Abstract
Aim
The Effectiveness of Guideline for Dissemination and Education in Psychiatric Treatment (EGUIDE) project has improved psychiatrists' adherence to guidelines and their treatment behavior for hospitalized patients. However, treatment behavior toward outpatients has not been sufficiently investigated. This study aimed to examine the effects of the EGUIDE program on the clinical behavior of psychiatrists toward outpatients with major depressive disorder (MDD).
Methods
A comparative study was conducted among outpatients at seven facilities. The study included 255 patients who had received a primary diagnosis of MDD at the initial visit and had been followed for 6 months or more since the initial visit. The prescription types were investigated at the 6‐month follow‐up. The primary outcomes were the rate of severity diagnosis, the rate of antidepressant monotherapy without other psychotropics, the rate of antidepressant monotherapy, the rate of no anxiolytic/hypnotic prescriptions, and the rate of intermittent psychotropic medication prescription. The secondary outcomes were the imipramine equivalent dose of antidepressants and the diazepam equivalent dose of anxiolytics/hypnotics.
Results
Patients treated by psychiatrists who were participating in the EGUIDE project had a significantly higher rate of severity diagnosis than patients treated by psychiatrists who were not participating in the EGUIDE project. However, there were no significant differences in the other primary outcomes. In terms of the secondary outcomes, the diazepam equivalent dose was significantly lower in patients treated by psychiatrists who were participating in the EGUIDE project.
Conclusion
Participation in the EGUIDE project was associated with improved severity diagnosis rates among outpatients with MDD, but its effect on prescribing behaviors was limited.
Keywords: depression, EGUIDE, guideline, polypharmacy, severity diagnosis
INTRODUCTION
The standardization of major depressive disorder (MDD) treatment is an urgent issue. We launched the Effectiveness of Guideline for Dissemination and Education in Psychiatric Treatment (EGUIDE) project to investigate the clinical behavior of psychiatrists toward hospitalized patients with schizophrenia and MDD and to address the gap between treatments recommended in guidelines and actual clinical practice. 1 , 2 , 3 , 4 Our reports indicate that participation in the EGUIDE project increases the knowledge, confidence, and clinical behavior of psychiatrists in accordance with the guidelines. 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 However, there were approximately 27,000 hospitalized patients with mood disorders in Japan in 2023, whereas there were approximately 1.57 million patients treated as outpatients, indicating that the majority of patients with mood disorders are treated in an outpatient setting. 11 We expect that investigating the clinical behaviors of psychiatrists participating in the EGUIDE project will clarify the issues in the treatment of outpatients with MDD and promote treatment better aligned with guidelines for MDD.
The treatment guidelines for MDD recommend different treatments on the basis of severity. 12 When deciding on a treatment plan in accordance with the guidelines, determining the severity of symptoms is essential. However, the severity diagnosis rate for depression in young people is reported to be approximately 50%. 13 The severity diagnosis rate for hospitalized patients with MDD is reported to be 56.8%. 14 Polypharmacy is still widespread among patients receiving pharmacotherapy. Monotherapy with antidepressants is recommended in the guidelines; however, the proportion of patients receiving antidepressant monotherapy is reported to be 60% on average. 3 , 15 Furthermore, although the long‐term use of anxiolytics/hypnotics is not recommended in the guidelines, concomitant use has been reported in many patients. 16
We previously investigated prescriptions for 147 patients with MDD who were continuing outpatient treatment, comparing prescriptions before and after participation in the EGUIDE project at a single facility. Although the use of benzodiazepines significantly decreased after participation in the EGUIDE project, the rate of monotherapy with antidepressants did not increase even after participation in the EGUIDE project. 9 However, the rate of severity diagnosis for outpatients with MDD has not been investigated. In addition, the previous study was limited to patients with MDD who received treatment continuously for three years at a single facility; therefore, the generalizability of the results is unclear. In this study, we investigated whether psychiatrists who participated in the EGUIDE project increased their guideline‐compliant clinical behaviors by conducting a prescription survey of patients with MDD followed for 6 months or more since diagnosis at seven facilities.
METHODS
This study was approved by the Ethics Committee of the National Center of Neurology and Psychiatry (NCNP). All procedures were conducted in accordance with the Declaration of Helsinki. The protocol for this study was registered with the University Hospital Medical Information Network (UMIN000022645). Written informed consent was obtained from all participants after a sufficient explanation of the study was provided. The EGUIDE program was conducted as previously reported. 1 , 4 In brief, the EGUIDE participants received approximately 2 h of education covering discrimination due to physical illnesses and other mental disorders, diagnostic criteria for MDD, and the consideration of severity in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5), methods of medical history collection, and review of treatment plans. Next, multiple groups discussed and presented treatment planning for two hypothetical cases and received explanations and feedback from other groups and the facilitators. Following the sessions, the participants were administered web questionnaires about their accordance with the clinical practice guidelines, and treatment data for patients with MDD were collected from the participating facilities every year. These results were fed back to each participant and facility to encourage continuous guideline learning.
This study included patients who had their first visit at one of the seven facilities (Akita University Hospital, Iwate Medical University Hospital, The University of Tokyo Hospital, Dokkyo Medical University Hospital, Ehime University Hospital, Kokoro Hospital Machida, and Katsumoto Mental Clinic) between April and September 2021 and April and September 2022 and whose primary diagnosis at the first visit was MDD. Patients of any age or sex were eligible. The attending psychiatrist at each facility made the diagnosis on the basis of the clinical interview. Patients who had been visiting the hospital for at least 6 months after their first visit were selected. If the attending psychiatrist changed within 6 months of the first visit, the psychiatrist who had treated the patient for at least 3 months was considered the new attending psychiatrist. Patients who met any of the following criteria were excluded from the study: (1) had no attending psychiatrist provide treatment for more than 3 months; (2) had a change in the primary diagnosis to a diagnosis other than MDD between the first visit and the follow‐up visit (after 6 months); and (3) had a history of hospitalization in a psychiatric ward between the first visit and the follow‐up visit.
We investigated the severity of MDD at the initial visit. The rate at which depression severity was diagnosed was determined based on whether the attending psychiatrist recorded the severity in the medical chart. The prescription data were collected at the follow‐up visit 6 months after the initial visit, assuming a maintenance therapy period following the acute phase. We compared patients treated by attending psychiatrists who had participated in the EGUIDE project with those who were not treated by such psychiatrists. The primary outcomes for guideline adherence were the rate of diagnosis of depression severity, the rate of antidepressant monotherapy without other psychotropics, the rate of antidepressant monotherapy, the rate of no hypnotic and anxiolytic prescriptions, and the rate of prescription of intermittent psychotropic prescriptions. As secondary outcomes, we examined the antidepressant‐equivalent dose of imipramine and the anxiolytic/hypnotic‐equivalent dose of diazepam (excluding orexin receptor antagonists and ramelteon). The doses of antidepressants and anxiolytics/hypnotics were calculated using a previously reported method. 17
Fisher's exact test was used to calculate the odds ratio and test the proportion of nominal variables. The odds ratio for age was obtained using univariate logistic regression analysis. The Shapiro–Wilk normality test was used for normality, and the Mann–Whitney U test was used to compare two groups of continuous variables. Using the Bonferroni correction, statistical significance was considered when the p value was less than 0.0083 (0.05/6) for the Shapiro–Wilk normality test (age in Table 1 and doses of antidepressants and anxiolytics/hypnotics in Table 4 in the EGUIDE group and the non‐EGUIDE group), less than 0.0056 (0.05/9) for Fisher's exact test (sex, institution, and no prescription before first visit in Table 1, each indicator in Table 2, and severity of depression in Supplementary Material S1), and less than 0.017 (0.05/3) for the Mann–Whitney U test (age in Table 1 and doses of antidepressants and anxiolytics/hypnotics in Table 4). For the severity diagnosis rate, we performed multivariate logistic regression analysis with EGUIDE program participation, no prescription before the first visit, age, sex, and institution as explanatory factors and adjusted the odds ratio. The statistical analysis was performed using EZR software version 1.68 (http://www.jichi.ac.jp/saitama‐sct/SaitamaHP.files/statmedEN.html). 18
Table 1.
Characteristics of patients with major depressive disorder.
| EGUIDE (+) | EGUIDE (−) | p value | |
|---|---|---|---|
| Number of patients | 144 | 111 | |
| Age, years | |||
| Median | 46 | 45 | 0.70 |
| IQR | 32–65 | 34–63 | |
| Range | 15–83 | 13–94 | |
| Sex, no. (%) | |||
| Male | 64 (44.4) | 52 (46.8) | 0.71 |
| Female | 80 (55.6) | 59 (53.2) | |
| Institution, no. (%) | |||
| University hospitals | 117 (81.3) | 46 (41.4) | 5.6 × 10 −11 |
| Private hospitals and clinics | 27 (18.8) | 65 (58.6) | |
| No prescription before first visit, no. (%) | 72 (50.0) | 44 (39.6) | 0.13 |
Note: Significant differences are shown in bold.
Abbreviations: EGUIDE (+), patients treated by psychiatrists participating in the EGUIDE project; EGUIDE (−), patients treated by psychiatrists not participating in the EGUIDE project; IQR, interquartile range.
Table 4.
Comparison of the doses of antidepressants and anxiolytics/hypnotics by participation in the EGUIDE project.
| EGUIDE (+) | EGUIDE (−) | p value | |
|---|---|---|---|
| Dose of antidepressants (mg/day) | |||
| Median | 75 | 75 | 0.84 |
| IQR | 0–150 | 30–150 | |
| Range | 0–525 | 0–325 | |
| Dose of anxiolytics/hypnotics (mg/day) | |||
| Median | 0 | 2 | 5.6 × 10 −4 |
| IQR | 0–3 | 0–8 | |
| Range | 0–24 | 0–30 | |
Note: Significant differences are shown in bold.
Abbreviations: EGUIDE (+), patients treated by psychiatrists participating in the EGUIDE project; EGUIDE (−), patients treated by psychiatrists not participating in the EGUIDE project; IQR, interquartile range.
Table 2.
Comparison of each indicator by participation in the EGUIDE project.
| EGUIDE (+) | EGUIDE (−) | OR [95% CI] | p value | |
|---|---|---|---|---|
| Severity diagnosis, no. (%) | 104 (72.2) | 18 (16.2) | 13.3 [6.94–26.5] | 9.1 × 10 −20 |
| Antidepressant monotherapy without other psychotropics, no. (%) | 55 (38.9) | 30 (27.0) | 1.67 [0.94–2.97] | 0.063 |
| Antidepressant monotherapy, no. (%) | 96 (66.7) | 87 (78.4) | 0.55 [0.30–1.01] | 0.049 |
| No prescription of anxiolytics or hypnotics, no. (%) | 81 (56.3) | 46 (41.4) | 1.81 [1.07–3.09] | 0.023 |
| No intermittent psychotropics, no. (%) | 121 (84.0) | 98 (88.2) | 0.70 [0.31–1.53] | 0.37 |
Note: Significant differences are shown in bold.
Abbreviations: CI, confidence interval; EGUIDE (+), patients treated by psychiatrists participating in the EGUIDE project; EGUIDE (−), patients treated by psychiatrists not participating in the EGUIDE project; OR, odds ratio.
RESULTS
The characteristics of the patients with MDD in this study are shown in Table 1. Patients treated by psychiatrists participating in the EGUIDE project (the EGUIDE group) had a significantly higher rate of university hospital patients than by psychiatrists not participating in the EGUIDE project (the non‐EGUIDE group). No significant differences were observed between the EGUIDE group and the non‐EGUIDE group in terms of age, sex, or prescription history before the initial visit. In terms of primary outcome measures, the EGUIDE group had a significantly higher rate of severity diagnosis (Table 2). Among patients whose depression severity was recorded, there were no significant differences in the proportions of mild, moderate, severe, or psychotic depression between the EGUIDE group and the non‐EGUIDE group (Supplementary Material S1). On the other hand, there were no significant differences between the two groups in terms of the rate of antidepressant monotherapy without other psychotropics, the rate of antidepressant monotherapy, the rate of no anxiolytic/hypnotic prescriptions, or the rate of intermittent psychotropic medication prescriptions.
We performed a multivariate logistic regression analysis of psychiatrist participation in the EGUIDE project and age, sex, facility, and prescription history before the initial visit as explanatory variables to evaluate the effects of factors contributing to severity diagnosis (Table 3). All explanatory variables had sufficiently small variance inflation factor (VIF) values, indicating minimal multicollinearity. Psychiatrist participation in the EGUIDE project and no prescription history before the initial visit were associated with the severity diagnosis rate, with adjusted odds ratios of 11.0 (95% confidence interval [CI]: 5.66–21.5, p < 0.001) and 2.18 (95% CI: 1.16–4.09, p = 0.015), respectively. Other factors were not associated with the severity diagnosis.
Table 3.
Logistic regression analysis adjusting for the effects of each explanatory factor on severity diagnosis.
| Objective factor | Explanatory factor | VIF | Unadjusted | Adjusted | ||
|---|---|---|---|---|---|---|
| OR [95% CI] | p value | OR [95% CI] | p value | |||
| Severity diagnosis | EGUIDE | 1.1 | 13.3 [6.94–26.5] | 9.1 × 10−20 | 11.0 [5.66–21.5] | 1.8 × 10 −12 |
| Age | 1.0 | 1.00 [0.99–1.02] | 1 | 1.01 [0.99–1.02] | 0.35 | |
| University | 1.2 | 3.35 [1.89–6.05] | 8.8 × 10−6 | 1.76 [0.87–3.55] | 0.11 | |
| Female | 1.0 | 1.24 [0.74–2.11] | 0.45 | 1.23 [0.67–2.27] | 0.50 | |
| No prescription before first visit | 1.1 | 1.95 [1.15–3.32] | 0.012 | 2.18 [1.16–4.09] | 0.015 | |
Note: Significant differences are shown in bold.
Abbreviations: CI, confidence interval; OR, odds ratio; VIF, variance inflation factor.
Compared with the non‐EGUIDE group, the EGUIDE group had significantly lower anxiolytics/hypnotic doses (Table 4). No significant differences were observed in the antidepressant doses between the EGUIDE group and the non‐EGUIDE group.
DISCUSSION
The severity diagnosis rate for patients treated by psychiatrists participating in the EGUIDE project was 72.2%, which was significantly higher than that of 16.2% for those treated by psychiatrists not participating in the EGUIDE project. The adjusted odds ratio was also high at 11.0. Severity diagnosis is one of the most important factors in determining whether the treatment provided is in compliance with the guidelines for patients with MDD. 12 , 19 , 20 , 21 A previous real‐world survey of inpatients at 51 hospitals reported that the diagnosis rate for severe depression was 56.8% and that the rates of electroconvulsive therapy and antipsychotic drug use varied depending on the severity of depression. Although the causal relationship between EGUIDE project participation and severity diagnosis rates is unclear, the EGUIDE program focuses not only on the pharmacological treatment of MDD but also on the formulation of treatment plans. 4 The recommended treatments in the guidelines are often based on evidence from rigorous double‐blind clinical studies in patients with a confirmed diagnosis. However, in real‐world practice, treatment begins with gathering information, evaluating symptoms, and diagnosing MDD. Therefore, MDD guidelines in various countries devoted many pages to the diagnosis and assessment of MDD. 12 , 19 , 20 , 21 Education on basic medical interviews, assessments, and diagnoses is essential for guideline utilization. We developed the individual fitness score (IFS) as an indicator of whether the treatment of individual patients complies with MDD treatment guidelines, and the severity of MDD is a mandatory item in the calculation of the IFS. 22 The impact of EGUIDE project participation on treatment planning, including the IFS and depression rating scales, needs to be verified.
In this prescription survey of outpatients with MDD, there were no significant differences between the patients treated by psychiatrists participating in the EGUIDE project and those treated by psychiatrists not participating in the EGUIDE project with respect to the rate of antidepressant monotherapy without other psychotropics, the rate of antidepressant monotherapy, the rate of no anxiolytic/hypnotic prescriptions, or the rate of intermittent psychotropic drug prescriptions. Among inpatients with MDD, the rate of antidepressant monotherapy without other psychotropics and the rate of no anxiolytic/hypnotic prescriptions were reported to be higher in patients treated by psychiatrists participating in the EGUIDE project. 4 The low frequency of medical visits and lower severity of symptoms among outpatients than among inpatients may influence the prescribing behavior of psychiatrists. Previous reports have shown that outpatients with depressive symptoms have lower Patient Health Questionnaire‐9 (PHQ‐9) scores and higher rates of selective serotonin reuptake inhibitor (SSRI) monotherapy than inpatients do. 23 In this study, the overall rate of antidepressant monotherapy exceeded 70%, suggesting that it may be difficult to assess the effects of the EGUIDE project in outpatient settings.
In terms of the secondary endpoints, psychiatrists participating in the EGUIDE project appeared to be working to reduce anxiolytic/hypnotic prescriptions. However, there was no significant difference in the rate of no hypnotic or anxiolytic prescriptions between the EGUIDE group and the non‐EGUIDE group. These results suggest that once anxiolytics/hypnotics are initiated, withdrawal is difficult. Benzodiazepines are associated with addiction, cognitive impairment, and paradoxical reactions. 24 This field requires intensive training in future EGUIDE projects.
This report reinforces the importance of the EGUIDE project, but there are several limitations. First, although patients were diagnosed and had their severity assessed by attending psychiatrists, how specific clinical symptoms were evaluated remains unclear. The EGUIDE program provides education on the diagnosis of MDD and the assessment of severity in accordance with the DSM‐5; however, the data in this analysis do not include whether the diagnosis and determination of severity were made in accordance with the DSM‐5. Second, no evaluation of treatment efficacy was conducted. Whether diagnosing severity and providing guideline‐based treatment are beneficial for patients remains unclear, and this study lacks the information necessary to make that determination. The more rigorous the assessment of treatment efficacy is, the more difficult it is to evaluate in real‐world practice due to patient selection bias, which is a limitation of this study. Third, the severity of depression may have influenced the primary outcome. For example, in mild depression, pharmacotherapy is recommended only as needed, potentially lowering the rate of antidepressant monotherapy. 12 In depression with psychotic symptoms, combination therapy with antidepressants and antipsychotics is the recommended treatment; therefore, antidepressant monotherapy without other psychotropics does not constitute the recommended treatment. 12 In our data for this paper, no significant difference in severity rates was observed between the EGUIDE group and the non‐EGUIDE group (Supplementary Material S1). Future research should utilize clinical indicators, such as IFS, tailored to severity. Fourth, patient background factors (such as comorbidities and socioeconomic status) were not sufficiently adjusted for in the analysis. These factors may have influenced both prescribing and diagnostic practices. Finally, significantly more university hospital patients were treated by psychiatrists participating in the EGUIDE project than by psychiatrists not participating in the EGUIDE project. In general, outpatients have fewer people involved in their diagnosis and treatment than inpatients do, and the decisions of attending psychiatrists are more directly reflected in treatment. The effect of different facilities on outpatients is considered smaller than that on inpatients. After adjustment using multivariate logistic analysis, the significant differences in facility differences in terms of severity diagnosis were not detected. To evaluate the effectiveness of the EGUIDE project across facilities, the following questions are presented as future research topics: Does selection bias within educational institutions facilitate the implementation of EGUIDE training content into clinical practice? Do academic conferences and other activities at the university make it more difficult to apply personal treatment approaches, thereby reducing training effectiveness? Do indirect training effects extend to individuals who did not participate in the training?
CONCLUSION
The depression severity diagnosis rate was high among patients treated by psychiatrists participating in the EGUIDE project; however, the effect on improving prescribing practices, including antidepressant monotherapy, was limited. Future challenges include updating the EGUIDE project while investigating whether adherence to the guidelines leads to symptom improvement in patients.
AUTHOR CONTRIBUTIONS
Hirotaka Yamagata: Conceptualization; methodology; formal analysis; investigation; resources; data curation; writing—original draft; writing—review and editing; visualization. Kenta Ide: Methodology; validation; formal analysis; investigation; resources; data curation; writing—review and editing. Shinichiro Ochi: Methodology; investigation; resources; writing—review and editing. Jun‐ichi Iga: Methodology; investigation; resources; writing—review and editing. Kentaro Fukumoto: Methodology; investigation; resources; writing—review and editing. Kayo Ichihashi: Methodology; investigation; resources; writing—review and editing. Eiichi Katsumoto: Methodology; investigation; resources; writing—review and editing. Masahiro Takeshima: Methodology; investigation; resources; writing—review and editing. Kota Imai: Methodology; investigation; resources; writing—review and editing. Yumi Shimamura: Methodology; investigation; resources; writing—review and editing. Junya Matsumoto: Methodology; data curation; writing—review and editing. Naomi Hasegawa: Methodology; data curation; writing—review and editing. Yasushi Kawamata: Investigation; writing—review and editing; supervision. Takashi Tsuboi: Investigation; writing—review and editing; supervision. Shusuke Numata: Investigation; writing—review and editing; supervision. Kazutaka Ohi: Investigation; writing—review and editing; supervision. Koichiro Watanabe: Conceptualization; methodology; investigation; writing—review and editing; supervision; project administration. Hisashi Yamada: Conceptualization; methodology; investigation; writing—review and editing; supervision; project administration. Hikaru Hori: Conceptualization; methodology; investigation; writing—review and editing; supervision; project administration. Ryota Hashimoto: Conceptualization; methodology; investigation; data curation; writing—review and editing; supervision; project administration; funding acquisition. Norio Yasui‐Furukori: Conceptualization; methodology; investigation; data curation; writing—review and editing; supervision; project administration; funding acquisition.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ETHICS APPROVAL STATEMENT
This study was approved by the Ethics Committees of the NCNP.
PATIENT CONSENT STATEMENT
Patient data were collected at each facility in the EGUIDE project. An opt‐out option was provided.
CLINICAL TRIAL REGISTRATION
The protocol for this study was registered with the University Hospital Medical Information Network (UMIN000022645).
DECLARATION OF GENERATIVE AI AND AI‐ASSISTED TECHNOLOGIES IN THE WRITING PROCESS
The authors used DeepL Pro to proofread the English. After using this tool, the authors reviewed and edited the content as necessary and take full responsibility for the content of this paper.
Supporting information
Supporting Information.
ACKNOWLEDGMENTS
The authors thank all the instructors and facility managers in the EGUIDE project. This study was supported by the Japan Agency for Medical Research and Development (AMED) (Grant Numbers JP16dk0307060, JP19dk0307083, and JP22dk0307112), the Japan Society for the Promotion of Science (JSPS) Grant‐in‐Aid for Scientific Research (Grant Numbers JP21K17261 and JP23K16273), the Ministry of Health, Labour and Welfare, Japan (Grant Numbers H29‐Seishin‐Ippan‐001 and 19GC1012), the Japanese Society of Neuropsychopharmacology, the Japanese Society of Mood Disorders, the Japanese Society of Clinical Neuropsychopharmacology, and the Japanese Society of Psychiatry and Neurology. The funders had no involvement in the research design, data collection and analysis, decision to publish, or preparation of the manuscript.
Yamagata H, Ide K, Ochi S, Iga J‐i, Fukumoto K, Ichihashi K, et al. Clinical behavior toward outpatients with major depressive disorder based on guideline education for psychiatrists. Psychiatry Clin Neurosci Rep. 2025;4:e70275. 10.1002/pcn5.70275
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.