Real-world predictors of changes in fear of COVID-19 in the Japanese general population: a large-scale internet-based cohort study with 20,712 participants.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory infection that considerably impacts both physical and mental health. In particular, the prolonged nature of psychological issues associated with COVID-19 has become a concern. However, evidence based on longitudinal studies investigating the changes in fear of COVID-19 has been limited, posing a public health challenge. METHODS: We investigated the predictors of changes in the Fear of COVID-19 Scale (FCV-19S) scores in the general Japanese population using data from a large-scale internet-based cohort study. RESULTS: We included 20,712 study participants (mean age = 51.1 years, percentage of males = 49.9%). The baseline FCV-19S score for the research participants was 17.0, and one year later, the FCV-19S score decreased to 15.8. The predictors of increase in FCV-19S scores were older age, male sex, COVID-19 requiring oxygen therapy, higher baseline FCV-19S total score, severe psychological distress, never married, worsening subjective health status, a greater number of COVID-19 vaccinations, a history of alcohol dependency, and living with family members. Conversely, the predictors of decrease in FCV-19S scores included habitual alcohol intake, COVID-19 not requiring oxygen therapy and a higher household income. Our study was an internet-based survey focused on residents of Japan, which raises the possibility of selection bias and makes it unclear whether the findings can be extrapolated to other countries and cultures. CONCLUSION: During the observation period, the FCV-19S scores significantly decreased. Severe COVID-19 requiring oxygen therapy within one year of baseline was the most impactful predictor of an increase in FCV-19S score. On the other hand, mild COVID-19 not requiring oxygen therapy was a predictor of a decrease in FCV-19S scores. Therefore, we believe that it is necessary to adopt individualized approaches stratified by the severity of the infection when addressing the fear of COVID-19.

The effect of education regarding treatment guidelines for schizophrenia and major depressive disorders on psychiatrists' hypnotic medication prescribing behavior: a multicenter study.

BACKGROUND: To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan. METHODS: The EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications. RESULTS: A total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients. CONCLUSION: This is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior.

Relationships Between Adherence to Guideline Recommendations for Pharmacological Therapy Among Clinicians and Psychotic Symptoms in Patients With Schizophrenia.

BACKGROUND: Clinician adherence to guideline recommendations in the pharmacological therapy of schizophrenia is important for favorable patient outcomes. To evaluate whether prescriptions followed the guidelines for pharmacological therapy of schizophrenia, we recently developed a summary indicator of multiple quality indicators: the individual fitness score (IFS). It is unclear whether adherence to the guidelines is related to patient outcomes. Here, we investigated correlations between the IFS values and psychotic symptoms in patients with schizophrenia. METHODS: We assessed whether patients' current prescriptions adhered to the guideline recommendations using the IFS in 47 patients with treatment-resistant schizophrenia (TRS) and 353 patients with non-TRS (total n = 400), respectively. We investigated correlations between the IFS and total scores and scores on the 5 subscales of the Positive and Negative Syndrome Scale (PANSS). Furthermore, we explored correlations between over 2-year longitudinal changes in IFS values and changes in psychotic symptoms in some patients (n = 77). RESULTS: We found significant negative correlation between the IFS and PANSS total score in all patients with schizophrenia (ß = -0.18, P = 9.80 × 10-5). The IFS was significantly and nominally negatively correlated with the PANSS total score in patients with non-TRS (Spearman's rho = -0.15, P = 4.40 × 10-3) and patients with TRS (rho = -0.37, P = .011), respectively. The IFS was also significantly and nominally negatively correlated with several factors, such as the negative and depressed factors, in patients with non-TRS and patients with TRS, respectively (P < .05). Furthermore, the change in IFS values was marginally negatively correlated with the changes in PANSS total scores and scores on the positive and depressed factors (P < .05). CONCLUSIONS: These findings suggest that efforts to improve clinician adherence to guideline recommendations for pharmacological therapy of schizophrenia, as assessed by the IFS, may lead to better outcomes in patients with schizophrenia.

Combination Psychotropic Use for Schizophrenia With Long-Acting Injectable Antipsychotics and Oral Antipsychotics: A Nationwide Real-World Study in Japan.

BACKGROUND: Although several guidelines recommend monotherapy with antipsychotics for the treatment of schizophrenia, patients who receive long-acting injectable antipsychotics (LAIs) are frequently treated with oral antipsychotics (OAPs). In the present study, we investigated the detailed use of psychotropic medications among patients throughout Japan with schizophrenia who received LAIs or OAPs. METHODS: The present study used data from the project for the Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment from 94 facilities in Japan. The LAI group included patients who received any LAI, and the non-LAI group included patients who took only OAP medications at discharge. The participants of this study were 2518 schizophrenia patients (263 in the LAI group and 2255 in the non-LAI group) who received inpatient treatment and had prescription information at discharge between 2016 and 2020. RESULTS: This study revealed significantly higher rates of polypharmacy antipsychotics, number of antipsychotics, and chlorpromazine equivalents in the LAI group than in the non-LAI group. In contrast, the LAI group showed lower rate of concomitant use of hypnotic and/or antianxiety medication than the non-LAI group. CONCLUSIONS: Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group.

Change of prescription for patients with schizophrenia or major depressive disorder during admission: real-world prescribing surveys from the effectiveness of guidelines for dissemination and education psychiatric treatment project.

BACKGROUND: Polypharmacy of additional psychotropics alongside the main treatment drug (antipsychotics in schizophrenia and antidepressants in major depressive disorder) is common in Japan. Our goal is to align psychotropic prescription in Japan with international standards, while reducing the differences between facilities. To achieve this goal, we aimed to compare prescriptions at the time of hospital admission and discharge. METHODS: Data on prescriptions at admission and discharge from 2016 to 2020 were collected. We divided the patients into four groups: (1) mono_mono group, monotherapy of the main drug at admission and discharge; (2) mono_poly group, monotherapy at admission and polypharmacy at discharge; (3) poly_poly group, polypharmacy at admission and discharge; and (4) poly_mono group, polypharmacy at admission and monotherapy at discharge. We compared the changes in dosage and number of psychotropics among the four groups. RESULTS: For both schizophrenia and major depressive disorder, the patients who received monotherapy with the main drug at admission were likely to receive main drug monotherapy at discharge and vice versa. For schizophrenia, the polypharmacy was prescribed more often in the mono_poly group than that in the mono_mono group. The prescription was not changed at all for more than 10% of the patients. CONCLUSIONS: It is critical to avoid a polypharmacy regimen to ensure that guideline-compliant treatment is provided. We expect higher rates of monotherapy with the main drug after the EGUIDE lectures. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network Registry (UMIN000022645).

Effects of electroconvulsive therapy on the use of anxiolytics and sleep medications: a propensity score-matched analysis.

AIM: We investigated the association of electroconvulsive therapy (ECT) with anxiolytic and sleep medication use in patients with major depressive disorder (MDD) and schizophrenia (SZ). METHODS: This nationwide observational study analyzed data from 3483 MDD inpatients and 6663 SZ inpatients. Patients with MDD and SZ were classified into those who underwent ECT during hospitalization and those who did not. A propensity score-matching method was performed to adjust for preadmission characteristics and clinical information, which were expected bias between the two groups. Rates of anxiolytic and sleep medication use at discharge were compared in the matched sample. RESULTS: 500 MDD patients were assigned to both groups. In the matched MDD sample, the rate of anxiolytic and sleep medication use at discharge was significantly lower in the ECT group than in the non-ECT group (64.9% vs. 75.8%, P = 1.7 × 10-4 ). In the ECT group, the rate of anxiolytic and sleep medication use at discharge was significantly lower than that prior to admission (64.9% vs. 73.2%, P = 1.2 × 10-14 ). 390 SZ patients were allocated. In the matched SZ sample, the ECT group was not significantly different from the non-ECT group in the rate of anxiolytics and sleep medications use at discharge (61.3% vs. 68.2%, P = 4.3 × 10-2 ). In the ECT group, the rate of anxiolytics and sleep medications use at discharge was significantly lower than that before admission (61.3% vs. 70.5%, P = 4.4 × 10-4 ), although this was not the primary outcome. CONCLUSION: Reduction of anxiolytic and sleep medication use may be considered positively when ECT is indicated for treatment of MDD.

Effect of education regarding treatment guidelines for schizophrenia and depression on the treatment behavior of psychiatrists: A multicenter study.

AIM: This study aims to examine the real-world effectiveness of education regarding clinical guidelines for psychiatric disorders using 'the Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)' project. METHODS: The EGUIDE project is a nationwide prospective implementation study of two clinical practice guidelines, i.e., the Guideline for Pharmacological Therapy of Schizophrenia and the Treatment Guidelines for Major Depressive Disorders, in Japan. Between 2016 and 2019, 782 psychiatrists belonging to 176 hospitals with psychiatric wards participated in the project and attended lectures on clinical practice guidelines. The proportions of guideline-recommended treatments in 7405 patients with schizophrenia and 3794 patients with major depressive disorder at participating hospitals were compared between patients under the care of psychiatrists participating in the project and those not participating in the project. Clinical and prescribing data on the patients discharged from April to September each year from participating hospitals of the project were also analyzed. RESULTS: The proportions of three quality indicators (antipsychotic monotherapy regardless of whether other psychotropics medication, antipsychotic monotherapy without other psychotropics and no prescription of anxiolytics or hypnotics) for schizophrenia were higher among participating psychiatrists than among nonparticipating psychiatrists. As similar results were obtained in major depressive disorder, the effectiveness of the project for the dissemination of guideline-recommended treatment has been replicated. CONCLUSION: This strategy of providing education regarding the clinical guidelines for psychiatric disorders was effective in improving the treatment-related behavior of psychiatrists. The use of this education-based strategy might contribute to resolving the mental health treatment gap.

Real-world predictors of divorce among outpatients with bipolar disorder: sex differences and clinical implications.

BACKGROUND: Bipolar disorder is a mental illness characterized by recurring episodes of mania and depression and is known to cause social impairment. Additionally, it has been revealed that bipolar disorder increases the risk of divorce and loss of family member support, which can worsen the prognosis. However, there is limited evidence regarding the predictive factors of divorce among patients with bipolar disorder in real-world settings. METHODS: This study utilized an observational approach and involved psychiatrists from 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics. They were requested to conduct a retrospective review of medical records and complete a questionnaire focused on patients diagnosed with bipolar disorder. The data collection period for baseline patient characteristics spanned from September to October 2017. Next, we investigated the incidence of divorce over a 2-year period, ranging from baseline to September to October 2019. RESULTS: A total of 1071 outpatients with bipolar disorder were included in the analysis, and 2.8% (30/1071) experienced divorce during the first 2 years of observation. The incidence of divorce in this population was considerably higher than that in the general Japanese population. Binomial logistic regression analysis confirmed that a younger baseline age and lower BMI values were statistically significant predictors of divorce occurrence for all study participants. The predictors of divorce were then examined separately by sex. The results revealed that for men, a younger age at baseline and having bipolar I disorder compared to bipolar II disorder were statistically significant predictors of divorce. In contrast, for women, having a lower BMI and using anxiolytics emerged as statistically significant predictors of divorce. CONCLUSIONS: In this study, a younger baseline age and lower BMI values were statistically significant predictors of divorce in patients with bipolar disorder. Notably, the predictors of divorce varied significantly between men and women. These findings provide important insights from a family perspective regarding social support for individuals with bipolar disorder in real-world clinical settings.

Predictors of psychological distress and sleep deprivation in caregivers of stroke survivors.

BACKGROUND: Caregivers for stroke survivors (CSS) suffer from long hours of care, limited support, and financial difficulties, which often affect their mental health. OBJECTIVES: This study sought to determine the factors affecting psychological distress and sleep duration among CSS. METHODS: We analyzed cross-sectional data from the 2013 Comprehensive Survey of the Living Conditions for Stroke Survivors and CSS. Linked data from 841 pairs of stroke survivors and CSS were extracted. Kessler's Psychological Distress scale (K6) was used to evaluate psychological distress. CSS who slept less than 5 hours per day were classified as having short sleep duration. Factors predictive of psychological distress and short sleep duration were evaluated using multivariable logistic regression analysis with the forward selection method. RESULTS: The mean (SD) age of the CSS was 65.4 (12.5) years. A total of 5.6% of these caregivers presented with serious psychological distress, and 12.0% were sleep deprived. Serious psychological distress was associated with not having someone to consult with, having subjective symptoms within a few days, and having short sleep duration, while having their own houses reduced the risk of serious psychological distress. Furthermore, short sleep duration was associated with stroke survivors in long-term care levels 4 or 5, not having someone to consult with, participation in sponge baths as part of nursing care activities, and having serious psychological distress. CONCLUSIONS: This nationwide survey identified several risk factors for psychological stress and sleep deprivation among CSS and suggests the need for multidimensional approaches to reduce their distress.

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.

New Insight Concerning Therapeutic Drug Monitoring-The Importance of the Concept of Psychonephrology.

Recently, the concept of psychonephrology was developed and has been recognized as a field of study that focuses on nephrology and mental health fields, such as psychiatry and psychosomatic medicine. Indeed, patients with chronic kidney disease frequently suffer from mental problems as the disease stage progresses. Most psychotropic drugs are hepatically metabolized, but some are unmetabolized and eliminated renally. However, renal disease may affect the pharmacokinetics of many psychotropic drugs, as the decreased renal function not only delays the urinary excretion of the drug and its metabolites but also alters various pharmacokinetic factors, such as protein-binding, enterohepatic circulation, and activity of drug-metabolizing enzymes. Therefore, when prescribing drug therapy for patients with both renal disease and mental issues, we should consider reducing the dosage of psychotropic drugs that are eliminated mainly via the kidney and also carefully monitor the blood drug concentrations of other drugs with a high extrarenal clearance, such as those that are largely metabolized in the liver. Furthermore, we should carefully consider the dialyzability of each psychotropic drug, as the dialyzability impacts the drug clearance in patients with end-stage renal failure undergoing dialysis. Therapeutic drug monitoring (TDM) may be a useful tool for adjusting the dosage of psychotropic drugs appropriately in patients with renal disease. We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis and offer new insight concerning TDM in the field of psychonephrology.

Toward recovery in schizophrenia: Current concepts, findings, and future research directions.

Schizophrenia was initially defined as "dementia praecox" by E. Kraepelin, which implies progressive deterioration. However, recent studies have revealed that early effective intervention may lead to social and functional recovery in schizophrenia. In this review, we provide an overview of current concepts in schizophrenia and pathophysiological hypotheses. In addition, we present recent findings from clinical and basic research on schizophrenia. Recent neuroimaging and neurophysiological studies have consistently revealed specific biological differences in the structure and function of the brain in those with schizophrenia. From a basic research perspective, to determine the essential pathophysiology underlying schizophrenia, it is crucial that findings from all lines of inquiry-induced pluripotent stem cell (iPSC)-derived neural cells from patients, murine models expressing genetic mutations identified in patients, and patient clinical data-be integrated to contextualize the analysis results. However, the findings remain insufficient to serve as a diagnostic tool or a biomarker for predicting schizophrenia-related outcomes. Collaborations to conduct clinical research based on the patients' and their families' values are just beginning, and further development is expected.

Effect of age and sex on prescriptions for outpatients with bipolar disorder in the MUSUBI study: a cross­sectional study.

BACKGROUND: Childbearing-aged female patients and elderly patients with bipolar disorder need special attention for pharmacological treatments, but current guidelines provide little information on their pharmacological treatment. In particular, the risk/benefit balance of pharmacological treatment for childbearing-aged females with bipolar disorder is a growing concern. Therefore, we aimed to address the effect of age and sex on psychotropic drug prescription for outpatients with bipolar disorder. METHODS: The MUlticenter treatment SUrvey for BIpolar disorder in Japanese psychiatric clinics (MUSUBI) study was conducted, and data on age, sex, and details of pharmacological treatment were collected. RESULTS: A total of 3106 outpatients were included in this study. Among young females (age ≤ 39), 25% were prescribed valproate. There was no significant difference in the frequency and daily dose of valproate prescription for young females among all groups. Valproate prescriptions were significantly less frequent among young males and more frequent among middle-aged males. Lithium prescriptions were significantly less frequent among young females and more frequent among older males (age ≥ 65) and older females. Lamotrigine prescriptions were significantly more frequent among young males and young females and less frequent among older males and older females. Carbamazepine prescriptions were significantly less frequent among young males and more frequent among older males. CONCLUSIONS: Biased information about the risk and safety of valproate and lithium for young females was suggested, and further study to correct this bias is needed. Older patients were prescribed lithium more commonly than lamotrigine. Further studies are needed to determine the actual pharmacotherapy for elderly individuals.

The characteristics of discharge prescriptions including pro re nata psychotropic medications for patients with schizophrenia and major depressive disorder from the survey of the "Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)" project.

BACKGROUND: Several guidelines recommend monotherapy in pharmacotherapy for schizophrenia and major depressive disorder. The content of regular prescriptions has been reported in several studies, but not enough research has been conducted on the content of pharmacotherapy, including pro re nata (PRN) medications. The purpose of this study was to evaluate the content of pharmacotherapy, including PRN medications, and to clarify the relationship with regular prescriptions. METHODS: We used data from the "Effectiveness of Guidelines for Dissemination And Education in psychiatric treatment" (EGUIDE) project to investigate the presence or absence of PRN psychotropic medications at discharge for each drug category. We compared the PRN psychotropic prescription ratio at discharge by diagnosis for each drug category. The antipsychotic monotherapy ratio and no prescription ratio of other psychotropics for schizophrenia at discharge and the antidepressant monotherapy ratio and no prescription ratio of other psychotropics for major depressive disorder at discharge were calculated for each regular prescription, including PRN psychotropic medications, as quality indicators (QIs). Spearman's rank correlation test was performed for QI values of regular prescriptions and the QI ratio between regular prescriptions and prescriptions including PRN medications for each diagnosis. RESULTS: The PRN psychotropic prescription ratio at discharge was 28.7% for schizophrenia and 30.4% for major depressive disorder, with no significant differences by diagnosis. The prescription ratios of PRN antipsychotic medications and PRN antiparkinsonian medications were significantly higher for schizophrenia. The prescription ratios of PRN anxiolytic and hypnotic and PRN antidepressant medications were significantly higher for patients with major depressive disorder. For both schizophrenia and major depressive disorder, the QI was lower for discharge prescriptions, including PRN medications, than for regular prescriptions. QI values for regular prescriptions and the QI ratio were positively correlated. CONCLUSIONS: Considering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.

HomotopicLI: Rationale, characteristics, and implications of a new threshold-free lateralization index of functional magnetic resonance imaging.

The reliable preoperative estimation of brain hemispheric asymmetry may be achieved through multiple lateralization indices using functional magnetic resonance imaging. Adding to our previously developed AveLI, we devised a novel threshold-free lateralization index, HomotopicLI, which computes a basic formula, (Left - Right) / (Left + Right), using voxel values of pairs located symmetrically in relation to the midsagittal line as the terms Left and Right, and averages them within the regions-of-interest. The study aimed to evaluate HomotopicLI before clinical applications. Data were collected from 56 healthy participants who performed four language tasks. We compared seven index types, including HomotopicLI, AveLI, and BaseLI; BaseLI was calculated using the sums of voxel values as the terms. Contrary to our expectations, HomotopicLI performed similarly to AveLI but better than BaseLI in detecting right dominance. A detailed analysis of unilaterally activated voxels of the homotopic pairs revealed that unilateral activation occurred more frequently on the right than on the left when HomotopicLI indicated right dominance. The voxel values during right unilateral activation were smaller than those in the left, causing right dominances in the homotopic pairs by HomotopicLI. These unique features provide an advantage in detecting residual, compensative functions spreading weakly in the non-dominant hemisphere.

Relationship of Prolactin Concentrations to Steady-State Plasma Concentrations of Aripiprazole in Patients With Schizophrenia.

BACKGROUND: Aripiprazole is regarded as the first-line antipsychotic medication. Long-term aripiprazole therapy can cause hypoprolactinemia, which may result from its activity as a dopamine agonist. However, there is little information on hypoprolactinemia and steady-state aripiprazole concentrations. METHODS: The subjects included 66 male and 177 female patients diagnosed with schizophrenia who were treated with aripiprazole. The plasma concentrations of aripiprazole and dehydroaripiprazole and the plasma concentration of prolactin were measured using high-performance liquid chromatography and enzyme immunoassay, respectively. A prolactin concentration of <5 ng/mL was defined as hypoprolactinemia. RESULTS: Fifty-two of the 66 male patients (79%) and 58 of the 177 female patients (33%) had hypoprolactinemia. There were significant inverse correlations between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.447, P < 0.001) and the active moiety (aripiprazole plus dehydroaripiprazole) (rs = -0.429, P < 0.001) in men. In women, significant inverse correlations were also found between plasma prolactin levels and plasma concentrations of aripiprazole (rs = -0.273, P < 0.01) and the active moiety (rs = -0.275, P < 0.01). CONCLUSIONS: These findings suggest that lower prolactin levels are, to some extent, associated with higher plasma drug concentrations in male and female patients with schizophrenia treated with aripiprazole.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

BACKGROUND: Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. METHODS: This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. RESULTS: Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). CONCLUSIONS: This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.

Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms.

OBJECTIVE: There are only a few treatment algorithms for first-episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first-episode schizophrenia. METHODS: The algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia. RESULTS: The acute treatment algorithm focuses on drug-naïve patients with first-episode schizophrenia who are not old or very agitated and recommends first-line treatment with aripiprazole, second- or third-line treatment with risperidone/paliperidone or olanzapine, and fourth-line treatment with clozapine. Long-acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first-line treatment with lorazepam and second- or third-line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms. CONCLUSIONS: We hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment.

Estimated model of psychotropic polypharmacy for bipolar disorder: Analysis using patients' and practitioners' parameters in the MUSUBI study.

OBJECTIVE: This study aims to clarify the relevant factors influencing practitioners' methods of prescribing medications for bipolar disorder, in a nation-wide survey in Japan. METHODS: The clinical records of 3130 outpatients with bipolar disorder were consecutively reviewed from 176 psychiatric outpatient clinics. Fifteen parameters, that is, five patients' including five general characteristics (sex, age, education, occupation, and social adjustment), five patients' aspects of mental functioning (onset age, comorbid mental illness, rapid-cycling, psychopathologic severity, and followed-up years), and five practitioners' characteristics (sex, age, specialist experience, clinic standing years, and location), were evaluated. The number of psychotropic drugs (mood stabilizers, antidepressants, antipsychotic drugs, anxiolytics, and hypnotics) was used as an index of pharmacotherapy. Converted data from each practitioner-unit were analyzed. RESULTS: Seven factors (patient's social adjustment, patient's psychopathology, patient's comorbid mental disorders, patient's followed-up years, doctor's age, clinic running years, and patient's education years) were correlated to the number of psychotropic drugs. Multiple regression analysis showed that the severity of illness (poor social adjustment, and comorbid mental illness) and an intractable disease course (long followed-up years), were significantly associated with the number of psychotropic drugs. CONCLUSION: Our findings indicated that patient-related conditions affected psychotropic polypharmacy more strongly than did practitioner-related conditions.

Pharmacological Treatment of Schizophrenia: Japanese Expert Consensus.

INTRODUCTION: Conventional treatment guidelines of schizophrenia do not necessarily provide solutions on clinically important issues. METHODS: A total of 141 certified psychiatrists of the Japanese Society of Clinical Neuropsychopharmacology evaluated treatment options regarding 19 clinically relevant situations in the treatment of schizophrenia with a 9-point scale (1="disagree" and 9="agree"). RESULTS: First-line antipsychotics varied depending on predominant symptoms: risperidone (mean±standard deviation score, 7.9±1.4), olanzapine (7.5±1.6), and aripiprazole (6.9±1.9) were more likely selected for positive symptoms; aripiprazole (7.6±1.6) for negative symptoms; aripiprazole (7.3±1.9), olanzapine (7.2±1.9), and quetiapine (6.9±1.9) for depression and anxiety; and olanzapine (7.9±1.5) and risperidone (7.5±1.5) for excitement and aggression. While only aripiprazole was categorized as a first-line treatment for relapse prevention (7.6±1.0) in patients without noticeable symptoms, aripiprazole (8.0±1.6) and brexpiprazole (6.9±2.3) were categorized as such for social integration. First-line treatments in patients who are vulnerable to extrapyramidal symptoms include quetiapine (7.5±2.0) and aripiprazole (6.9±2.1). DISCUSSION: These clinical recommendations represent the expert consensus on the use of a particular antipsychotic medication for a particular situation, filling a current gap in the literature.