2025; 23(1): 144-154  https://doi.org/10.9758/cpn.24.1255
Effectiveness of Buspirone in Alleviating Anxiety Symptoms in Patients with Depressive Disorder: A Multicenter Prospective Observational Study in Korea
Young Sup Woo1,2,*, Won-Seok Choi1,*, Jong-Hyun Jeong1, Jonghun Lee3, Do-Hoon Kim4, Jong-Chul Yang5, Se-Hoon Shim6, Seung-Gul Kang7, Young-Eun Jung8, Won Kim9, Chi-Un Pae1, Won-Myong Bahk1
1Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
2Woo and Bahk Psychiatry Clinic, Seoul, Korea
3Department of Psychiatry, College of Medicine, Daegu Catholic University, Daegu, Korea
4Department of Psychiatry, Hallym University College of Medicine, Chuncheon, Korea
5Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Korea
6Department of Psychiatry, Soonchunhyang University Cheonan Hospital, College of Medicine, Soonchunhyang University, Cheonan, Korea
7Department of Psychiatry and Sleep Medicine Center, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
8Department of Psychiatry, Jeju National University Hospital, Jeju, Korea
9Department of Psychiatry, Sanggye Paik Hospital, College of Medicine, Inje University, Seoul, Korea
Correspondence to: Won-Myong Bahk
Department of Psychiatry, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Korea
E-mail: wmbahk@catholic.ac.kr
ORCID: https://orcid.org/0000-0002-0156-2510

*These authors contributed equally to this study as co-first authors.
Received: October 28, 2024; Revised: November 12, 2024; Accepted: November 13, 2024; Published online: December 3, 2024.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Objective: We aimed to investigate the effectiveness of buspirone as an adjunctive therapy for alleviating anxiety symptoms in patients with depressive disorders who are already taking antidepressants.
Methods: This was an open-label prospective multicenter non-interventional observational study conducted over 12 weeks. We enrolled 180 patients diagnosed with depressive disorders according to DSM-5 criteria and Hamilton Anxiety Rating Scale (HAMA) scores ≥ 18. Participants were already taking selective serotonin reuptake inhibitors or serotoninnorepinephrine reuptake inhibitors and were prescribed adjunctive buspirone. Efficacy was assessed using HAMA, Hamilton Depression Rating Scale (HAMD), Clinical Global Impression Scale-Improvement, Clinical Global Impression Scale-Severity, Sheehan Disability Scale (SDS), and WHO-5 Well-Being Index.
Results: The efficacy analysis included 161 patients. HAMA scores decreased significantly from 25.2 ± 6.7 at baseline to 15.4 ± 8.6 at 12 weeks (p < 0.001), whereas HAMD scores decreased from 19.4 ± 4.6 to 12.7 ± 5.7 (p < 0.001). WHO-5 and SDS scores showed significant improvements. The HAMA response rate was 39.1% and the remission rate was 13.7% at 12 weeks. Adverse drug reactions were reported in 3.7% of participants. Subgroup analyses showed no significant differences in treatment response based on buspirone dosage, baseline anxiety/depression severity, or benzodiazepine use.
Conclusion: Adjunctive buspirone therapy effectively improved anxiety symptoms in depressed patients taking antidepressants, regardless of baseline symptom severity or buspirone dosage. The treatment was well-tolerated with few adverse events. Future studies using a control group are needed.
Keywords: Depression; Anxiety; Anxious depression; Buspirone
INTRODUCTION

Depressive disorder is a common condition with a high prevalence that negatively impacts the lives of patients [1-3]. Moreover, it is known that patients with comorbid conditions have more severe and chronic symptoms and suffer significant impairments in occupational functioning, psychosocial functioning, and quality of life compared to those without comorbid conditions [4]. In depressive disorder, comorbid anxiety disorder is very common [5]. According to the National Comorbidity Survey Replication in the United States, the lifetime comorbidity rate of anxiety disorder in patients with major depressive disorder (MDD) is reported to be 59.2%, with a one-year comorbidity rate of 57.5% [6]. Failure to accurately diagnose coexisting anxiety disorders in patients with depressive disorder can affect the long-term course of the depressive disorder, leading to missed opportunities for effective treatment of anxiety disorders and potentially poor prognosis [7]. The treatment of patients with coexisting anxiety and depressive disorders largely includes pharmacotherapy, psychosocial therapy, and a combination of both [7]. In pharmacotherapy, antidepressants are generally chosen as the first-line treatment for this condition [8,9]. Antidepressants primarily include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, agomelatine, and vortioxetine [10]. Among these, SSRIs and SNRIs are effective not only for depressive disorders but also for anxiety disorders [5,11]. Therefore, these medications are preferred as first-line treatments in cases of coexisting depressive and anxiety disorders. Benzodiazepine class drugs, classified as anxiolytics, are helpful in treating anxiety disorders but are not effective for coexisting depressive disorders, and because of concerns related to abuse and dependence with long-term use, they are not suitable first-line treatments [12].

Clinical practice guidelines for anxiety disorders recommend using SSRIs, SNRIs, or buspirone as initial pharmacotherapy or in combination with benzodiazepine anxiolytics for a short duration based on clinical judgment [13,14]. Azapirone class drugs, including buspirone, have been reported to have some antidepressant effects at high doses in addition to their anxiolytic effects, making them a potential choice for coexisting anxiety and depressive disorders [15,16]. Buspirone was approved by the US Food and Drug Administration as a treatment for anxiety disorders in 1986 and is currently used in Korea. The exact mechanism of the anxiolytic effect of buspirone is not clear, but it is thought to be related to its partial agonistic action on presynaptic serotonin 1A autoreceptors, thereby reducing the firing of serotonergic neurons [17]. Buspirone does not have an antidepressant effect in severe depression but is known to have some antidepressant effect in mild depression, especially in anxious depression [18,19]. Additionally, buspirone partially antagonizes postsynaptic serotonin 1A receptors, enhancing the activity of serotonergic antidepressants [20]. However, there is still insufficient research on the effectiveness of buspirone as a combination therapy with antidepressants in patients with depressive disorders. Therefore, this prospective observational study aims to investigate the effects of buspirone as an adjunct to antidepressants in Korean patients with coexisting anxiety and depressive disorders in a clinical setting.

METHODS

Study Population and Design

This was an open-label prospective multicenter non-interventional observational 12-week study that included 180 patients diagnosed with depressive disorders according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 16 university hospitals in Korea. The inclusion criteria for this study were as follows: 1) voluntarily signed informed consent forms and agreed participation; 2) adults aged 19 years and older; 3) diagnosis of a depressive disorder according to the DSM-5 criteria; 4) Hamilton Anxiety Rating Scale (HAMA) score of 18 or higher at enrollment; 5) subjects who had been prescribed SSRIs and/or SNRIs at or above the effective dosage for 4 weeks or more, and were found to require additional buspirone for the management of anxiety symptoms by the investigator (the combination of one SSRI and one SNRI was allowed, but the use of two or more SSRI or SNRI combinations, or switching between SSRIs and SNRIs was not permitted); and 6) ability to read and comprehend self-report scales. The exclusion criteria were as follows: 1) contraindicated for buspirone; 2) received azapirone class anxiolytics, including buspirone, in the past 4 weeks; 3) initiated or had changed the dosage of benzodiazepine class anxiolytics within the past week; 4) received psychostimulants or other attention-deficit/hyperactivity disorder (ADHD) medications in the past 4 weeks; 5) pregnant or breastfeeding status; 6) participation in other clinical trials within 12 weeks of the baseline; 7) risk of suicide, self-harm, or harm to others, as assessed by the investigator; and 8) considered inappropriate for the study by the investigator.

Medication

This study was designed as a non-interventional observational study, and the treatment of subjects was determined individually by the investigators in their routine clinical settings. Therefore, the study protocol did not provide consistent guidelines for specific details including the dosage of medications. The investigators made appropriate determinations taking into consideration the prescribing information of the medications and the psychiatric and medical status of the subjects. Although specific prohibited concomitant medications were not specified, the need to prescribe any of the following medications would lead to study discontinuation: 1) any antidepressant other than current medication during the study period; 2) newly prescribed antipsychotic drugs, mood stabilizers, or anticonvulsants during the study period (if the same dosage had been maintained for at least 4 weeks before the start of the study, the dosage could be continued during the study); 3) newly prescribed psychostimulants or other ADHD medications during the study; 4) newly prescribed benzodiazepines during the study (if the same dosage had been maintained for at least 1 week before the start of the study, the dosage could be continued or reduced during the study); 5) newly prescribed beta-blockers, including propranolol, during the study (if the same dosage had been maintained for at least 4 weeks before the start of the study, the dosage could be continued during the study). In addition, other concomitant medications with a low likelihood of impacting depressive symptoms could be used at the discretion of the investigators. However, all concomitant medication use was documented in the case report form.

Efficacy and Safety Assessment

Before beginning the treatment with buspirone (base-line visit, week 0), the HAMA, Hamilton Depression Rating Scale (HAMD), and the Clinical Global Impression Scale-Severity Scale (CGI-S) were applied. Evaluation for the efficacy of the buspirone combination was carried out with the HAMA, HAMD, CGI-S, and the Clinical Global Impression Scale-Improvement (CGI-I) in weeks 4, 8, and 12. To evaluate functioning and psychosocial well-being, the Sheehan Disability Scale (SDS) and 5-item World Health Organization Well-Being Index (WHO-5) were applied at baseline and week 12. The primary efficacy outcome was defined as the mean change from baseline to week 12 on the HAMA total score. Additional efficacy measures included the mean change in HAMD, CGI-S, CGI-I, SDS, and WHO-5 scores and response and remission rates on HAMA and HAMD. A response was defined as a decrease in the HAMD or HAMA total score ≥ 50%. Remission was defined as HAMA or HAMD total score ≤ 7. All adverse drug reactions (ADRs), serious adverse events (SAEs), and serious adverse drug reactions (SADRs) occurring after the administration of buspirone were investigated at each visit.

Statistical Analyses

The efficacy analysis set (EAS) was defined as all subjects for whom data on primary efficacy outcome measure (HAMA) were recorded at least once, and the last-observation-carried-forward (LOCF) method was applied for endpoint analysis. All subjects who received at least one dose of the study medication (buspirone) and attended at least one follow-up visit were included in the safety set. Quantitative data are expressed as mean ± standard deviation, and categorical variables are described as absolute and relative frequencies. For the analysis of quantitative outcome variables, a paired ttest and repeated measure analysis of variance were used. For the analysis of categorical variables, the chi-squared test was used.

For subgroup analysis, the subjects were categorized as follows: low-dose group (30 mg/day or less) versus standard-dose group (more than 30 mg/day) based on the mean daily dose of buspirone; moderate anxiety group with baseline HAMA score of 18 to 24 versus severe anxiety group with baseline HAMA score of 25 or higher; mild to moderate depression group with baseline HAMD score of less than 24 versus severe depression group with a baseline HAMD score of 24 or higher. For subgroup analysis, repeated measures of analysis of covariance were used for age, sex, benzodiazepine use, baseline anxiety, and/or depression severity as covariates. All statistical tests were two-tailed with a significance level of 0.05.

Ethics

The study was conducted according to the Declaration of Helsinki and Good Clinical Practices. Written informed consent was obtained from all subjects after the subjects were given an extensive explanation of the nature and procedures of the study. The study protocol was approved by the Institutional Review or Ethics Committees at Yeouido St. Mary’s Hospital (SC20OODE0149).

RESULTS

Baseline Characteristics and Medications during the Study

In this study, a total of 180 participants were enrolled. Among these, 17 subjects did not attend subsequent visits following visit 1. Therefore, the number of participants included in the safety set was 163, whereas 161 were included in the EAS because an evaluation of the efficacy variable was not conducted for 19 subjects after the baseline visit. The baseline characteristics of the participants included in the EAS are presented in Table 1. The mean age of subjects was 39.1 ± 17.2 years, and 48.5% (n = 78) were male. The baseline scores on HAMA were 25.2 ± 6.7, indicating moderate to severe anxiety, and HAMD scores were 19.4 ± 4.6, indicating moderate depression. Among the subjects, the most prevalent diagnosis was MDD (n = 129, 80.1%), followed by persistent depressive disorder (n = 19, 11.8%) and other specified/unspecified depressive disorders (n = 12, 7.5%). Common psychiatric comorbidities included panic disorder/agoraphobia (n = 28, 17.4%) and other specified/unspecified anxiety disorders (n = 12, 7.5%). At baseline, the most frequently prescribed antidepressants were milnacipran (n = 43, 26.7%), escitalopram (n = 42, 26.1%), and paroxetine (n = 21, 13.0%). Additionally, 31 patients (19.3%) were receiving antipsychotics or mood stabilizers, with a prevalence of aripiprazole (n = 20, 12.4%) and quetiapine (n = 9, 5.6%). During the study period, 109 patients (67.7%) received benzodiazepines. The average dosage of buspirone administered throughout the entire study duration was 17.7 ± 8.6 mg/day.

Efficacy

During the 12-week study period, HAMA scores significantly decreased from a baseline of 25.2 ± 6.7 to an endpoint of 15.4 ± 8.6 (p < 0.001, Fig. 1A). Similarly, HAMD scores decreased from a baseline of 19.4 ± 4.6 to 12.7 ± 5.7 at 12 weeks (p < 0.001, Fig. 1B), and CGI-S scores also showed a significant reduction from a baseline of 4.3 ± 0.7 to 3.2 ± 1.0 points at 12 weeks (p < 0.001, Fig. 1C). Additionally, SDS scores decreased from a baseline of 20.3 ± 10.2 points to 15.4 ± 10.1 points at 12 weeks (p < 0.001, Fig. 2A), and WHO-5 scores increased from a baseline of 5.6 ± 4.4 points to 8.2 ± 5.4 points at 12 weeks (p < 0.001, Fig. 2B), indicating significant improvement in functioning and disability over the 12-week buspirone treatment. The CGI-I scores at week 12 indicated a minimal to much-improved status, with a score of 3.2 ± 1.0. The response and remission rates evaluated through HAMD and HAMA are presented in Figure 2. At 12 weeks, the HAMA response rate was 39.1% (n = 63), with a remission rate of 13.7% (n = 22). The HAMD response rate was 27.3% (n = 44), and the remission rate was 17.4% (n = 28) (Fig. 3).

Safety

Among 180 subjects who were included in this study, 132 (73.3%) subjects completed the 12-week study and 48 (26.7%) subjects dropped out. The reason for study incompletion was the loss of follow-up (n = 20), use of prohibited concomitant medication (n = 10), discontinuation of buspirone due to adverse events or lack of efficacy (n = 9), the decision of the investigator (n = 6), and withdrawal of consent (n = 3). During the study, ADRs occurring after the administration of investigational drugs were observed in six individuals (3.7%), totaling nine incidents. There was one incident (0.6%) of a serious adverse event, and no instances of SADRs. One suicide attempt was recorded following the administration of investigational drugs during the study period. However, the causality was assessed as ‘unlikely’. ADRs leading to discontinuation of the investigational drugs occurred in four individuals (2.5%), accounting for seven cases. ADRs reported after the administration of investigational drugs during the study period included nausea in three individuals (1.8%), whereas vomiting, dizziness, somnolence, fatigue, insomnia, and pruritus were each reported in one individual (0.6%). ADRs leading to premature withdrawal from the study occurred in four individuals (2.5%) and involved seven incidents: nausea was reported by two individuals, and vomiting, dizziness, somnolence, insomnia, and pruritus were each reported by one individual.

Subgroup Analysis

Among the 161 subjects in the EAS, 147 were categorized into the low-dose group, with a mean daily dose of buspirone at 30 mg/day or below, and 14 were classified into the high-dose group, exceeding 30 mg/day. In both groups, the HAMA total score and HAMD total score at 12 weeks significantly decreased compared to baseline, with no significant differences observed between the two groups (Table 2). During the study period, 109 individuals were included in the benzodiazepine-use group, and 52 individuals were included in the non-use group. Similar to the low and high-dose groups, both groups exhibited a significant reduction in HAMA and HAMD total scores at 12 weeks compared to baseline, with no significant differences between the two groups. The moderate anxiety group, comprising 99 individuals with a baseline HAMA total score of 24 or below, and the severe anxiety group, consisting of 62 individuals with a baseline HAMA total score 25 or higher, both demonstrated a significant reduction in HAMA and HAMD total scores at 12 weeks, irrespective of baseline anxiety severity. No significant differences were observed between the two groups (Table 2). In terms of baseline HAMD total score, the mild to moderate depression group included 135 individuals with a score below 24, whereas the severe depression group comprised 26 individuals with a score of 24 or above. Both groups showed a significant reduction in HAMA and HAMD total scores during the 12-week study period, with no significant differences in the extent of reduction between the two groups (Table 2).

DISCUSSION

In this study, subjects with anxious depression exhibited significant reductions in anxiety and depression scores. Additionally, WHO-5 scores increased, which reflected improved well-being and SDS scores and suggested better functioning and reduced disability. The study reported a HAMA response rate of approximately 39% and a HAMD response of around 27%. In terms of safety, 73% of participants completed the study, and ADRs were observed in a small percentage of participants. Subgroup analyses revealed that augmentation of SSRI or SNRI treatment with buspirone improved depression and anxiety symptoms in patients with severe depression or anxiety at baseline to the same extent as those with moderate depression or anxiety. Interestingly, the dosage of buspirone did not affect the improvement in depression and anxiety symptoms.

The improvement in depressive symptoms observed with buspirone augmentation in our study is consistent with the findings of previous studies. Earlier studies that examined the effectiveness of buspirone in treating depression suggested that buspirone offers significant benefits as both a primary and adjunctive treatment for depression, with its antidepressant effects shown to be independent of its anxiolytic effects [21]. Subsequent studies have further explored the efficacy of buspirone in untreated patients with depression. In a placebo-controlled study by Landén et al. [22], patients with major depressive episodes unresponsive to SSRI treatment were randomly assigned to either buspirone or placebo augmentation for 4 weeks. The study found no statistically significant difference in response rates between the buspirone and placebo groups. However, an optional open-label phase showed a 69.4% response rate to buspirone augmentation, indicating potential efficacy in some patients despite a high placebo response rate. In a double-blind, placebo-controlled study by Appelberg et al. [23], patients with major depressive episodes unresponsive to fluoxetine or citalopram were treated with either buspirone or a placebo. Results indicated a significantly greater reduction in depressive symptoms in the buspirone group compared to placebo after the first week, especially in patients with initially high MADRS scores. The sequenced treatment alternatives to relieve depression (STAR*D) trial [24] also found that buspirone augmentation for an average of 9.2 weeks in patients with MDD who did not achieve remission after approximately 12 weeks of SSRI (citalopram) treatment resulted in about a 30% remission rate (HAMD score ≤ 7) and a 17.1% reduction in the symptom scores as measured by the Quick Inventory of Depressive Symptomatology. Additionally, in another double-blind placebo-controlled clinical trial by Fava et al. [25], a combination of low-dose buspirone and melatonin significantly improved depressive symptoms compared to placebo or buspirone monotherapy, highlighting its potential as an effective treatment strategy for MDD. Collectively, this evidence suggests that buspirone augmentation can effectively improve depressive symptoms.

The anxiolytic efficacy of buspirone in generalized anxiety disorder is well established [26] and has high tolerability [27]. However, previous studies have also shown that buspirone can treat comorbid depression associated with anxiety disorders along with improvement in anxiety symptoms. In a 6-week double-blind trial evaluated by HAMD and HAMA [28], buspirone improved depressive and anxiety symptoms in patients with generalized anxiety disorder comorbid mild depression. In a previous meta-analysis [29], compared to placebo, buspirone showed an improvement in the symptoms of anxiety and depression. Moreover, physicians measured a global improvement, regardless of the severity of comorbid depression in generalized anxiety disorder. This evidence suggests that buspirone is helpful in the treatment of comorbid depressive symptoms as well as primary anxiety symptoms in anxiety disorders. In this study, buspirone was also effective in treating comorbid anxiety in patients with a primary diagnosis of depression. To the best of our knowledge, this is the first study to identify the anxiolytic effects of buspirone on anxious depression. Our findings suggest the potential use of buspirone in depression with anxiety symptoms, in addition to its established use for generalized anxiety disorder.

Of the participants in this study, about half were taking milnacipran (n = 43, 26.7%) and escitalopram (n = 42, 26.1%). In global treatment guidelines, SSRIs are the recommended first-line medication for the treatment of MDD [9,30], and this is also the case in Korea [10]. Milnacipran, an SNRI, was the medication used most commonly for depression in this study. This was probably because patients had co-occurring anxiety symptoms at the onset of their illness, which led physicians to choose an SNRI, or patients were switched to an SNRI because their initial SSRI monotherapy did not improve their anxiety. Approximately 19% of patients were also taking an augmentation drug for depression, such as antipsychotics and mood stabilizers, indicating that they were less responsive to initial treatment with SSRIs.

Another unique aspect of this study is the relatively low dose of buspirone (17.7 ± 8.6 mg/day) used throughout when compared to previous studies of buspirone augmentation with SSRIs, which have used doses as low as 20 mg/day and as high as 60 mg/day [22-24,29]. The dose in our study is also considered low given that the recommended starting dose of buspirone is 15 mg/day [21]. One possible explanation is that our study is open-label and low doses of medication may have been used as an adjunctive medication along with antidepressants. In other words, the presence of antidepressants already being taken might have made it difficult to add a relatively high dose of buspirone. Accordingly, the use of lower doses may have resulted in a lower rate of adverse events in this study.

In subgroup analysis, patients did not differ in their response to buspirone adjunctive therapy based on the severity of depressive and anxiety symptoms. Furthermore, there was no difference in response to treatment based on the dose of buspirone. This is consistent with previous meta-analyses that have shown buspirone to be effective regardless of the degree of comorbid depression or anxiety in generalized anxiety disorder. This may be because anxiety and depression are thought to be on a continuum and to be highly comorbid, so when one improves, the other improves in parallel [31,32]. In this study, the improvement in anxiety and depressive symptoms could be attributed to the augmentation of buspirone in patients taking SSRIs or SNRIs, which may have enhanced the therapeutic effects of the antidepressant and buspirone.

The limitations of this study are as follows. First, this is an open-label observational study, meaning there is no control group. This makes it difficult to know whether buspirone use improved anxiety symptoms associated with depression independent of antidepressants. In addition, in this study, we did not compare the anxiolytic effects of buspirone between groups using SSRI or SNRI monotherapy or a combination of both medications. Second, the low dose of the drug used suggests that the improvement in anxiety may not be due to the actual pharmacologic mechanism of buspirone. Third, we did not check the past drug use of the patient and resistance to treatment. While these are important factors in determining patient prognosis and treatment effectiveness, this study did not include these criteria in patient selection and analysis. Finally, the number of participants was not large, around 180, which limits the generalizability of the results. In addition, the LOCF method used to correct for missing values in this study may introduce bias into the results of the analysis. This may also have affected the interpretation of the study results. Nevertheless, the study has value in that it included patients using a variety of medications, including SSRIs and SNRIs, over a 12-week period at multiple sites.

In conclusion, our study found that adjunctive therapy with buspirone effectively treated anxiety symptoms in patients with depression taking antidepressants. In addition, it has significantly improved the quality of life for patients. These benefits were seen regardless of the severity of depression or anxiety, and the incidence of adverse effects was low throughout the trial. Future research will require larger studies with controlled groups, including comparisons of buspirone’s anxiolytic effects in patients taking SSRIs versus SNRIs. Additionally, further investigation of the pharmacologic interactions between antidepressants and buspirone is needed to verify the effectiveness and safety of combination therapy.

Funding

This study was funded by the Boryung Corporation.

Conflicts of Interest

Won-Myong Bahk is a member of the Editorial Board of Clinical Psychopharmacology and Neuroscience, Chi-Un Pae is an editor-in-chief of Clinical Psychopharmacology and Neuroscience, Young-Eun Jung and Young Sup Woo are the associate editors of Clinical Psychopharmacology and Neuroscience. These authors were not involved in the journal’s review of, or decisions related to, this manuscript. No other potential conflicts of interest pertinent to this article were reported.

Author Contributions

Conceptualization: Young Sup Woo, Won-Myong Bahk. Investigation: Young Sup Woo, Won-Seok Choi, Jong-Hyun Jeong, Jonghun Lee, Do-Hoon Kim, Jong-Chul Yang, Se-Hoon Shim, Seung-Gul Kang, Young-Eun Jung, Won Kim, Chi-Un Pae, Won-Myong Bahk. Formal analysis: Young Sup Woo. Data curation: Young Sup Woo, Won-Myong Bahk. Supervision: Won-Myong Bahk. Funding: Won-Myong Bahk. Writing–original draft: Young Sup Woo, Won-Seok Choi. Writing–review & editing: Won-Myong Bahk.

Figures
Fig. 1. Changes in (A) WHO-5 and (B) SDS scores during the study.
Values are presented as mean ± standard deviation.
SDS, Sheehan Disability Scale; WHO-5, 5-item World Health Organization Well-Being Index.
*Statistically significant, p < 0.001.
Fig. 2. Changes in (A) WHO-5 and (B) SDS scores during the study.
Values are presented as mean ± standard deviation.
SDS, Sheehan Disability Scale; WHO-5, 5-item World Health Organization Well-Being Index.
*Statistically significant, p < 0.001.
Fig. 3. Response and remission rate during the study.
HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale.
Tables

Baseline demographic and clinical characteristics of included subjects (total n = 161)

Variables Value
Age (yr) 39.1 ± 17.2
Male 78 (48.5)
Educationa Elementary school 13 (8.1)
Middle school 9 (5.6)
High school 90 (55.9)
College degree or higher 48 (29.8)
Diagnosis Major depressive disorder 129 (80.1)
Persistent depressive disorder 19 (11.8)
Other specified depressive disorder/unspecified depressive disorder 12 (7.5)
Disruptive mood dysregulation disorder 1 (0.6)
Psychiatric comorbidity Social anxiety disorder 6 (3.7)
Panic disorder/agoraphobia 28 (17.4)
Generalized anxiety disorder 3 (1.9)
Other specified anxiety disorder/unspecified anxiety disorder 12 (7.5)
Obsessive-compulsive and related disorders 3 (1.9)
Posttraumatic stress disorder 8 (5.0)
Dissociative disorders 1 (0.6)
Somatic symptom and related disorders 6 (3.7)
ADHD 4 (2.5)
Avoidant personality disorder 1 (0.6)
Physical comorbidity Dyslipidemia 33 (20.5)
Hypertension 14 (8.7)
Diabetes mellitus 5 (3.1)
Gastrointestinal disorders 31 (19.3)
Musculoskeletal and connective tissue disorders 11 (6.8)
Hepatobiliary disorders 5 (3.1)
Neoplasms (benign, malignant and unspecified) 5 (3.1)
Respiratory, thoracic and mediastinal disorders 4 (2.5)
Cardiac disorders 4 (2.5)
Anemia 3 (1.9)
Hypothyroidism 1 (0.6)
Antidepressants Milnacipran 43 (26.7)
Escitalopram 42 (26.1)
Paroxetine 21 (13.0)
Sertraline 15 (9.3)
Fluoxetine 16 (9.9)
Desvenlafaxine 11 (6.8)
Duloxetine 9 (5.6)
Venlafaxine 5 (3.1)
Antipsychotics Aripiprazole 20 (12.4)
Quetiapine 9 (5.6)
Olanzapine 1 (0.6)
Mood stabilizers Lithium 1 (0.6)
Baseline scores HAMA 25.2 ± 6.7
HAMD 19.4 ± 4.6
CGI-S 4.3 ± 0.7
SDS 20.3 ± 10.2
WHO-5 5.6 ± 4.4

Values are presented as number (%) or mean ± standard deviation.

ADHD, attention-deficit hyperactivity disorder; CGI-S, Clinical Global Impression Scale-Severeity; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; SDS, Sheehan Disability Scale; WHO-5, 5-item World Health Organization Well-Being Index.

aData for 1 subject was missing.

Changes in HAMA and HAMD total score during the study based on subgroup analysis

Subgroups Category Scale Baseline
(na = 161)
Week 4
(na = 152)
Week 8
(na = 155)
Week 12
(na = 161)
pvalueb
Buspirone dose Low dose (≤ 30 mg/day) HAMA 25.3 ± 6.9 19.8 ± 7.7 17.2 ± 8.3 15.1 ± 8.8 0.118
Standard dose (> 30 mg/day) 24.1 ± 3.2 19.9 ± 4.8 20.0 ± 4.1 18.2 ± 5.6
Low dose (≤ 30 mg/day) HAMD 19.6 ± 4.6 16.1 ± 5.0 14.2 ± 5.5 12.5 ± 5.7 0.203
Standard dose (> 30 mg/day) 17.6 ± 4.3 15.3 ± 3.2 14.7 ± 3.8 14.5 ± 4.6
Baseline HAMA Moderate anxiety (HAMA ≤ 24) HAMA 21.1 ± 2.0 16.4 ± 4.8 13.9 ± 5.4 11.9 ± 6.0 0.856
Severe anxiety (HAMA ≥ 25) 31.8 ± 6.3 25.2 ± 7.8 23.2 ± 8.4 20.8 ± 9.4
Moderate anxiety (HAMA ≤ 24) HAMD 17.7 ± 3.9 14.7 ± 4.3 12.5 ± 4.6 10.8 ± 4.9 0.107
Severe anxiety (HAMA ≥ 25) 22.2 ± 4.1 18.0 ± 5.0 16.9 ± 5.4 15.7 ± 5.5
Baseline HAMD Mild to moderate depression (HAMD < 24) HAMA 23.8 ± 5.2 18.7 ± 6.6 16.3 ± 7.3 14.0 ± 7.5 0.751
Severe depression (HAMD ≥ 24) 32.4 ± 8.7 25.2 ± 9.2 23.9 ± 9.1 22.3 ± 10.9
Mild to moderate depression (HAMD < 24) HAMD 18.0 ± 3.6 15.1 ± 4.4 13.3 ± 5.0 11.9 ± 5.4 0.152
Severe depression (HAMD ≥ 24) 26.4 ± 2.3 20.6 ± 4.6 18.8 ± 5.0 16.8 ± 5.0

HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale.

aNumber of participants included in analysis adjusted with last-observation-carried-forward (LOCF) method.

bpvalue based on between-group repeated measure of analysis of covariance.

References
  1. Hirschfeld RM. Clinical importance of long-term antidepressant treatment. Br J Psychiatry Suppl 2001;42:S4-S8.
    Pubmed CrossRef
  2. Unützer J, Patrick DL, Diehr P, Simon G, Grembowski D, Katon W. Quality adjusted life years in older adults with depressive symptoms and chronic medical disorders. Int Psycho-geriatr 2000;12:15-33.
    Pubmed CrossRef
  3. Sheehan DV, Nakagome K, Asami Y, Pappadopulos EA, Boucher M. Restoring function in major depressive disorder: a systematic review. J Affect Disord 2017;215:299-313.
    Pubmed CrossRef
  4. Emmanuel J, Simmonds S, Tyrer P. Systematic review of the outcome of anxiety and depressive disorders. Br J Psychiatry Suppl 1998;34:35-41.
    CrossRef
  5. Shin C, Jeon SW, Lee SH, Pae CU, Hong N, Lim HK, et al. Efficacy and safety of escitalopram, desvenlafaxine, and vortioxetine in the acute treatment of anxious depression: a randomized rater-blinded 6-week clinical trial. Clin Psychopharmacol Neurosci 2023;21:135-146.
    Pubmed KoreaMed CrossRef
  6. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. ; National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-3105.
    Pubmed CrossRef
  7. Belzer K, Schneier FR. Comorbidity of anxiety and depressive disorders: issues in conceptualization, assessment, and treatment. J Psychiatr Pract 2004;10:296-306.
    Pubmed CrossRef
  8. Malhi GS, Bell E, Singh AB, Bassett D, Berk M, Boyce P, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: major depression summary. Bipolar Disord 2020;22:788-804.
    Pubmed CrossRef
  9. Lam RW, Kennedy SH, Adams C, Bahji A, Beaulieu S, Bhat V, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023 : Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes. Can J Psychiatry 2024;69:641-687.
    Pubmed KoreaMed CrossRef
  10. Woo YS, Bahk WM, Seo JS, Park YM, Kim W, Jeong JH, et al. The Korean Medication Algorithm Project for Depressive Disorder 2021: comparisons with other treatment guidelines. Clin Psychopharmacol Neurosci 2022;20:37-50.
    Pubmed KoreaMed CrossRef
  11. Levine J, Cole DP, Chengappa KN, Gershon S. Anxiety disorders and major depression, together or apart. Depress Anxiety 2001;14:94-104.
    Pubmed CrossRef
  12. Rao S, Zisook S. Anxious depression: clinical features and treatment. Curr Psychiatry Rep 2009;11:429-436.
    Pubmed CrossRef
  13. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, Van Ameringen M, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry 2014;14 Suppl 1:S1.
    Pubmed KoreaMed CrossRef
  14. Baldaçara L, Paschoal AB, Pinto AF, Loureiro FF, Antonio LAVG, Veiga DL, et al. Brazilian Psychiatric Association treatment guidelines for generalized anxiety disorder: perspectives on pharmacological and psychotherapeutic approaches. Braz J Psychiatry 2024;46:e20233235.
    CrossRef
  15. Dimitriou EC, Dimitriou CE. Buspirone augmentation of antidepressant therapy. J Clin Psychopharmacol 1998;18:465-469.
    Pubmed CrossRef
  16. Park YM. The hypothesis on the prediction of treatment response with buspirone augmentation along with serotonergic antidepressant in patients with major depressive disorder using loudness dependence of auditory evoked potentials: two cases and review of the literature for evidence. Psychiatry Investig 2020;17:222-224.
    Pubmed KoreaMed CrossRef
  17. Taylor DP. Serotonin agents in anxiety. Ann N Y Acad Sci 1990;600:545-556; discussion 556-557.
    Pubmed CrossRef
  18. Feighner JP, Merideth CH, Hendrickson GA. A double-blind comparison of buspirone and diazepam in outpatients with generalized anxiety disorder. J Clin Psychiatry 1982;43:103-108.
  19. Robinson DS, Rickels K, Feighner J, Fabre LF Jr, Gammans RE, Shrotriya RC, et al. Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. J Clin Psychopharmacol 1990;10:67S-76S.
    Pubmed CrossRef
  20. Redrobe JP, Bourin M. Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test. Psychopharmacology (Berl) 1998;138:198-206.
    Pubmed CrossRef
  21. Loane C, Politis M. Buspirone: what is it all about? Brain Res 2012;1461:111-118.
    Pubmed CrossRef
  22. Landén M, Björling G, Agren H, Fahlén T. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depres-sion. J Clin Psychiatry 1998;59:664-668.
    Pubmed CrossRef
  23. Appelberg BG, Syvälahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psy-chiatry 2001;62:448-452.
    Pubmed CrossRef
  24. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, et al. ; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252.
    Pubmed CrossRef
  25. Fava M, Targum SD, Nierenberg AA, Bleicher LS, Carter TA, Wedel PC, et al. An exploratory study of combination buspirone and melatonin SR in major depressive disorder (MDD): a possible role for neurogenesis in drug discovery. J Psychiatr Res 2012;46:1553-1563.
    Pubmed CrossRef
  26. Garakani A, Murrough JW, Freire RC, Thom RP, Larkin K, Buono FD, et al. Pharmacotherapy of anxiety disorders: current and emerging treatment options. Front Psychiatry 2020;11:595584.
    Pubmed KoreaMed CrossRef
  27. Ortiz A, Pohl R, Gershon S. Azaspirodecanediones in generalized anxiety disorder: buspirone. J Affect Disord 1987;13:131-143.
    Pubmed CrossRef
  28. Sramek JJ, Tansman M, Suri A, Hornig-Rohan M, Amsterdam JD, Stahl SM, et al. Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms. J Clin Psychiatry 1996;57:287-291.
  29. Gammans RE, Stringfellow JC, Hvizdos AJ, Seidehamel RJ, Cohn JB, Wilcox CS, et al. Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms: a meta-analysis of eight randomized, controlled studies. Neuropsychobiology 1992;25:193-201.
    Pubmed CrossRef
  30. Cleare A, Pariante CM, Young AH, Anderson IM, Christmas D, Cowen PJ, et al. ; Members of the Consensus Meeting. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015;29:459-525.
    Pubmed CrossRef
  31. Kalin NH. The critical relationship between anxiety and depression. Am J Psychiatry 2020;177:365-367.
    Pubmed CrossRef
  32. Stavrakaki C, Vargo B. The relationship of anxiety and depression: a review of the literature. Br J Psychiatry 1986;149:7-16.
    Pubmed CrossRef


This Article

Close ✕


Cited By Articles
  • CrossRef (0)
  • Scopus (0)
  • Download (120)

Author ORCID Information

Services
Social Network Service

e-submission

Archives