Metabolic Effects of Antidepressants: Results of a Randomized Study’s Interim Analysis

Background and objectives: Individuals with major depressive disorder exhibit a dysregulated metabolic profile. There are few studies on how vilazodone, escitalopram, and vortioxetine alter metabolic parameters. Our study aimed to determine the change in plasma glucose, HbA1c, serum cholesterol, triglyceride, and creatinine at 12 weeks. Methods: An ongoing randomized, open-label, three-arm study's interim analysis is portrayed here. The participants were assessed at baseline, 4, 8, and 12 weeks after receiving oral tablets of either vilazodone (20-40mg/d), escitalopram (10-20mg/d), or vortioxetine (5-20mg/d). This study is CTRI-registered (2022/07/043808). Results: Of 71 recruited participants, 49 (69%) completed the 12-week visit. The median Hamilton Depression Rating Scale (HDRS) scores of the participants in vilazodone, escitalopram, and vortioxetine groups were 30.0, 29.5, and 29.0 at baseline (p=0.76) and 19.5, 19.5, and 18.0 (p=0.18) at 12 weeks, respectively. The median fasting blood sugar (FBS) values were 98.5, 105.5, and 98.0 at baseline (p=0.07) and 94.0, 99.5, and 96.0 (p=0.19) at 12 weeks, for vilazodone, escitalopram, and vortioxetine groups, respectively. The post hoc analysis did not yield statistically significant differences regarding any parameters. Conclusion: According to this interim study, the HDRS scores declined after 12 weeks of therapy. The subjects' metabolic parameters did not significantly change. It is essential to perform further investigation regarding these impacts.


Introduction
Major depressive disorder (MDD) creates havoc on an individual's physical, psychological, and interpersonal life. Through significant neurohormonal mechanisms, MDD and metabolic disorders can coexist [1]. During the preceding twenty years, the prevalence of MDD has fostered a sharp rise around the globe [2]. According to recent statistics, the annual prevalence of MDD is 15.9% in India [3]. The metabolic parameters like blood glucose, serum creatinine, serum total cholesterol, and triglyceride tend to derange as MDD advances. These parameters are somewhat fixed via antidepressants [4][5][6][7].
While there exist several effective antidepressants on the shelves, it is unexplored which drug optimizes these metabolic traits. Plus, less information exists about the magnitude and longevity of these amenities [8]. Based on the literature survey, we planned this study with three antidepressant drugs, namely, escitalopram, a selective serotonin receptor inhibitor (SSRI); vilazodone, an SSRI with partial agonistic action at 5-HT1A receptors; and vortioxetine, a serotonin modulator plus transporter inhibitor [9][10][11]. This study was backed by the contention that newer antidepressants could aid in improving the metabolic parameters of patients with MDD. Recent studies advocate the betterment of such metabolic parameters in patients on regular antidepressants [12][13][14].
This study aimed to determine the metabolic parameters in patients with MDD after 12-week antidepressant monotherapy of vilazodone, escitalopram, or vortioxetine. Here we reported the interim results of a more extensive ongoing study focused on changes at week 12 in the fasting blood sugar (FBS), glycosylated or glycated hemoglobin (HbA1c), serum total cholesterol, triglyceride, serum creatinine, body mass index (BMI) along with the Hamilton Depression Rating Scale (HDRS) score [15]. We also analyzed the association between the changes in FBS and HDRS at week 12.

Materials And Methods
This randomized, open-label, three-arm, open-label study seeks to determine the effects of vilazodone, escitalopram, and vortioxetine on the metabolic parameters of individuals with MDD. In July 2022, we started recruiting participants in the Department of Psychiatry, Burla, VIMSAR, India. Before group allocation, the participants or their relatives signed written informed consent for the study. Before the study commenced, the Institutional Ethics Committee, VIMSAR, Burla, Odisha, India, provided us with ethical permission (No. 029-2022/I-S-T/03 dated 17.05.2022). Our study is prospectively registered with the Clinical Trial Registry, India (CTRI/2022/07/043808). The study adhered to the International Council for Harmonization's recommendations for Good Clinical Practice, Declaration of Helsinki, and institutional norms.

Study participants
Individuals 18-65 years of age diagnosed with MDD, with an HDRS score of ≥ 24, were included. This study excluded patients with degenerative neurological illnesses, psychotic symptoms, kidney disease (estimated glomerular filtration rate at baseline < 45ml/min/1.73m2), cardiovascular incidents within the preceding six months, serum alanine transaminase (ALT) or aspartate transaminase (AST) levels > 150% the upper limit of normal, serum triglyceride > 400 mg/dl, and pregnant or nursing women. The participants are free to retract their consent at any moment without elucidation.

Study design and endpoints
In a 1:1:1 ratio, the participants received a random selection to commence intervention with tablets of either vilazodone 20-40mg once daily (group A), escitalopram 10-20mg once daily (group B), or vortioxetine 5-20mg once daily (group C). Permuted block randomization with blocks 12 and 24 was adopted to accomplish this. We stratified randomization according to gender (male or female) and disease condition (treatment naïve or on antidepressants for < 6 months. For the assessment involving metabolic parameters in this interim analysis, we sorted the participants as diabetics and non-diabetics. The change in FBS from baseline at week 12 was the primary objective for this interim analysis. Secondary objectives were changes in the HDRS score, glycated hemoglobin (HbA1c), serum total cholesterol, triglyceride, serum creatinine, and body mass index (BMI) at week 12. The analyses were concentrated on the per-protocol (PP) population.

Study procedure
Throughout the study span, each participant received one of these antidepressant tablets: vilazodone 20-40mg once daily (group A), escitalopram 10-20mg once daily (group B), or vortioxetine 5-20mg once daily (group C). The lead investigator supplied these medications to the participants free of cost. Conforming the participant's clinical outcome to the drugs given, the psychiatrist tuned their dosages. No cross-over was allowed. At the initial excursion, all participants comprehensively assessed their mental and physical health. We scheduled follow-up appointments after 4, 8, and 12 weeks of the baseline visit. At baseline and after that, every four weeks through week 12, the participant's HDRS scores and the abovementioned metabolic parameters were evaluated. We correlated the changes in FBS and HDRS at week 12 from the respective baseline values. Lower HDRS scores infer tremendous therapeutic success and less depressed symptoms.

Statistical analysis
The sample size was finalized for the primary endpoint of the whole study. Considering a mean difference in the HDRS of 10.0 from baseline and a standard deviation of 2.0, 87 patients (29 in each group) were needed to measure a change in the HDRS with an 80% power at a 0.05 two-sided significance level. Ninety-six participants (32 in each group) were finalized for this study considering a 10% attrition rate into account. After completing the 12-week visit by the first 48 subjects, we performed an interim analysis.
To verify the normality of the data, the Shapiro-Wilk test was implemented. The continuous data were displayed as median with interquartile range (IQR), and the Kruskal-Wallis test was applied to gauge them prior to post hoc analysis by the Bonferroni test. The categorical data were shown as the frequency with proportion, and Pearson's chi-square ( 2) test was adopted for their evaluation. For data computation, we leveraged the R software (version 4.2.3) [16]. Each statistical test was two-tailed, and a p-value of 0.05 or lower was treated as statistically significant.

Results
For eligibility, 71 patients underwent screening. Four individuals who hesitated to express their consent, one pregnant woman, and 10 others who fell short of the age limits were dropped from the research study. Each of the remaining 56 participants received a random assignment to one of the three study groups. One participant in the escitalopram arm revoked her consent, and six additional individuals (two, one, and three among the pertinent study groups) failed to turn up for their follow-up visits. Forty-nine participants (24 women and 25 men; 16,16, and 17 in the vilazodone, escitalopram, and vortioxetine arms, respectively) were assessed in this interim analysis (Figure 1). Participants possessed similar baseline traits across the three study groups ( Table 1).

FIGURE 3: Glycemic parameters and HDRS scores of the study participants
The plots illustrate the glycemic parameters and HDRS scores of all study participants (sub-grouped as diabetic or non-diabetic at the baseline visit) at the baseline and week 12. The metabolic parameters, e.g., serum total cholesterol, triglyceride, body mass index, and serum creatinine of the study population at baseline and week 12, are illustrated in Figure 4.  (Figure 4d). Post hoc analysis with the Bonferroni test revealed no statistically significant difference among the groups regarding any of the parameters mentioned earlier.

FIGURE 4: Other metabolic parameters of the study participants
The jitter plots illustrate other metabolic parameters of all study participants (sub-grouped as diabetic or nondiabetic at the baseline visit) at the baseline and week 12. The horizontal lines represent the corresponding median values. The intergroup comparisons at each visit were made with the Kruskal-Wallis test. Parts a, b, c, and d demonstrate the serum cholesterol, triglyceride, body mass index (BMI), and serum creatinine values, respectively, of diabetic and non-diabetic participants at the baseline and week 12.

Discussion
This interim analysis revealed that all three study medications had analogous effects on the metabolic markers in individuals with diabetes and those without diabetes. Nearly all participants complied with the study protocol and had reduced HDRS scores after 12 weeks of therapy. Differences in HDRS and FBS values had a non-significant correlation. Our findings on metabolic parameters and HDRS scores accorded with those from two previous investigations [8,12].
20-40 mg of vilazodone and 5-20 mg of vortioxetine were the daily doses for the experimental groups, while 10-20 mg of escitalopram was the daily dose for those enrolled in the control arm. Escitalopram, which serves as the control, has only one mechanism of action, while vilazodone has the bonus of being a partial agonist at the 5-HT1A receptor. Vortioxetine, meanwhile, interferes with serotonin receptors and hinders its transport. We noticed that the reduction in HDRS scores and improved quality of life in the vortioxetine group were more significant than in the remaining two groups [17,18]. These results hint that vortioxetine monotherapy may be viable for managing MDD.
Regardless of the groups they were allocated to, all trial participants acquired no-cost medication. The low attrition rate could have ensued from this. All the study participants had plummeted HDRS scores after 12 weeks of antidepressant medications. Nonetheless, neither of the studied drugs prompted any metabolic parameter to change in a way that could be deemed clinically or statistically significant. Per some previous studies, vortioxetine proved its potential to improve the metabolic parameters of patients with MDD [12][13][14]. However, our results did not align with the studies cited above. According to our preceding analyses, optimal antidepressant activity mandates frequent visits, superior quality of life, and excellent drug compliance [17,18]. This study explores the metabolic parameters and HDRS scores to illuminate what ensued. As mentioned earlier, the findings must be perceived as preliminary, as this was merely an initial audit of a larger research project. Furthermore, additional evaluations are crucial to determine whether the medications have a noticeable impact on the metabolic indicators after an extended follow-up.
Permuted block randomization and subgroup analysis of the study objectives were this study's core strengths. Regular follow-up visits and gauging depression symptoms employing a widely acknowledged and adopted HDRS offered additional advantages [15]. Our study had a few drawbacks, likewise. First, the dropouts and computation issues of the metabolic parameters might be traced to the open-label trial design. Second, the medications utilized for this study were offered without charge. The dearness of the study medications could constrain the practical relevancy of the study findings. Third, the abovementioned findings hinge on an interim analysis of a more extensive and continuing study. It is necessary to explicitly validate the coherence between these results and those from the ongoing larger study.

Conclusions
According to this interim analysis, after completing the therapeutic intervention for 12 weeks, each participant's HDRS scores significantly decreased. The metabolic indices of the participants were not changed significantly. Further analysis of these effects is imperative.

Additional Information
Disclosures