Abstract
Objective
Benzodiazepines (BZPs) continue to be widely prescribed in non-psychiatric settings, despite clinical guideline recommendations favouring selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) for the treatment of anxiety and depressive disorders. Long-term, hospital-based evidence comparing these prescribing patterns in Japan remains limited. The study aim was to evaluate long-term trends in BZP prescribing relative to SSRI/SNRI use and to identify factors associated with anxiolytic BZP versus SSRI/SNRI prescriptions.
Methods
We conducted a database study of all 16,886,524 prescriptions issued between April 2001 and March 2022 at a tertiary university hospital in Japan. Anxiolytic and hypnotic BZPs, SSRIs, SNRIs, and related antidepressants were identified. The ratio of anxiolytic BZP to SSRI/SNRI prescriptions (B/S ratio) was calculated according to department group. Factors associated with anxiolytic BZP versus SSRI/SNRI prescribing were examined using multiple logistic regression analysis.
Results
Anxiolytic BZP prescriptions accounted for 2.3% of all prescriptions and declined over time, whereas SSRI/SNRI prescriptions (1.4%) remained largely stable throughout the study period. The B/S ratio was consistently higher in internal medicine than in psychiatry, although a gradual reduction was observed over time. Multivariable analysis demonstrated that anxiolytic BZP prescribing was independently associated with the internal medicine department, female sex, outpatient status, younger age, and earlier calendar years.
Conclusion
Despite a temporal decline, anxiolytic BZPs continue to be preferentially prescribed over SSRIs/SNRIs in non-psychiatric settings. These findings underscore persistent gaps between evidence-based recommendations and clinical practice and highlight the need for targeted educational and policy interventions to optimise psychotropic prescribing.
Keywords: Benzodiazepines, Prescriptions, Selective serotonin reuptake inhibitors, Serotonin and noradrenaline reuptake inhibitors
INTRODUCTION
Although benzodiazepines (BZPs) may represent an appropriate therapeutic option in specialised settings, such as for the short-term management of acute anxiety [1], the risk of inappropriate overprescribing and subsequent long-term use remains substantial in primary care settings [2]. Accordingly, BZP prescriptions should be carefully monitored, particularly in non-psychiatric clinics, given the psychopharmacological properties and dependence potential of these agents [3]. Long-term BZP use has been associated with tolerance, dependence, withdrawal symptoms, cognitive impairment, and an increased risk of falls, particularly in older adults [1-3].
In Japan, patients have a relatively high threshold before seeking care at psychiatric clinics [4], and it has been estimated that 60−70% of patients with depression initially present to internal medicine clinics rather than to psychiatric services [5]. For example, our previous study demonstrated that the prevalence of major depressive disorder was 32% among chronic BZP users attending internal medicine clinics [6].
Since the 1980s, selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) have been introduced into clinical practice and are currently recommended as first-line treatments for depression [7], as well as for various anxiety disorders [8]. Compared with BZPs, these agents are considered more appropriate for long-term treatment because they carry a lower risk of dependence and tolerance [7,8]. Although these agents have been approved for use in Japan since 1998, no hospital-based longitudinal studies have documented both excessive BZP prescribing and trends in SSRI/SNRI prescribing in Japanese clinical settings.
Under these circumstances, we previously reported the volume of BZP prescriptions issued between September 2002 and August 2003 in the outpatient clinics of a Japanese university hospital [9]. That study revealed that BZP prescriptions were highly prevalent among more than 644,000 prescriptions issued annually and suggested that excessive BZP use was attributable, at least in part, to prescribing practices by internists and other non-psychiatric physicians. However, the analysis was limited to outpatient settings and covered only a single year. Given that multiple new SSRIs and SNRIs have been successively introduced over the past two decades [10], an examination of long-term trends in prescriptions of both BZPs and SSRIs/SNRIs is warranted.
The present study investigated temporal changes in BZP prescribing over a 21-year period in a single university hospital distinct from that examined in our previous study [9]. During this period, new electronic medical systems were implemented, enabling the integration of all medical records and the construction of a comprehensive clinical database. Using this database, we compared BZP prescriptions with prescriptions of SSRIs, SNRIs, and other antidepressants over time, stratified by prescribing department.
METHODS
Study Setting
This database study counted the exact number of all prescriptions issued at a university hospital between 1 April 2001 and 31 March 2022. The hospital is a tertiary care centre with 689 licensed beds; approximately 60,000−70,000 patients visit the hospital annually. It is located in a metropolitan area of Japan. Each prescription recorded in the hospital information system was counted as an individual prescription event. Repeated prescriptions for the same patient were therefore counted separately. The database used in this study was designed primarily for administrative prescription recording and did not include detailed information on prescription duration, dosage, cumulative exposure, or patient-level longitudinal treatment trajectories. There were no missing data in this study, as all clinical activities, including medical prescribing, were conducted using a hospital-wide computerised system [11].
During the study period, 23 hospital departments were categorised into four groups: internal medicine (general internal medicine, respiratory medicine, gastroenterology, cardiology, endocrinology, and palliative care), psychiatry (general psychiatry), surgery (general surgery, neurosurgery, cardiac surgery, thyroid surgery, orthopaedics, plastic surgery, obstetrics and gynaecology, ophthalmology, otorhinolaryngology, dermatology, urology, oral surgery, and anaesthesia), and others (paediatrics, radiology, and emergency medicine).
In total, 1,305,506 patients were registered during the study period. The cumulative number of hospital visits was 15,589,000, and the total number of hospitalisations was 1,579,000. The most frequent ICD-10 diagnoses in the internal medicine group were angina pectoris (6.7%), acute upper respiratory inflammation (5.6%), bronchitis (4.7%), gastric ulcer (4.5%), acute gastroenteritis (4.2%), hypertension (2.9%), diabetes mellitus (2.5%), constipation (2.4%), bronchial asthma (2.4%), and tension-type headache (2.2%). In the psychiatry group, the most frequent diagnoses were major depression (29.5%), schizophrenia (11.3%), anxiety disorders (9.8%), bipolar disorder (5.9%), epilepsy (5.1%), adjustment disorder (3.8%), delirium (3.2%), eating disorders (1.8%), somatoform disorders (1.7%), and alcohol dependence (1.6%).
Prescriptions Assessed
In total, 24 BZPs are approved for prescription in Japan. These BZPs are classified by the Japanese Ministry of Health, Labour, and Welfare [12] into 14 anxiolytic BZPs (alprazolam, bromazepam, chlordiazepoxide, clorazepate dipotassium, clotiazepam, cloxazolam, diazepam, ethyl loflazepate, etizolam, lorazepam, medazepam, mexazolam, oxazolam, and tofisopam) and 10 hypnotic BZPs (brotizolam, estazolam, flunitrazepam, flurazepam, haloxazolam, lormetazepam, nitrazepam, quazepam, rilmazafone hydrochloride, and triazolam). Although etizolam has been approved by the Japanese Ministry of Health, Labour, and Welfare for use as both an anxiolytic and a hypnotic BZP, it was classified as an anxiolytic BZP for the purposes of analysis in this study. All BZPs included in the analysis had been approved for prescription by 2000.
Four SSRIs (escitalopram [2011], fluvoxamine [1999], paroxetine [2000], and sertraline [2006]); three SNRIs (duloxetine [2010], milnacipran [2000], and venlafaxine [2015]); and two related agents (mirtazapine [2009] and vortioxetine [2019]) have been registered for prescription at the study hospital (years in parentheses indicate approval in Japan). In this study, prescriptions for these agents were compared to BZP prescriptions. In addition, eight tricyclic antidepressants (amitriptyline, amoxapine, clomipramine, dosulepin, imipramine, lofepramine, nortriptyline, and trimipramine) and four other antidepressants (maprotiline, mianserin, setiptiline, and trazodone) were included to calculate the total number of antidepressant prescriptions.
Data Analysis
The data were analysed using the SAS Statistical Package (SAS Institute) [13]. Based on the definition used in a previous study [9], the ratio of the number of anxiolytic BZP prescriptions (excluding hypnotic BZPs) to the numbers of prescriptions of SSRIs, SNRIs, and related agents was calculated as an indicator (the B/S ratio) to compare BZP prescribing with antidepressant prescribing. This indicator was intended to reflect the potential for substituting some anxiolytic BZPs with SSRIs or SNRIs in clinical practice. The B/S ratio was assessed according to department group.
Multiple logistic regression analysis was then performed to construct a model explaining the tendency toward prescribing either an anxiolytic BZP or an SSRI/SNRI, focusing on differences between the internal medicine and psychiatry groups. Independent variables included department group (internal medicine or psychiatry), patient age (years), patient sex (female or male), hospitalisation status (inpatient or outpatient), and calendar year. A two-sided p value of < 0.05 was considered statistically significant.
The study was approved by the university ethics committee (22-038-A), and was listed in the information disclosure regarding clinical research at the university (https://www.showa-u.ac.jp/research/activitiy/opt_out.html).
RESULTS
BZP Prescriptions
BZP prescriptions accounted for 4.4% (n = 738,096/16,886,524) of the total number of prescriptions; anxiolytic BZPs comprised 2.3% (n = 390,413/16,886,524) and hypnotic BZPs comprised 2.1% (n = 347,683/16,886,524) (Table 1). Among anxiolytic BZPs, the most frequently prescribed agent (> 10,000 prescriptions) was etizolam (n = 124,179), followed by alprazolam (n = 67,954), lorazepam (n = 64,498), ethyl loflazepate (n = 49,745), diazepam (n = 38,289), bromazepam (n = 27,286), and clotiazepam (n = 14,466). Among hypnotic BZPs, brotizolam was the most frequently prescribed agent (n = 149,184), followed by nitrazepam (n = 78,054), triazolam (n = 45,672), lormetazepam (n = 25,194), flunitrazepam (n = 23,240), and quazepam (n = 15,058).
Table 1.
Comparison of prescription of anxiolytic benzodiazepines, SSRIs, SNRIs, and related drugs in a university hospital
| Variables | Benzodiazepines, n (%) | Antidepressants, n (%) | B/S ratio | |||
|---|---|---|---|---|---|---|
| All | Anxiolytics | All | SSRIs, SNRIs, and related drugs | |||
| Department group | ||||||
| Internal medicine (n = 7,841,461) | 179,230 (24) | 89,633 (23) | 30,485 (9) | 16,959 (7) | 5.29 | |
| Psychiatry (n = 2,545,600) | 460,052 (62) | 238,025 (61) | 281,817 (83) | 199,172 (86) | 1.20 | |
| Surgery and allied (n = 2,156,893) | 57,371 (8) | 37,201 (10) | 15,797 (5) | 11,947 (5) | 3.11 | |
| Others (n = 4,342,570) | 41,443 (6) | 25,554 (7) | 11,126 (3) | 4,720 (2) | 5.41 | |
| Age group, yr | ||||||
| < 15 (n = 1,099,311) | 7,884 (1) | 7,366 (2) | 619 (0.2) | 114 (0.01) | 64.6 | |
| 15−65 (n = 7,366,192) | 444,771 (60) | 242,960 (62) | 190,916 (56) | 134,715 (58) | 1.80 | |
| > 65 (n = 8,421,021) | 285,441 (39) | 140,087 (36) | 147,690 (44) | 97,969 (42) | 1.43 | |
| Sex | ||||||
| Females (n = 8,588,857) | 461,826 (63) | 253,785 (65) | 217,561 (64) | 150,280 (65) | 1.69 | |
| Males (n = 8,297,667) | 276,270 (37) | 136,628 (35) | 121,664 (36) | 82,518 (35) | 1.66 | |
| Hospitalisation | ||||||
| Outpatients (n = 11,113,378) | 536,349 (73) | 291,587 (75) | 250,424 (74) | 180,619 (78) | 1.61 | |
| Inpatients (n = 5,773,146) | 201,747 (27) | 98,826 (25) | 88,801 (26) | 52,179 (22) | 1.89 | |
| 5-year course group | ||||||
| 2001−2005 (n = 3,462,534) | 168,551 (23) | 92,383 (24) | 75,544 (22) | 46,983 (20) | 1.97 | |
| 2006−2010 (n = 4,299,721) | 216,089 (29) | 115,296 (30) | 102,517 (30) | 66,568 (29) | 1.73 | |
| 2011−2015 (n = 4,229,145) | 175,026 (24) | 92,911 (24) | 73,234 (22) | 51,230 (22) | 1.81 | |
| 2016−2020 (n = 4,041,709) | 153,159 (21) | 76,220 (20) | 73,045 (22) | 55,796 (24) | 1.37 | |
| 2021 (n = 853,415) | 25,271 (3) | 13,603 (3) | 14,885 (4) | 12,221 (5) | 1.11 | |
| Total (n = 16,886,524) | 738,096 (100) | 390,413 (100) | 339,225 (100) | 232,798 (100) | 1.68 | |
SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin noradrenaline reuptake inhibitors; B/S ratio, ratio of the number of prescriptions of “anxiolytic benzodiazepines” to those of “SSRIs, SNRIs, and related drugs.”
Of the anxiolytic BZP prescriptions, 36% were issued to patients aged over 65 years, 65% to females, and 75% to outpatients. The proportion of anxiolytic BZP prescriptions among all prescriptions showed a slight decrease over time: 2.7% (n = 92,383/3,462,534) in 2001−2005, 2.7% (n = 115,296/4,299,721) in 2006−2010, 2.2% (n = 92,911/4,229,145) in 2011−2015, 1.9% (n = 76,220/4,041,709) in 2016−2020, and 1.6% (n = 13,603/853,415) in 2021. More specifically, time-trends of all and major three anxiolytic BZP prescriptions were shown in Supplementary Tables 1−4 (available online), associated with departments, age groups, sex, and hospitalisation.
SSRIs and SNRIs Prescriptions
SSRI/SNRI prescriptions accounted for 1.4% (n = 232,798/16,886,524) of all prescriptions. Paroxetine was prescribed 65,595 times, fluvoxamine 50,523 times, mirtazapine 30,002 times, duloxetine 27,991 times, milnacipran 24,748 times, sertraline 17,730 times, and escitalopram 12,036 times (each > 10,000 prescriptions).
Of the SSRI/SNRI prescriptions, 42% were issued to patients aged over 65 years, 65% to females, and 78% to outpatients. The proportion of SSRI/SNRI prescriptions among all prescriptions remained relatively stable at approximately 1.4% over time: 1.4% (n = 46,983/3,462,534) in 2001−2005, 1.5% (n = 66,568/4,299,721) in 2006−2010, 1.2% (n = 51,230/4,229,145) in 2011−2015, 1.4% (n = 55,796/4,041,709) in 2016−2020, and 1.4% (n = 12,221/853,415) in 2021. More specifically, time-trends of all and major three SSRI/SNRI prescriptions were shown in Supplementary Tables 5−8 (available online), associated with departments, age groups, sex, and hospitalisation.
Comparisons between Anxiolytic BZPs and SSRIs/SNRIs
Over the study period, the total number of anxiolytic BZP prescriptions was 390,413, whereas the total number of SSRI/SNRI prescriptions was 232,798, yielding an overall B/S ratio of 1.7 (Table 1). When stratified by department group, the B/S ratio was highest in the internal medicine group (= 5.3) and lowest in the psychiatry group (= 1.2), excluding the other departments group (= 5.4).
To identify factors associated with the likelihood of prescribing an anxiolytic BZP versus an SSRI/SNRI, the results of the multiple logistic regression analysis are presented in Table 2, focusing on differences between internal medicine and psychiatry. The odds of prescribing an anxiolytic BZP rather than an SSRI/SNRI were significantly higher in internal medicine than in psychiatry, among females than among males, and among outpatients than among inpatients. Both patient age and calendar year were significantly and negatively associated with the likelihood of anxiolytic BZP prescribing relative to SSRI/SNRI prescribing. Among the independent variables examined, department group (internal medicine vs. psychiatry) was the strongest factor discriminating between anxiolytic BZP and SSRI/SNRI prescriptions (odds ratio = 5.8).
Table 2.
Factors affecting B/S ratio in the internal medicine and psychiatry departments: results of multiple logistic analysis using “anxiolytic benzodiazepines” (= 1)a or “SSRIs, SNRIs, and related drugs” (= 0)b as the dependent variable
| Independent variables | Odds ratio [95% CI] |
|---|---|
| Internal medicine (= 1) or psychiatry (= 0) | 5.839 [5.731, 5.948] |
| Female (= 1) or male (= 0) sex | 1.252 [1.237, 1.267] |
| Outpatients (= 1) or inpatients (= 0) | 1.114 [1.098, 1.130] |
| Age, yr | 0.983 [0.983, 0.984] |
| Calendar year | 0.999 [0.998, 1.000] |
SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin noradrenaline reuptake inhibitors; CI, confidence interval.
aThe number of prescription of “anxiolytic benzodiazepines” was 327,685 (89,633 in internal medicine and 238,025 in psychiatry).
bThe number of prescription of “SSRIs, SNRIs, and related drugs” was 216,131 (16,959 in internal medicine and 199,172 in psychiatry).
Figure 1 illustrates annual changes in the B/S ratio for internal medicine and psychiatry. The B/S ratio declined over time in internal medicine (range: 1.9−10.2) but remained relatively stable in psychiatry (range: 1.0−1.4). Although the B/S ratio was consistently higher in internal medicine than in psychiatry throughout the study period, the gap between the two groups tended to narrow over time.
Fig. 1.
Annual change in B/S ratio in the internal medicine and psychiatry groups.
B/S ratio, ratio of the number of prescriptions of “anxiolytic benzodiazepines” to those of “SSRIs, SNRIs, and related drugs.”
DISCUSSION
Among all prescriptions, the proportion of BZP prescriptions, including anxiolytic BZPs, decreased to some extent over the study period. This decrease was also observed in the final year, 2021 (April 2021 and March 2022), when coronavirus disease 2019 (COVID-19) began to spread in Japan. Although several previous studies have reported a temporary increase in BZP prescribing associated with psychosocial stress during the COVID-19 pandemic [14-17], such an increase was not observed in the present study. Depending on the region and study period, some studies have reported decreases or no significant changes in prescription volumes; therefore, further multicentre cohort studies are required to confirm the present findings.
In contrast, the proportion of SSRI/SNRI prescriptions did not change substantially over the study period. Although several SSRIs and SNRIs were approved as first-line treatments for depression in Japan between 1999 and 2019 [18], with expanded indications for anxiety disorders such as generalised anxiety disorder, panic disorder, and social anxiety disorder [19-21], the impact of the introduction of these newer agents appeared to be limited in the study hospital. This finding implies a need for further facilitation of the dissemination and implementation of evidence-based clinical practice guidelines.
The results of the multiple logistic regression analysis indicate that anxiolytic BZPs, rather than SSRIs/SNRIs, were significantly more likely to be prescribed by internists than by psychiatrists, even after adjustment for age, sex, inpatient or outpatient status, and calendar year. Although the B/S ratio among internists decreased over time, it remained higher than that observed among psychiatrists. In light of the need for improved dissemination of SSRI/SNRI prescribing practices, as discussed above, some internists may have limited knowledge of, or experience with, SSRIs/SNRIs, indicating that there remains a need for education regarding appropriate SSRI/SNRI prescribing, as well as strategies to prevent BZP overuse [22,23].
In addition to differences in prescribing between internists and psychiatrists, a higher B/S ratio was significantly associated with outpatient status, female sex, younger age, and earlier calendar year. First, the higher adjusted odds of anxiolytic BZP prescribing among outpatients compared to inpatients may be reasonable, as hospitalised patients who had previously been prescribed anxiolytic BZPs in outpatient settings may have had these medications withheld or discontinued under 24-hour monitoring and comprehensive inpatient care. Inpatient care often involves multidisciplinary medication review, which may facilitate the reassessment and discontinuation of previously prescribed BZPs. In contrast, SSRIs and SNRIs, which are generally intended for long-term treatment, are more likely to be continued during hospitalisation [24,25].
Second, the association between female sex and a higher B/S ratio is consistent with previous studies reporting a higher prevalence of BZP use among females [26,27]. Third, with regard to age, it is noteworthy that the B/S ratio was lower among patients aged over 65 years (1.4) than among those aged 15−65 years (1.8), and that younger age was an independent predictor of a higher B/S ratio in this study. Given the risk of adverse drug events in older adults, including falls, fractures, and functional as well as cognitive decline, BZPs should be prescribed with particular caution in elderly patients [28]. These risks are thought to be related to the sedative and psychomotor-impairing effects of BZPs. In this context, the present findings may be interpreted as a positive trend. The final significant factor, earlier calendar year, indicates that the B/S ratio gradually decreased over time. A future objective of this research is to extend the database through 2025 to examine prescribing trends during and after the COVID-19 pandemic.
Before drawing conclusions, several limitations should be considered when interpreting the findings. First, because the database consisted primarily of prescription records, detailed information on prescription duration, dosage, and cumulative exposure was not available. Therefore, the present study focused on prescription-level patterns rather than patient-level treatment trajectories. In addition, Supplementary Tables 1−8 (available online) provide detailed information on drug-level prescribing patterns across the study period. Second, reliable linkage between prescriptions and specific diagnostic categories was not available in the extracted dataset. Third, detailed annual case-mix information and departmental patient volume were not available for reconstruction of yearly structural changes. These factors should be considered when interpreting the temporal trends observed in this study.
Fourth, the findings of this study cannot be compared directly with those of other medical institutions in Japan, as this is the only study of its kind conducted to date. To mitigate this limitation, we used the same B/S ratio parameter as used in our previous study [9], which was conducted in a different university hospital and was limited to outpatient prescriptions over a single year (2002−2003). For reference, the overall B/S ratio in the previous study was 3.7 (13.0 in internal medicine and 2.6 in psychiatry), reflecting a similar gap between these two department groups. In addition, we provided a detailed description of the study hospital, which is a large university teaching hospital with physicians across more than 20 departments. Prescribing practices in such settings may reflect the influence of national educational meetings and supervisory guidance rather than individual physician preferences [29]. Further studies involving other institutions in Japan and abroad are required before these findings can be generalised.
Despite these limitations, this study provides important implications for clinical practice and health policy. It has frequently been noted that the volume of BZP prescriptions in Japan is exceptionally high from an international perspective [30]; however, no previous cohort study has examined this issue using a large sample size and a long follow-up period. As in other countries, BZPs in Japan are prescribed not only in psychiatric settings but also across multiple medical specialties, including internal medicine and surgery. Although the Japanese government implemented policy interventions between 2012 and 2018 to promote the appropriate use of psychotropic medications, including BZPs, the effectiveness of those interventions in reducing long-term use and high-dose prescribing has been limited [31]. From a clinical and policy perspective, the present findings underscore the importance of targeted educational interventions aimed at non-psychiatric physicians, particularly internists who frequently encounter patients with anxiety and depressive symptoms. Educational programs focusing on guideline-concordant pharmacotherapy, including the appropriate use of SSRIs/SNRIs and the risks associated with long-term BZP use, may help reduce inappropriate prescribing. In addition, institutional strategies such as clinical decision support systems, prescription monitoring, and multidisciplinary collaboration may further facilitate safer and more evidence-based prescribing practices. At a broader level, continued efforts to disseminate clinical guidelines and to integrate psychiatric expertise into general medical care are essential to optimise psychotropic medication use.
Acknowledgments
We thank Kasumi Hashimoto for her assistance with the data collection.
Footnotes
Funding
This study was financially supported by Research Grant of the Japanese Ministry of Education, Culture, Sports, Science and Technology (Kiban C, 2023-2026) and the KDDI Foundation (Academic Research Grant for Social Implementation of Digital Innovation 2025-2028).
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: Mutsuhiro Nakao, Yumiko Kurata. Data curation: Mutsuhiro Nakao, Hokuto Morohoshi, Akiou Nakamura. Funding acquisition: Mutsuhiro Nakao, Akiou Nakamura. Methodology: Mutsuhiro Nakao, Hokuto Morohoshi, Akiou Nakamura. Project administration: Mutsuhiro Nakao. Resources: Mutsuhiro Nakao, Akiou Nakamura. Writing—original draft: Mutsuhiro Nakao, Hokuto Morohoshi, Yumiko Kurata. Writing—review & editing: Mutsuhiro Nakao, Yumiko Kurata, Akiou Nakamura.
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