Changes in psychopharmacotherapy for patients with schizophrenia in a psychiatric institution in Japan: A 12-year prescription survey pre- and post-introduction of clozapine.

Psychopharmacotherapy for patients with schizophrenia in Japan has a long history of polypharmacy, which is rare worldwide but remains a critical problem. One reason for this is that clozapine was not available in Japan until 2009. We aimed to investigate the changes in psychopharmacotherapy in patients with schizophrenia over 12 years pre- and post-introduction of clozapine to clarify how psychopharmacotherapy for patients with schizophrenia has changed with the introduction of clozapine. We retrospectively collected data from the medical records of inpatients diagnosed with schizophrenia at the Okayama Psychiatric Medical Center. Chlorpromazine equivalent (CP-eq) decreased from 1276.6 mg/day in 2009 to 613.9 mg/day in 2020. The prescribed daily dose/defined daily dose (PDD/DDD) decreased from 3.0 in 2009 to 1.2 in 2020. The monotherapy rate increased from 24.4 % in 2009 to 74.6 % in 2020. Our institution began using clozapine in 2010, and the prescription rate for clozapine increased to 37.3 % in 2020. The prescription rate for more than three antipsychotics decreased from 27.8 % in 2009 to 0.8 % in 2020. The increase in clozapine prescription has contributed to an increased rate of antipsychotic monotherapy and a decreased rate of polypharmacy, promoting the optimization of schizophrenia medication. Clozapine therapy should be further promoted in Japan to reduce treatment-resistant schizophrenia due to polypharmacy as much as possible.

A feasibility study of provider-level implementation strategies to improve access to colorectal cancer screening for patients with schizophrenia: ACCESS2 (N-EQUITY 2104) trial.

BACKGROUND: People with schizophrenia have a lower colorectal screening rate than the general population. A previous study reported an intervention using case management to encourage colorectal cancer screening for patients with schizophrenia in psychiatric outpatient settings. In this feasibility study, we developed provider-level implementation strategies and evaluated the feasibility of conducting a definitive trial in terms of the penetration of the intervention assessed at the patient level. Additionally, we examined the fidelity of strategies to implement the intervention at the provider level in a routine clinical psychiatric setting. METHODS: This was a multicenter, single-arm feasibility study with medical staff at psychiatric hospitals in Japan. The provider-level implementation strategies developed in this study included three key elements (organizing an implementation team appointed by the facility director, interactive assistance using a clear guide that outlines who in the hospital should do what, and developing accessible educational materials) to overcome major barriers to implementation of the intervention and four additional elements (progress monitoring, joint meetings and information sharing among participating sites, adaptation of encouragement methods to specific contexts, and education of on-site staff), with reference to the elements identified in the Expert Recommendations for Implementing Change (ERIC). The feasibility of the strategies was evaluated by the proportion of patients who were eligible for encouragement (patients with schizophrenia aged 40, 50, or 60) who received encouragement. We set the goal of providing encouragement to at least 40% of eligible patients at each site. RESULTS: Two public and four private psychiatric hospitals in Okayama and Shimane prefectures participated in this study. Regarding fidelity, all elements of the strategies were conducted as planned. Following the procedures in the guide, each team prepared and provided encouragement according to their own facility and region. Penetration, defined as the proportion of eligible patients who received encouragement, ranged from 33.3 to 100%; five of the six facilities achieved the target proportion. CONCLUSIONS: The provider-level implementation strategies to implement encouragement were feasible in terms of penetration of the intervention assessed at the patient level. The results support the feasibility of proceeding with a future definitive trial of these strategies. TRIAL REGISTRATION: jRCT, jRCT1060220026 . Registered on 06/04/2022.

Effect of smoking habits and concomitant valproic acid use on relapse in patients with treatment-resistant schizophrenia receiving clozapine: A 1-year retrospective cohort study.

INTRODUCTION: No study has investigated the impact of smoking habits and concomitant valproic acid (VPA) use on clinical outcomes in maintenance treatment with clozapine. Thus, we aimed to examine the effect of smoking habits and concomitant VPA use on relapse during the first year after discharge in patients with treatment-resistant schizophrenia (TRS) receiving clozapine. METHODS: This retrospective cohort study included patients with TRS who were initiated on clozapine during hospitalization and discharged between April 2012 and January 2021 in two tertiary psychiatric hospitals in Japan. Relapse was defined as rehospitalization due to psychiatric exacerbation during the first year after discharge. A multivariable Cox proportional hazards regression analysis was performed to analyze the effect of smoking habits and concomitant VPA use on relapse. Subgroup analyses were also conducted to examine potential interactions between smoking habits and concomitant VPA use. RESULTS: Among the included 192 patients, 69 (35.9%) met the criteria of relapse. While smoking habits (adjusted hazard ratio [aHR], 2.27; 95% confidence interval [CI], 1.28-4.01; p < 0.01) independently increased the risk of relapse, a significant interaction for relapse risk was found between smoking habits and concomitant VPA use (p-interaction = 0.015). Concomitant VPA use may be an effective modifier of the increased relapse risk associated with smoking habits. Among patients who smoked, those using VPA concomitantly exhibited a higher risk of relapse (aHR, 5.32; 95% CI, 1.68-16.9; p < 0.01) than those not using VPA (aHR, 1.41; 95% CI, 0.73-2.70; p = 0.30). CONCLUSION: The findings suggest that the combination of smoking habits and concomitant VPA use may increase the risk of relapse after discharge. Future studies are required to elucidate the mechanisms underlying these findings, such as a decrease in clozapine blood levels.

Comparison between olanzapine and aripiprazole treatment for 104 weeks after hospital discharge in schizophrenia spectrum disorders: a multicenter retrospective cohort study in a real-world setting.

RATIONALE: The long-term effectiveness of olanzapine and aripiprazole in real clinical conditions at flexible doses in patients after hospital discharge has not been evaluated yet. OBJECTIVES: This study was a multicenter retrospective cohort study. Patients with schizophrenia (n = 398) were prescribed olanzapine (n = 303) or aripiprazole (n = 95) at hospital discharge. The continuation of olanzapine or aripiprazole at 26, 52, or 104 weeks after the hospital discharge were compared using a Cox proportional hazards model and adjusted for possible confounders. RESULTS: The Kaplan-Meier survival curves revealed that the continuation of olanzapine at 26 (P = 0.001) and 52 weeks (P = 0.018) was significantly higher than that of aripiprazole but not at 104 weeks. Olanzapine was better than aripiprazole in efficacy at 26 (hazard ratio: 0.321, 95% confidence interval: 0.159-0.645, P = 0.001), 52 (hazard ratio: 0.405, 95% confidence interval: 0.209-0.786, P = 0.008), and 104 weeks (hazard ratio: 0.438, 95% confidence interval: 0.246-0.780, P = 0.005). Aripiprazole was better than olanzapine in tolerability at 104 weeks (hazard ratio: 4.574, 95% confidence interval: 1.415-14.787, P = 0.011). Rates after two years continuation of olanzapine and aripiprazole were not significantly different in patients with less than five years' duration of illness, but olanzapine was more commonly maintained for more than two years in those patients who had been ill for over five years' due to its greater efficacy. CONCLUSION: Olanzapine treatment showed better continuation rates at 26 and 52 after hospital discharge than aripiprazole, whereas maintenance with the two antipsychotics did not differ significantly at 104 weeks, due reduced tolerability of long-term olanzapine treatment.

Prevalence and modifiable risk factors for dementia in persons with intellectual disabilities.

BACKGROUND: People with intellectual disability (ID) without Down syndrome (DS) are presumed to be at higher risk of developing dementia due to their lower baseline cognitive reserve. We aimed to determine the prevalence of dementia in people with ID without DS and to identify risk factors of dementia. METHODS: This was a cross-sectional survey and multicenter study in Japan. Adults with ID without DS residing in the facilities were included. Caregivers of all participants were interviewed by medical specialists, and participants suspected of having cognitive decline were examined directly. ICD-10 criteria for dementia, DC-LD criteria for dementia, and DSM-5 criteria for neurocognitive disorders were used to diagnose dementia. The severity of ID, educational history, and comorbidities were compared by dividing the groups into those with and without dementia. RESULTS: A total of 1831 participants were included; 118/1831 (6.44%) were diagnosed with dementia. The prevalence of dementia for each age group was 8.8%, 60-64 years; 9.0%, 65-69 years; 19.6%, 70-74 years; and 19.4%, 75-79 years. Age, severity of ID, duration of education, hypertension, depression, stroke, and traumatic brain injury were significantly associated with the presence of dementia. CONCLUSIONS: Although the prevalence of dementia in people with ID without DS was found to be higher at a younger age than in the general population, the results of this study suggested that adequate education, prevention of head trauma and stroke, and treatments of hypertension and depression may reduce the risk of dementia. These may be potentially important modifiable risk factors for the prevention of dementia in these people.

Venous Thromboembolism in Eating Disorders: A Retrospective Observational Study.

Eating disorders (EDs) are associated with a high mortality rate. Patients with EDs often experience severe dehydration due to food restriction and/or vomiting. Severely underweight patients are often prescribed bed rest during inpatient care to reduce their energy consumption, and they may thus develop multiple risk factors for venous thromboembolism (VTE). We compared the clinical features of ED inpatients with VTE to those of ED inpatients without VTE. Seventy-one inpatients with ED were treated at Okayama University Hospital's psychiatric ward in 2016-2020; five were experienced a VTE. Compared to the non-VTE group, the VTE group's median age and disease duration were greater and the median body mass index (BMI) was lower. The VTE group's D-dimer peak values were > 5 mg/L. Physical restraint and central venous catheter use were associated with VTE. Longer ED duration and lower BMI might be risk factors for VTE. To make inpatient treatment for ED safer, it is important to avoid the use of physical restraints and central venous catheters. Continuous D-dimer monitoring is necessary for the early detection of VTE in ED patients at high risk of VTE.

Perceptions toward issues in cancer care for people with mental illness among psychiatric care providers: A questionnaire study.

OBJECTIVES: To reduce cancer care disparities in people with mental illness, this study aimed to quantify psychiatric care providers' perceptions regarding issues that are insufficiently addressed or difficult to address. METHODS: Psychiatric care providers at 23 psychiatric hospitals in Japan were surveyed using mail questionnaires. Respondents were asked to rate 15 items with four categories related to insufficiencies/difficulties in cancer care for patients with mental illness on a five-point Likert scale. We analyzed the proportion of respondents who answered "insufficient/difficult" for each item. RESULTS: A total of 255 (76.3%) psychiatric care providers responded. For questions related to the skills and attitudes of psychiatric professionals, 48.3%-58.4% of respondents perceived that efforts for supporting cancer screening and treatment were insufficient. For the questions related to collaborations between cancer and psychiatric care providers, 75.3% of respondents perceived that inpatient visits between psychiatric and cancer hospitals were insufficient. For the questions related to in-psychiatric-hospital medical systems, 50.2%-87.2% of respondents perceived that support for screening, diagnosis/treatment, and palliative care for psychiatric inpatients were insufficient/difficult. 41.9%-57.4% of respondents perceived that social services in the community were insufficient. CONCLUSIONS: This study clarified the level of insufficiency/difficulty perceived by psychiatric care providers regarding issues related to cancer care for people with mental illness. Psychiatric care providers are required to have knowledge and skills in cancer screening and treatment. To improve access to cancer prevention, treatment, and palliative care, it may be helpful to establish systems to promote coordination between cancer hospitals and psychiatric hospitals.

Four-repeat tauopathies and late-onset psychiatric disorders: Etiological relevance or incidental findings?

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n = 7; age at onset: 41-75 years), depressive disorder (n = 1; 49 years), bipolar disorder (n = 2; 32 and 37 years) and somatoform disorder (n = 1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

Secondary autoimmune hypothalamitis with severe memory impairment 7 years after the onset of diabetes insipidus due to lymphocytic hypophysitis: a case report.

BACKGROUND: Autoimmune hypothalamitis is a very rare neuroendocrine disorder that causes central diabetes insipidus, headache, visual impairment, and sometimes cognitive impairment. Autoimmune hypothalamitis may occur in association with autoimmune hypophysitis, including lymphocytic hypophysitis, or in isolation. It is not known whether autoimmune hypothalamitis and autoimmune hypophysitis are consecutive diseases. CASE PRESENTATION: A 52-year-old woman developed autoimmune hypothalamitis 7 years after developing central diabetes insipidus due to lymphocytic hypophysitis, resulting in severe memory impairment. High-dose intravenous methylprednisolone therapy improved her cognitive function and decreased the size of the lesion. CONCLUSION: This case presented a unique clinical course, with a long period of time between the onset of autoimmune hypopituitaritis and the development of autoimmune hypothalamitis.

The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms.

Anti-NMDAR encephalitis has a psychotic presentation that is difficult to distinguish from primary psychosis. An atypical psychosis that is similar to schizophrenia, mood disorder, and epilepsy is unique, and the original diagnostic criteria exist only in Japan. The clinical symptoms and courses of anti-NMDAR encephalitis and atypical psychosis are very similar. We investigated whether the diagnostic criteria of atypical psychosis are useful to increase the detection rate of anti-NMDAR encephalitis with psychiatric symptoms. The presence of anti-NR1/NR2B IgG antibodies in the cerebrospinal fluid of 218 newly admitted inpatients initially diagnosed with schizophrenia (n = 151), mood disorder (n = 47), or epilepsy with psychiatric symptoms (n = 20) was assessed by cell-based assay. Of 218 patients, 123 (36.3 years ± SD 17.2, 69.9 % females) fulfilled the diagnostic criteria of category B for atypical psychosis. All 12 patients (9.8 %, 12/123) with anti-NR1/NR2B IgG antibodies fulfilled category B of atypical psychosis statistically better than the patients without anti-NR1/NR2B IgG antibodies (P = 0.0009). Of the 12 patients with anti-NMDAR antibodies, two did not fulfill either criteria of catatonia (DSM-5) or Graus' diagnostic criteria of anti-NMDAR encephalitis during the time course, and 11 patients showed good prognosis with early immunotherapies. In ROC analysis, abnormal electroencephalogram findings showed the highest sensitivity (0.833) for detection of anti-NR1/NR2B IgG antibodies, and 31.3 % of patients with category B atypical psychosis and abnormal electroencephalogram findings had anti-NMDAR antibodies. Lumbar puncture and detection of anti-NMDAR antibodies should be considered for patients who fulfill atypical psychosis diagnosis criteria with an abnormal electroencephalogram.

Patients' acceptability and implementation outcomes of a case management approach to encourage participation in colorectal cancer screening for people with schizophrenia: a qualitative secondary analysis of a mixed-method randomised clinical trial.

OBJECTIVES: We examined the efficacy of case management (CM) interventions to encourage participation in colorectal cancer screening for patients with schizophrenia. This study aimed to clarify patients' acceptability of the intervention and the helpful components of the intervention. Simultaneously, the study aimed to determine the acceptability, appropriateness and feasibility of the intervention from the perspective of psychiatric care providers. STUDY DESIGN AND SETTING: This study was a secondary qualitative analysis of a mixed-method randomised controlled trial that evaluated the efficacy of the CM approach to encourage participation in cancer screening for people with schizophrenia. The intervention comprised education and patient navigation for colorectal cancer screening. Interviews were conducted with patients who received the intervention and staff from two psychiatric hospitals in Japan who delivered the intervention. PARTICIPANTS: Of the 172 patients with schizophrenia who participated in the trial, 153 were included. In addition, three out of six providers were included. DATA COLLECTION AND ANALYSIS: Using a structured interview, the case manager asked participants about patient acceptability and the helpful components of the intervention. Content analysis was conducted for the responses obtained, and the number of responses was tabulated by two researchers. For the interviews with the providers, opinions obtained from verbatim transcripts were extracted and summarised. RESULTS: Forty-three of the 56 patients perceived that the intervention was acceptable. For the intervention component, inperson counselling with an explanation of the screening process by psychiatric care providers was most frequently reported by the patients as helpful (48 of the 68 respondents). Psychiatric care providers evaluated the intervention as acceptable, appropriate and easy to understand and administer. However, providing the intervention to all patients simultaneously was considered difficult with the current human resources. CONCLUSIONS: This study showed that the CM intervention was perceived as acceptable by patients and acceptable and appropriate by psychiatric care providers. TRIAL REGISTRATION NUMBER: UMIN000036017.

Issues of cancer care in people with mental disorders as perceived by cancer care providers: A quantitative questionnaire survey.

OBJECTIVES: To reduce cancer care disparities, this study aimed to clarify the difficulties in cancer care for people with mental disorders as perceived by cancer care providers. METHODS: Cancer care providers at 17 designated cancer hospitals in Japan were surveyed using mail questionnaires. Respondents were asked to rate 29 items related to difficulties or insufficiencies in cancer care for patients with mental disorders on a five-point Likert scale. We analyzed the proportion of respondents who answered "difficult/insufficient" in each item. We also calculated the proportions of responders stratified according to the presence of psychiatric support systems within their hospitals. RESULTS: A total of 388 (58.4%) cancer care providers responded. Among the issues related to "difficulties in diagnosing and treating cancer," support for decision-making, assessment of treatment adherence, and assessment of physical symptoms were perceived as most difficult (73.5%-81.5% of respondents). Among the issues related to 'difficulties or insufficiencies in collaboration among multidisciplinary health care providers,' the issue of advance consultation and sharing information with the patient's primary psychiatric care provider was perceived as most difficult (52.2%). Among the issues related to "insufficiencies of in-hospital and community medical systems," education to provide reasonable accommodation was perceived as most insufficient (47.4%). The perceived difficulties of over half of the issues varied significantly between hospitals depending on the level of psychiatric support systems. CONCLUSIONS: This study clarified the difficulties of cancer care in patients with mental disorders as perceived by cancer care providers. Some issues may be resolved by psychiatric liaison teams.

Changes in Plasma Clozapine Levels after Smoking Cessation in Japanese Inpatients with Schizophrenia: A Retrospective Cohort Study.

Although reported for Caucasians, changes in plasma clozapine levels after smoking cessation in East Asians remain unclear. We here investigated plasma clozapine levels before and after smoking cessation in Japanese inpatients with schizophrenia. We conducted a retrospective chart review of 14 inpatients with schizophrenia who were being treated with clozapine between June 1, 2019, and July 31, 2019 and who were smokers as of July 1, 2019, the day on which a smoking ban was instituted in the tertiary public psychiatric hospital. The primary outcome was individual differences in plasma clozapine levels between before and after the smoking ban, which were compared using paired t-tests. The mean plasma clozapine level was significantly increased, by 213.4 ng/mL (95% CI 119.9-306.8; p<0.01) or 53.2%. Four of the 14 inpatients experienced clinically significant side effects, such as myoclonus, drooling, and amnesia, due to the development of high plasma clozapine levels. Our findings indicated that close monitoring of plasma clozapine levels before and after smoking cessation and prior dose adjustment of clozapine may be necessary, to prevent a significant risk of developing high plasma clozapine levels, even in Japanese patients.

Safety and Effectiveness of Perospirone in Comparison to Risperidone for Treatment of Delirium in Patients with Advanced Cancer: A Multicenter Prospective Observational Study in Real-World Psycho-Oncology Settings.

The clinical benefit of perospirone for treatment of delirium in patients with advanced cancer is not sufficiently clear. The objective of this study was to compare the safety and effectiveness of perospirone to those of risperidone for the treatment of delirium in patients with advanced cancer. This is a secondary analysis of a multicenter prospective observational study in nine psycho-oncology consultation services in Japan. The study used the Delirium Rating Scale (DRS) Revised-98 to measure effectiveness and the CTCAE (Common Terminology Criteria for Adverse Events) version 4 to assess safety. Data from 16 patients who received perospirone and 53 patients who received risperidone were analyzed. The mean age was 70 years in the perospirone group and 73 years in the risperidone group. Both groups showed a significant decrease in the total score of DRS-R-98 after three days of treatment (perospirone: 11.7 (7.9-15.4) to 7.0 (3.3-10.7), difference -4.7, effect size=0.72, p=0.003; risperidone: 15.5 (13.6-17.4) to 12.2 (10.1-14.2), difference -3.3, effect size=0.55, p=0.00). The risperidone group showed significant improvements in sleep-wake cycle disturbance, orientation, attention, and visuospatial ability. In the perospirone group, there was a significant improvement of sleep-wake cycle disturbance. The median daily dose of perospirone was 4 mg/day. There were fewer episodes of somnolence as an adverse event in the perospirone group. Low-dose perospirone was thus found to be effective for the treatment of delirium in patients with advanced cancer and may be associated with fewer episodes of over-sedation as an adverse event.

Prevalence of Gender Dysphoria by Gender and Age in Japan: A Population-Based Internet Survey Using the Utrecht Gender Dysphoria Scale.

BACKGROUND: Several studies have attempted to estimate the prevalence of gender dysphoria (GD) from a general population sample. However, no previous studies used reliable questionnaires. AIM: To estimate the prevalence of GD in Japan by gender and age using the Utrecht Gender Dysphoria Scale (UGDS). METHODS: A cross-sectional observational study was conducted with 20,000 respondents between the ages of 20 and 69 who were registered with an internet research company. The study consisted of two phases. First, the participants were asked to self-identify their gender on two 5-point Likert scales. Second, the screened participants completed the UGDS. OUTCOMES: Self-identified gender and GD were defined as follows: ambivalent gender (equally feeling like the birth gender and another gender), incongruent gender (a stronger sense of the latter vs the former), narrow GD (incongruent gender + UGDS score ≥ 41), and broad GD (ambivalent or incongruent gender + UGDS score ≥ 41). RESULTS: Among the eligible participants, the age-adjusted proportions of those classified as male (n = 7827) and female (n = 8903) at birth were 6.0% and 5.9%, respectively, for ambivalent gender, and 0.93% and 1.0%, respectively, for incongruent gender. The age-adjusted prevalence of GD was 0.27% (95% confidence interval, 0.18-0.42) and 0.35% (95% confidence interval, 0.25-0.50) for narrow GD and 0.87% (95% confidence interval, 0.69-1.1) and 1.1% (95% confidence interval, 0.86-1.3) for broad GD, respectively. No significant gender differences were found within the age groups, except for broad GD in respondents in their 50s (P = .016). However, for both genders, significant differences were found between age groups such that GD was more prevalent in younger vs older respondents, except for broad GD in respondents classified as female at birth (P = .063). CLINICAL IMPLICATIONS: Clinicians should be aware that the prevalence of GD is not negligible and that it varies with age. GD should be assessed in detail from various perspectives in addition to self-identified gender. STRENGTHS & LIMITATIONS: This study used a reliable questionnaire to examine the prevalence of GD in a large population. However, the participants did not represent the general population because this was an internet survey. CONCLUSION: The prevalence of GD was much higher than previously estimated by clinic-based studies, and was more frequently associated with participant age vs gender. Oshima Y, Matsumoto Y, Terada S, et al. Prevalence of Gender Dysphoria by Gender and Age in Japan: A Population-based Internet Survey Using the Utrecht Gender Dysphoria Scale. J Sex Med 2022;19:1185-1195.

Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: An exploratory analysis.

BACKGROUND: Nalmefene is the only medication marketed to reduce the consumption of alcohol in patients with alcohol dependence, but it remains unclear which patients could most benefit from it. This study aimed to identify clinical moderators that affect treatment response to nalmefene in patients with alcohol dependence. METHODS: In a multicenter, randomized, controlled, double-blind, phase 3 study of nalmefene on Japanese patients with alcohol dependence, the relationship between the reduction of heavy drinking days (HDD) and total alcohol consumption (TAC) at 12 and 24 weeks of treatment and baseline variables of the participants were analyzed in a linear regression and multiple adjusted analysis. RESULTS: Age < 65, no family history of problem drinking, age at onset of problem drinking ≥ 25, and not currently smoking were possible positive moderators. Nalmefene showed a significant HDD reduction in patients with age < 65 or no family history of problem drinking, and a significant TAC reduction in patients with age at onset of problem drinking ≥ 25 or who were not currently smoking. After multiple adjusted analyses, age < 65 (p = .028), no family history of problem drinking (p = .047), and age at onset of problem drinking ≥ 25 (p = .030) were statistically significant. Not currently smoking (p = .071) was marginally significant. In combination, these moderators indicated synergistic effects. CONCLUSIONS: Alcohol-dependent patients with favorable prognostic factors such as non-smoking status, no family history of problem drinking, and a late-onset of problem drinking selectively benefit from nalmefene. Further research is needed to validate these exploratory results.