for their potential to lead to stigma. Hence, mental health service users in Melbourne recently proposed new terms illustrating the at-risk concept ['pre-diagnosis stage' (PDS), 'potential of developing a mental illness' (PDMI), and 'disposition for developing a mental illness' (DDMI)]. We aimed at testing the suitability of these existing and new terms in the clinical settings of early psychiatric intervention in Japan. METHODS: At two centers of early intervention (Toyama and Tokyo), a questionnaire on the understanding and opinion of high-risk terminology was administered to 62 high-risk patients, 44 caregivers, and 64 clinicians. The questionnaire contained the existing and new terms, where the term ARMS was translated into two different Japanese terms ARMS-psychosis and ARMS-kokoro. Participants' opinion on the disclosure of high-risk status was also obtained. RESULTS: ARMS-kokoro was most preferred, least stigmatizing, and best explaining the patients' difficulties for all groups, while UHR and other terms including the Japanese word 'psychosis' (i.e., APS and ARMS-psychosis) were not preferred. New labeling terms were generally not well received. All groups preferred full disclosure of high-risk terms by the psychiatrist with or without the presence of family members. CONCLUSION: The term ARMS-kokoro was commonly accepted as a favorable labeling term for the high-risk state for psychosis in Japan. However, another translation ARMS-psychosis was considered stigmatizing, demonstrating the importance of appropriate translation of high-risk terminology into local languages.

Increased inosine levels in drug-free individuals with at-risk mental state: A serum metabolomics study.

AIM: At-risk mental state (ARMS) has been recently attracting attention with respect to the improvement of the management and outcome of psychiatric diseases, such as schizophrenia. Since only a few studies have reported on biological alterations in ARMS, serum metabolomics was carried out in ARMS subjects and healthy controls using liquid chromatography with high-resolution mass spectrometry. METHODS: Serum samples were collected from ARMS subjects (n = 24; male: 12; female 12) and age- and sex-matched healthy controls (n = 23 male: 11, female: 12). After serum pre-treatment, liquid chromatography with high-resolution mass spectrometry was performed. Multivariate analyses, such as orthogonal partial least-squares discriminant and volcano plot analyses, were performed. RESULTS: Serum inosine, lactate, taurine, 2,3-dihydroxypropanoate and glutamate levels differed between the two groups. A significant increase in inosine levels was detected in the positive- and negative-ion modes; however, significant differences were not observed in the levels of other purine-related metabolites (hypoxanthine, xanthine and urate) between the two groups. CONCLUSION: Increased inosine levels may serve as biological markers for ARMS, in addition to alterations in the levels of lactate and certain amino acids.

Association between the examination rate of treatment-resistant schizophrenia and the clozapine prescription rate in a nationwide dissemination and implementation study.

BACKGROUND: The decision to initiate clozapine treatment should be made on an individual basis and may be closely related to the early detection of treatment-resistant schizophrenia (TRS), although there is evidence that the early use of clozapine results in a better response to treatment. Therefore, we investigated the relationship between the examination rate of TRS and the prescription rate of clozapine. METHODS: After attending a 1-day educational program on schizophrenia based on the "Guidelines for the Pharmacological Treatment of Schizophrenia," we asked the participating facilities to submit records of whether or not TRS was evaluated for each patient. We calculated the clozapine prescription rate from the schizophrenic patients prescribed clozapine and all of the schizophrenic patients. Forty-nine facilities in 2017 were included in the study. RESULTS: There were dichotomous distributions in the examination rate of TRS and a non-normal distribution in the prescription rate of clozapine. There was a significant correlation between the prescription rate of clozapine and the examination rate of TRS (r s  = 0.531, P = 1.032 × 10-4 ). A significant difference was found in the prescription rate of clozapine between the three groups of facilities according to the examination rate of TRS. CONCLUSION: As a preliminary problem for the use of clozapine, in Japan, the examination rate of TRS varies, and there are many facilities that typically do not consider the possibility of TRS; this trend leads to a low rate of clozapine use. Clearly, further clinician training is needed for the early detection and appropriate management of TRS that includes an explanation of TRS and how to introduce clozapine therapy to patients and their families.

Prescription of Anticholinergic Drugs in Patients With Schizophrenia: Analysis of Antipsychotic Prescription Patterns and Hospital Characteristics.

In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups-low rate group (LG), medium rate group (MG), and high rate group (HG)-according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.

Characteristics of the treatments for each severity of major depressive disorder: A real-world multi-site study.

PURPOSE: In the treatment guidelines for major depressive disorder (MDD), the recommended treatment differs based on the severity. However, the type of treatment provided based on the severity of MDD in real-world clinical practice has not been investigated. In this study, we clarified the actual situation of MDD treatment in clinical practice and compared the treatment based on the severity of MDD. METHODS: We used data from 1484 patients with MDD at discharge from October 2016 to March 2020. RESULTS: The number of psychotropic prescriptions tended to be lower in those diagnosed with MDD in the severe group compared to in the non-severe group. There were significant differences among the three groups (mild, moderate/severe, and psychotic) in the percentage of patients who were not prescribed antipsychotics (p = 1.9 ×10-6), a combination of antipsychotics and antidepressants (p = 5.0 ×10-4), and the implementation rate of modified electroconvulsive therapy (m-ECT) (p = 3.4 ×10-9). The percentage of patients with a severe diagnosis who underwent m-ECT was higher, which corresponded to the severity. CONCLUSION: Our findings showed that the use of psychotropics decreased when the severity of MDD was diagnosed, and the rate of a combination of antipsychotics and antidepressants and the implementation rate of m-ECT increased with the severity. However, this study suggests that there is still an evidence-practice gap in the treatment of MDD in Japan, and guidelines are only partially adhered to in the treatment of depression.

Subjective assessment of participants in education programs on clinical practice guidelines in the field of psychiatry.

The Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE) project, which is a nationwide dissemination and implementation program for clinical practice guidelines (CPGs) in the field of psychiatry, is currently ongoing. In the current study, a subjective assessment of the participants in the EGUIDE programs was assessed using a questionnaire. Then, the relationships between the subjective assessment, the characteristics of the participants, and the clinical knowledge of the CPGs were evaluated. More than 90% of the participants gave a high rating for the components of content, recommendation, knowledge, skill, and adherence, but not for the component of confidence. A positive correlation was found between years of professional experience and the score of confidence. These results suggest that it may be necessary to apply the knowledge and skills of CPGs obtained in the education programs into practice to increase confidence in the proper use of psychiatric therapies based on CPGs.

Can reduced leftward asymmetry of white matter integrity be a marker of transition to psychosis in at-risk mental state?

As a biomarker for the degree of psychosis development, the lateral asymmetry of white matter (WM) integrity in each area of the cerebrum has been investigated; as a result, a reduced leftward asymmetry of WM integrity has been reported in patients with schizophrenia. Although individuals with an at-risk mental state for psychosis (ARMS) who subsequently develop psychosis are believed to have poorer social functioning, only a few studies have actually examined the associations between WM abnormalities and social functioning. The aim of the present study was to clarify the possibly predictive association between a reduced asymmetry of WM integrity and impairments in social functioning in patients with ARMS. Thirty ARMS subjects underwent MRI scanning and were assessed using the Social Functioning Scale (SFS). We examined the fractional anisotropy (FA) values in the cingulum bundle (CB) and the uncinate fasciculus (UF) using a tract-specific analysis. Lateral asymmetry was assessed using the laterality index (LI). The LI of the FA value was positive (leftward) in the CB and negative (rightward) in the UF. Although the LI was not correlated with the Scale of Prodromal Symptoms (SOPS) score, the LI in the CB was positively correlated with the SFS score. In ARMS patients, the degree of reduced leftward asymmetry in the CB might affect deteriorations in social functioning and may be useful as a biomarker for predicting future outcomes at an early stage of psychosis.

Serum d- and l-lactate, pyruvate and glucose levels in individuals with at-risk mental state and correlations with clinical symptoms.

AIM: Little information exists on the peripheral metabolite levels in individuals with at-risk mental state who meet the criteria for a high-risk state of psychosis. Here, we aimed to investigate serum levels of glucose, pyruvate and d- and l-lactate, which may act as a signalling molecule for learning and memory in neuronal cells. METHODS: High performance liquid chromatography or commercial kits were used to assess serum metabolites in individuals with attenuated psychosis symptoms of at-risk mental state (n = 24, men = 12) who were not receiving antipsychotics. The metabolite levels of these individuals were compared with those of age- and sex-matched healthy individuals (controls, n = 23, men = 11). Correlations between the metabolites and clinical symptoms of at-risk mental state were also examined. RESULTS: Individuals with at-risk mental state had higher serum glucose levels than did controls (P = 2.18 × 10-3 ), while no significant difference in pyruvate levels were observed between the groups. Individuals with at-risk mental state had significantly lower serum l-lactate levels than did controls (P = 6.31 × 10-5 ), while no differences in d-lactate levels were observed. Furthermore, a negative correlation was identified between serum l-lactate levels and Positive and Negative Syndrome Scale negative symptoms scores (r = -0.5651, P = 4.01 × 10-3 ) in individuals with at-risk mental state. CONCLUSIONS: We found that, compared with controls, individuals with at-risk mental state have reduced serum l-lactate levels, which may predate psychosis onset, and may be involved in the related negative symptoms.

Alterations in methionine to homocysteine ratio in individuals with first-episode psychosis and those with at-risk mental state.

BACKGROUND: Disturbance of the methionine (Met) cycle, which produces Met from homocysteine (Hcy), is suggested to be involved in several diseases, including psychiatric disorders. This study was aimed to investigate both levels of Met and Hcy in serum from individuals with first-episode psychosis (FEP) and individuals with at-risk mental state (ARMS). METHOD: We measured serum Met and Hcy levels in individuals with FEP (n = 13) and ARMS (n = 30) using HPLC with fluorescence detection and LC-ESI-MS/MS. Met and Hcy levels in healthy controls (n = 41) were also measured. Differences between the 3 groups were analyzed by one-way analysis of variance (ANOVA) with Bonferroni correction. RESULTS: Serum Met levels were decreased (p = 0.038) and Hcy levels were increased (p = 0.017) in the FEP group. Hcy levels were also significantly increased compared to the ARMS group (p = 0.016), while Met levels were not significantly different between the FEP and ARMS groups. A significant decrease in the Met to Hcy ratio (Met/Hcy) was observed in the FEP group compared to both the control (p = 4.58 × 10-4) and ARMS (p = 8.07 × 10-3) groups. Furthermore, Met/Hcy ratio was correlated with Positive and Negative Syndrome Scale, especially positive scores (p = 5.90 × 10-5). CONCLUSION: Taken together, these data indicate that a decrease in the serum Met/Hcy ratio may be a risk factor for developing psychosis during the transition from ARMS to FEP, and may prove to be a useful marker of the phase between ARMS and FEP.

Psychiatrists' opinion towards medication discontinuation in remitted first-episode psychosis: A multi-site study of the Asian Network for Early Psychosis.

AIM: The study investigated psychiatrists' views towards the issue of medication discontinuation for patients in remission from first-episode psychosis in four countries (Hong Kong, Korea, Singapore and Japan) that are part of the Asian Network for Early Psychosis, focusing on whether the views of these countries differ with one another. METHODS: A questionnaire was distributed to psychiatrists for completion. The questionnaire contained three sections: direct questions probing at views on medication discontinuation, case vignettes to assess applied decision-making and a checklist of criteria psychiatrists may view as necessary for the patient to satisfy before discontinuation. Total of 484 psychiatrists (97 from Hong Kong, 88 from Korea, 64 from Singapore and 233 from Japan) completed the questionnaire. RESULTS: We found that (a) Asian psychiatrists believed that 1% to 19% of remitted patients can discontinue medication, an estimation that was lower than Western psychiatrists; (b) in agreement with clinical guidelines, Asian psychiatrists believed that patients should remain on medication for at least 1 to 2 years following the absence of psychotic symptoms; (c) "Absence of any relapsing episode following first episode" was considered the most important criterion when making a decision; and (d) there were significant differences in clinicians' perceptions across the four countries: for instance, Korean psychiatrists were more conservative with the duration of antipsychotics maintenance, while Singaporean psychiatrists were more open-minded towards clinical trials. CONCLUSIONS: Culture and social norms appear to determine the relative importance of factors that psychiatrists might consider during the decision-making process, thereby producing variations in the views held in different countries.