Existing literatures suggest that between 54% and 78% of individuals with major depressive disorder (MDD) also experience anxious distress (ADS), emotional anguish, and suffering due to MDD [1,2]. MDD with ADS (MDDA) includes main symptoms such as tense feeling, restlessness, concentration difficulties by worry, fear to awful events, and feeling of losing control [3,4].

MDDA patients are known to have some characteristic clinical features including, early onset, chronic course, severe depressive symptoms, poor adaptive functioning, decreased quality of life, increase of care costs, and poor responsiveness to treatment [5]. Therapy is more effective when targeted to the needs of specific subpopulations such as MDDA patients [5-8], however, there has been limited clinical data regarding the use of diverse psychotropics in addition to current antidepressants in the treatment of MDDA based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V). Indeed a recent small controlled clinical trial has shown similar effects among treatment tactics including antidepressant monotherapy, antidepressant combination, antidepressant plus cognitive behavioral therapy (CBT) and antidepressant plus physiotherapy, where atypical antipsychotics (AAs) augmentation was not tried [9].

In Korea, interestingly updated official 2021 treatment guideline (Korean Medication Algorithm Project Depressive Disorder, KMAP-DD 2021) by Korean College of Neuropsychopharmacology (KCNP) proposes the possible utility of AAs for the treatment of MDDA based on the experts’ consensus stating that AAs augmentation should be one of the 1st treatment strategy in the treatment of MDDA along with antidepressant monotherapy [10]. Indeed many AAs including aripiprazole have shown their potential benefit in the treatment of anxiety symptom in various psychiatric population such as psychotic disorders, anxiety disorder and MDD [8,11-13]. However, there has been a dearth of specific data regarding the use of AA for the treatment of MDDA yet.

The unique action mechanisms and proven efficacy of aripiprazole augmentation (ARPA) for MDD warrant its use for the treatment of MDDA. Aripiprazole has distinct action mechanisms such as partial agonist effects on D2/D3 and 5-HT1A as well as antagonist effects on 5-HT2A, 5-HT6, 5-HT7, and 5-HT2C receptors, leading to regulation of dopamine, serotonin and norepinephrine in specific brain areas involving in improvement of mood and anxiety symptoms [14].

Hence this study aims to investigate the possible utility of ARPA in the treatment of MDDA under naturalistic treatment setting since observational study may implicate more practice-based clinical information than controlled study, also leading to collection and coalition of clinical evidence in line with experts’ consensus and treatment guidelines.

Inclusion criteria was minimal since the study was observational. MDDA treated with ARPA were included without other comorbid AXIS I/II disorders. MDDA was confirmed by the criteria of DSM-V, without structured interview. Medical records were retrieved from those who were needed additional treatment for reduction of anxiety symptoms and thereby treated with ARPA in patients with MDDA in routine practice in 2022. The observation period was 8 weeks (± 2 weeks) and ARPA was done on current treatments, with flexible dose adjustment. Data with complete records, both HMAD and HAMA were only retrieved. Forty-one patients met the criteria among 77 patients with ARPA. The data were retrieved form one teaching hospital.

All endpoints were collected from baseline to the end of 8 weeks treatment. The primary endpoint was the mean change of total scores of Hamilton Anxiety Rating scale (HAMA) [15]. The changes of total scores of Hamilton Depression Rating scale (HAMD) [16], Clinical Global Impression-Clinical Benefit (CGI-CB) [17] and Clinical Global Impression Score-Severity (CGI-S) [17] were included as the secondary endpoints. Other secondary endpoint were the remission (HAMD score ≤ 7 and CGI-Improvement score 1 or 2 at the end of study) and response (≥ 50% reduction of HAMD score at endpoint) rates. The proportions of patients who achieved ≥ 30% and ≥ 50% reduction of HAMA scores at endpoint were also analyzed. The cutoff points of mild anxiety and depression were 17, respectively. McNemar Test was done for comparison of mild severity in anxiety and depression between baseline and the endpoint.

Non-parametric analyses were done if the data distribution was not in normative range after Kolmogorov–Smirnov test, otherwise all data was analyzed by parametric analyses. Descriptive statistics, Wilcoxon Signed Rank (or paired ttest) test, chi-squared test were performed where appropriate. Statistical significance was determined at p < 0.05. Statistical analysis was performed using the NCSS v07 for Windows (NCSS Inc.) program. The power of the present sample size was 80%, with observed mean difference in HAMA at the end of treatment (effect size = 0.6667, β = 0.2), under drop-out rate of 15% and an alpha value of 0.05 with two tailed. The present study has been thoroughly reviewed and approved by local Institutional Review Board (approval number: HC23RISE0014).

Forty-one patients were enrolled and analyzed during the observation. The sample included a greater proportion of female patients (n = 26, 63.4%) with mean age of 42.9 years. The mean onset age of MDD was 37.7 years. One (2.4%) patient had family history of psychiatric disorders. Twelve (29.2%) patients had concurrent and stable medical disorders. The mean number of antidepressant change was 2.7. The initial and final doses of ARP were 1.6 and 1.9 mg/d, respectively (range: 1−5 mg/d throughout the observation period). Eleven (26.8%) patients were on antidepressant monotherapy while patients (73.2%) were on two or more antidepressant treatment. Thirty-seven (90.2%) patients were on antianxiety medications. The baseline HAMD, HAMA and CGI-S scores were 19.5, 21.2, and 4.0, respectively.

The changes of primary endpoint HAMA (t = 5.731, −4.6, p = 0.001), and secondary endpoints including HAMD (t = 4.284, −3.4, p < 0.001), CGI-CB (−0.9, t = 1.821, p = 0.026), and CGI-S (t = 3.556, −0.4, p < 0.001) scores were also significantly improved during the study. At the endpoint, the responder and remitter rates by HAMD scores were 14.6% (n = 6) and 9.8% (n = 4), respectively. The remission rate by CGI-I score at the endpoint was 24.4% (n = 10). The proportions of patients who achieved ≥ 30% and ≥ 50% reduction of HAMA scores at endpoint were 14 (34.1%) and 6 (14.6%), respectively. The proportions of patients with mild anxiety and/or depression were significantly increased at the endpoint, compared to those of baseline as seen in Figure 1.

The proportion of patients on CGI-CB 1−4 at endpoint was 9 (22.0%), while it was 2 (4.9%) at baseline, favoring ARPA of 3.5 times increase in CGI-CB improver rate. No significant adverse events were observed where one patient was observed weight gain. Table 1 displays detailed baseline characteristics and clinical parameters of all patients during the study.

We may assume the potential role of ARP for treating anxious depression would be in that unique action mechanism of the drug including partial agonist effects on D2/D3 and 5-HT1A as well as its antagonist effects on 5-HT2A, 5-HT6, 5-HT7, and 5-HT2C receptors, resulting in the regulation of dopamine, serotonin and norepine-phrine in specific brain areas involving in improvement of anxiety symptoms [14].

The use of ARPA for mood disorders has been in longstanding history, however, clinical data AA for anxiety alone and comorbid anxiety with mood disorders are still in lacking [18]. Fortunately, studies regarding the use of AA for various psychiatric conditions have dramatically increased with authorization in the market today and most currently available treatment guidelines are also favorable for the use of AA as supplementary medication to augment treatment effects in mood disorders [19]. According to a recent population-based data, AA preferential use was associated with some clinical factors including specific anxiety disorder such as generalized anxiety disorder and comorbidity with MDD or minor depression [20]. Especially physicians preferred AA for treating anxious mood and irritability in patients with difficult-to-treat MDD [21]. Indeed the potential role of ARPA for MDDA has been consistently demonstrated in numerous clinical trials, although such studies are not specifically designed for the effect of ARPA for MDDA [22-25]. For instance, a pooled study (n = 742) including two 14-week trials has shown that ARPA proved consistent efficacy for treating MDD regardless of presence of anxiety vs. placebo [23]. Hence previous trials are in line with the present findings and furthermore our data has added the potential role of ARPA for MDDA on the existing literatures.

However, the improvement of primary and secondary endpoints were moderate but not huge, even the remission and response rates were quite low than we expected. With this regard, the significant but moderate decrease in HAMD, HAMA, CGI-S, and CGI-CB scores and the number of remitters/responders might be caused by multiple clinical factors including baseline effects in relation with the severity of MDD and past resistance to antidepressant treatments, etc. In fact, pharmacological treatment effects were found to be substantially different in accordance with symptom severity, symptom domain, assessment scale and sex [26,27]. Interestingly in our previous study using ARPA for residual depression patients, the additional reduction of HAMD was 3 points [28]. Untreated residual anxiety symptoms are consistently found to be a definite huddle in achievement of sufficient clinical outcome in MDD in past studies [28,29]. In a recent study investigating the effect of ARPA for MDD patients with somatic symptoms, the decrease of Beck Anxiety Inventory score was also approximately 3 points, which is quite similar with our finding [30]. In addition the mean number of antidepressant change was almost 3 in our study corresponding to the level 3 of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial which has shown that the treatment effects are substantially decreased by failure of treatment [31]. Another point is that the mean dose of ARPA for MDDA was low ranging 1.6 mg/d to 1.9 mg/d, not greater than 2 mg/d, which is in line with Japanese controlled trial for MDD [32] where 3 mg/d of ARPA was equal or greater in treatment outcomes vs. 9.8 mg/d group. The mean dose of ARP was also 3 mg/d in a recent trials for MDD patients with somatic symptoms [30]. We may carefully assume that low dose of ARP should be adequate for subpopulation of MDD based on above findings.

Our study has clear pitfalls in generalization of the findings. The study design was retrospective (lack of control group) with small samples (recall bias) and thereby natural improvement of the illness should be considered. Antidepressant type and dose of ARP were fully flexible under naturalistic treatment setting. Rating scale biases could not be excluded. In addition, diagnosis of MDD, comorbid psychiatry disorder were not based on structured interviews, and AEs reporting was based on self-rating and could have been underreported. Finally, 8-week observation may not be proper duration for accurate evaluation of clinical outcome in MDDA patients.

In conclusion, our study calls the potential role of ARPA for MDDA in routine practice. Adequately-powered and well-controlled studies are mandatory for proving whether ARPA should be one of the next treatment option for MDDA.

None.

No potential conflict of interest relevant to this article was reported.

Conceptualization: Changsu Han, Chi-Un Pae. Protocol development: Kyung Ho Lee, Chi-Un Pae. Daft writing: Seung-Hoon Lee, Kyung Ho Lee, Tae Sun Han, Chi-Un Pae. Intellectual comments and critics on the content: Won-Myong Bahk, Soo-Jung Lee, Ashwin A. Patkar, Prakash S. Masand. Data acquisition: Kyung Ho Lee, Chi-Un Pae. Data analysis: Kyung Ho Lee, Chi-Un Pae.