Antidepressant Treatment Strategy with an Early Onset of Action Improves the Clinical Outcome in Patients with Major Depressive Disorder and High Anxiety: A Multicenter and 6-Week Follow-Up Study
Major depressive disorder (MDD) is a prevalent, chronic, and highly disabling psychiatric illness that affects millions of individuals worldwide. A significant challenge in the treatment of MDD is the frequent co-occurrence of anxiety symptoms, which are present in up to 90% of patients. High levels of anxiety symptoms are particularly concerning because they are associated with poorer clinical outcomes and reduced response to pharmacotherapy. This has led to increased interest in developing treatment strategies that can address both depressive and anxiety symptoms effectively, particularly in the early stages of treatment.
The importance of early improvement in depressive symptoms has been increasingly recognized in the literature. Studies have shown that a lack of early improvement, defined as less than a 20% reduction in depression scale scores within the first two weeks of treatment, is a reliable predictor of eventual non-response to antidepressants. This observation has prompted researchers to explore the potential benefits of early intervention strategies, including the use of augmentation or combination therapies, to improve outcomes in patients with MDD and high anxiety.
This study aimed to evaluate the impact of early onset of antidepressant action on clinical outcomes in patients with MDD and high anxiety. Additionally, the study sought to identify potential factors influencing early improvement, with a particular focus on the role of sedative-hypnotic drugs in augmenting the early effects of antidepressant treatment.
The study was conducted as a post-hoc analysis of a multicenter, randomized, parallel-controlled, open-label trial. A total of 245 patients aged 18 to 65 years, diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria, were included. All participants had a current major depressive episode with a Hamilton Depression Rating Scale 17-item (HAMD-17) total score of 17 or higher and a Hamilton Anxiety Rating Scale (HAMA) total score of 14 or higher at baseline.
Participants were assigned to receive at least six weeks of antidepressant treatment, which included selective serotonin reuptake inhibitors (SSRIs) alone or in combination with a flexible dose of tandospirone. The SSRIs used in the study were fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, and escitalopram. Notably, not all patients were antidepressant-naive at the start of the study, but none had received an adequate dose of antidepressants for more than two weeks in the current episode. Short-term use of sedative-hypnotic drugs, such as zopiclone, lorazepam, alprazolam, clonazepam, midazolam, zaleplon, and zolpidem, was permitted as needed for sleep disorders.
Efficacy measurements were conducted at weeks 2, 4, and 6 using several assessment tools, including the HAMD-17, HAMA, Clinical Global Impressions Severity Subscale (CGI-S), and the Short Form-12 (SF-12) Physical Component Score (PCS) and Mental Component Score (MCS) to evaluate quality of life. Remission was defined as an HAMD-17 total score of 7 or lower.
At the end of week 2, 240 patients remained in the study and were divided into two groups based on the reduction rate of their HAMD-17 total scores compared to baseline: the early-improvement group (≥20% decrease in HAMD-17 total score, n=134) and the early-unimproved group (<20% decrease in HAMD-17 total score, n=106). By the end of the 6-week follow-up, 230 patients had completed the study, including 128 in the early-improvement group and 102 in the early-unimproved group.
The analysis revealed several key findings. At baseline, the early-improvement group had significantly higher HAMD-17 (24.76 vs. 23.11) and CGI-S (4.89 vs. 4.54) scores and lower SF-12 PCS (38.77 vs. 41.65) and MCS (26.01 vs. 28.05) scores compared to the early-unimproved group. Over the course of the study, the early-improvement group showed statistically superior improvements in HAMD-17, HAMA, CGI-S, SF-12 PCS, and SF-12 MCS scores compared to the early-unimproved group. By week 6, the least-squares mean HAMD-17 total score was significantly lower in the early-improvement group (6.48 vs. 12.17), as were the HAMA (7.19 vs. 11.8) and CGI-S (1.91 vs. 2.65) scores. The early-improvement group also showed greater improvements in SF-12 PCS (48.26 vs. 45.36) and MCS (44.21 vs. 36.36) scores. Importantly, the remission rate at week 6 was significantly higher in the early-improvement group (62.8% vs. 29.4%).
Logistic regression analysis was used to identify factors influencing early improvement. The model included variables such as treatment type (SSRIs + tandospirone vs. SSRIs alone), combination with sedative-hypnotic drugs, age, body weight, sex, age of onset of psychiatric symptoms, course of the recent episode, and baseline scores on the HAMD-17, HAMA, CGI-S, SF-12 PCS, and SF-12 MCS scales. The analysis revealed that the combination with sedative-hypnotic drugs was a significant predictor of early improvement, with an odds ratio of 7.556 (95% confidence interval: 1.607–35.530).
The findings of this study are consistent with previous research demonstrating the importance of early improvement in predicting treatment outcomes in MDD. Specifically, the study highlights the value of early improvement in patients with MDD and high anxiety, showing that those who achieve early improvement are more likely to experience sustained symptom relief and improved quality of life. The study also underscores the potential benefits of combining sedative-hypnotic drugs with antidepressants in the early stages of treatment, particularly for patients with high anxiety symptoms.
In conclusion, this study provides strong evidence that early improvement within the first two weeks of antidepressant treatment is a powerful predictor of clinical outcomes in patients with MDD and high anxiety. The findings suggest that short-term combination therapy with sedative-hypnotic drugs may enhance the early onset of antidepressant effects, leading to better overall outcomes. These results have important implications for the development of treatment strategies aimed at improving the prognosis of patients with MDD and comorbid anxiety.
doi.org/10.1097/CM9.0000000000000673
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