A 6-Month Open-Label Study of Vortioxetine among Cancer Patients with Major Depressive Disorder (MDD)

Objective: Vortioxetine is a monoaminergic drug with a novel multimodal mechanism of action. We investigated its efficacy on depressive symptoms, cognitive function, and quality of life among cancer patients. Methods: In this multicenter, open-label, single-arm, observational study, patients received flexible doses of Vortioxetine for a period of six months. All participants were assessed at baseline and scheduled for monitoring at weeks 2, 4, 8, 12, 16, 20, and 24. Depression severity was assessed using Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale. The Perceived Deficiency Questionnaire (PDQ-5) assessed the perceived cognitive difficulties in concentration, executive functioning, and memory. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) was used to assess the patients’ quality of life. Side effects of vortioxetine were monitored using the Antidepressant Side-Effect Checklist (ASEC). Results: Patients experienced a reduction in MADRS scores from 29.89 ± 5.997 at baseline to 11.59 ± 4.629 by Week 24. The PDQ-5 scores showed significant change from Week-4, whereas the EORTC role, emotional, and cognitive functioning scores showed a significant change from Week 2 onwards. CGI-Severity scores decreased from a baseline of 4.39 ± 0.746 to 2.41 ± 1.085 by Week 24. During the 24-Weeks of therapy, around three-quarters of the patients (73.3%) had one or more adverse events reported on the ASEC. The most frequently reported TEAEs were dry mouth, insomnia, somnolence, and headache, with more than a 30% incidence rate. Conclusion: Vortioxetine seems promising in the management of depression and enhancement of cognitive function and quality of life of cancer patients with Major Depressive Disorder.

Introduction energy, and cognitive impairment (Niedzwiedz et al., 2019). Furthermore, research suggests that there may be bidirectional influences between pain, cognitive dysfunction, and depression: such that chronic pain and cognitive dysfunction may lead to higher risks of depression while depression may amplify the pain severity as well as exacerbate existing cognitive dysfunctions (Chochinov, 2001;Di Iulio et al., 2019). Cognitive impairments are a clinically significant problem for cancer patients, especially during chemotherapy, and its effects may last long after treatment and remission (Di Iulio et al., 2019).
While various antidepressants effectively treat depression within the general population irrespective of age (Katona et al., 2012;McIntyre et al., 2014), MDD remains challenging to treat among those with cancer. This is especially true in balancing potential adverse effects resulting from antidepressants, already taxing cancer treatments, and any potential drug interactions that may arise. Over the last few decades, new classes of antidepressants with fewer adverse effects have emerged. Of these, vortioxetine, for which a dearth of research exists within oncological settings, is of particular interest. Vortioxetine is a monoaminergic drug with a novel multimodal mechanism of action. It functions by combining the modulation of the 5-HT receptors (an agonist of 5-HT1A; partial agonist of the 5-HT1B; antagonist of the 5-HT3, 5-HT1D, and 5-HT7) and the inhibition of serotonin reuptake transporters (SERT). While long-term or chronic therapy with early-approved antidepressants often desensitizes 5-HT1A at the presynaptic neuron, creating a negative feedback loop that eventually reduces their anti-depressive effects, vortioxetine is an agonist of 5-HT1A, which may instead accelerate and maintain antidepressant effects (D'agostino et al., 2015).
More notably, vortioxetine is currently the only FDA-approved pharmacological agent for the treatment of MDD through the direct targeting of cognitive dysfunction (Lundbeck, 2018). This unique clinical feature has been demonstrated in both preclinical and clinical studies, whereby it exerts additional efficacy in improving cognitive function in individuals with depression independent of its effects as an antidepressant (Lundbeck, 2018;Mahableshwarkar et al., 2015;McIntyre et al., 2014;Smith et al., 2018). Its combined effect on SERT and 5-HT receptors has been suggested to significantly improve attention, executive function, learning, processing speed, and memory (Lundbeck, 2018) and enhance neurogenesis and plasticity-promoting effects (Bennabi et al., 2019). In head-to-head trials with escitalopram, vortioxetine more significantly improved short-term memory, attention, and processing speed parameters and had a greater positive influence on social, working, and total functioning (Levada and Troyan, 2019). Similarly, direct comparison studies of vortioxetine and duloxetine found that vortioxetine more greatly enhanced all measured parameters of cognitive function (Katona et al., 2012;Mahableshwarkar et al., 2015).
In addition to the above, vortioxetine demonstrates an efficacy profile comparable to that of other effective treatments of MDD and a favorable safety profile (Connolly and Thase, 2016;D'agostino et al., 2015;Nomikos et al., 2017), characterized by a lower incidence of sexual dysfunction and sleep disruption (Sanchez et al., 2015). Due to its relatively long half-life, vortioxetine is also generally well-tolerated with a low level of discontinuation symptoms in short-term and long-term clinical studies (Mahableshwarkar et al., 2015;McIntyre et al., 2014;Sanchez et al., 2015). Vortioxetine has also demonstrated good tolerability among multi-morbid MDD patient populations on various concomitant medications (Nomikos et al., 2017). In terms of pharmacokinetic drug interactions, vortioxetine has little to no effect on various cytochrome P450 (CYP) isoforms (Spina and Santoro, 2015), thus putting it at a major advantage compared to other widely-used antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, and citalopram (Hemeryck and Belpaire, 2002).
As such, it is conceivable that vortioxetine could potentially be a viable or preferable treatment for depression in patients experiencing depressive episodes associated with cognitive dysfunction, such as those with cancer-related cognitive impairment. Hence the objectives of our study were to determine the efficacy of vortioxetine on depression and cognitive function and to elucidate its potential effects on quality of life in patients with cancer of any origin.

Study Design
This was an open-label, single-arm, observational study conducted in six public hospitals across Malaysia over a period of twenty months. Patient recruitment started on 1st November 2019 and lasted until 31st December 2020; follow-up continued for six months after that, following which the trial officially ended on 31st May 2021. Ethics approval was obtained from the Medical Research Ethics Committee at Universiti Malaya (UMMC MREC; 201972-7593) and the National Medical Research and Ethics Committee (MREC; NMRR-19-2850-50323). Furthermore, the trial protocol was registered at ClinicalTrials.gov (NCT04253678).
Patient recruitment was done at the psychiatry clinics of the included hospitals, following a consecutive sampling technique. Eligible patients received flexible doses of vortioxetine and were monitored closely during scheduled follow-up visits. Since the study was conducted during routine medical care, augmentation of treatment with chemotherapy and radiotherapy was permitted according to the attending physicians' best clinical judgment. If patients did not respond favorably to the drug treatment, they were withdrawn from the study and received standard care as per the discretion of their attending psychiatrist.

Study Participants
The study participants were outpatients aged 18 years and above with cancer of any origin and a primary diagnosis of MDD based on the DSM-IV-TR criteria.
ASEC to assess the 21 common adverse reactions to antidepressants, such as dry mouth, drowsiness, insomnia, and appetite. The severity of each item is rated on a 4-point scale (0 absent; 1 mild; 2 moderate; 3 severe), and it is specified whether the symptom, if present, was likely to be a side-effect of the antidepressant (yes or no) (Uher et al., 2012).

Data Collection
All eligible patients were briefed on the study protocol. Consenting patients were initiated on vortioxetine (Brintellix tablets) flexible dosing from 5mg to 10mg daily, at the discretion of their consulting psychiatrist. They were dispensed enough medication for self-administration to last until the following visit. A baseline measure for MADRS, CGI, PDQ-5, and EORTC QLQ-C30 was done. Patients were followed up either in person at the outpatient clinic or through scheduled phone calls at weeks 2, 4, 8, 12, 16, 20, and 24. The same measures were administered during the scheduled follow-ups along with the ASEC.

Sample Size Calculations
The sample size was calculated to detect at least a mean difference of 6.6 units in MADRS total score with a pooled standard deviation of 7.8 units (Baldwin et al., 2012) at 90% power and a 5% level of significance (two-sided). Hence 30 subjects were required for the study; however, accounting for a drop-out rate of 50%, 45 subjects were recruited.

Statistical Analysis
Statistical analyses were carried out using SPSS Statistics (IBM) version 25. Data analysis was based on the all-patients-treated set, i.e., all patients who took at least one vortioxetine dose. Descriptive statistics were used to summarise the patients' baseline demographic characteristics and the Treatment-Emergent Adverse Events (TEAE). Multiple imputations were carried out to account for missing data. The primary efficacy analysis was a repeated measures Analysis of Variance (ANOVA) of the change from baseline in total mean MADRS, CGI, PDQ-5, and EORTC QLQ-C30 scores at Weeks 2, 4, 8, 12, 16, 20, and 24. A graph was plotted to illustrate the changes in mean scores throughout the six months for MADRS and EORTC QLQ-C30. The primary outcome was changes in MADRS and PDQ-5 scores, while changes in EORTC QLQ-C30 and CGI were considered secondary outcomes. All statistical analyses were set at a significance level of p<0.05.

Patient Baseline Characteristics
A total of 45 patients were included in the study; details of patients' allocation and follow-up are illustrated in Figure  1. Their baseline clinical and demographic characteristics are detailed in Table 1. The average age of the participants was around 53 years, with almost two-thirds females. More than half were Chinese (57.8%), 26.7% were Malay, and 6.7% were Indian. The mean baseline MADRS total score was 29.89 ± 5.997, indicating moderate to severe At baseline screening, patients were administered the Montgomery-Åsberg Depression Rating Scale (MADRS), and a score of at least 20 was required for eligibility, indicating moderate to severe depression.

Perceived Deficits Questionnaire -5 items (PDQ-5)
PDQ-5 is a 5-item self-report scale that assesses perceived cognitive difficulties in concentration, executive functioning, and memory. This brief version of the original 20-item PDQ has been adapted and validated for use in patients with MDD (Lam et al., 2018). The questionnaire estimates symptoms based on the past week, with each item rated on a scale of 0 to 3, where a higher score reflects greater severity of cognitive dysfunction.

Clinical Global Impression (CGI)
The CGI is used in clinical trials to provide a brief clinician's view of the patient's global functioning. The CGI is a one-item measure that consists of two components: (a) severity of clinical condition from 1 to 7 and (b) change from the initiation of treatment on a similar seven-point scale ranging from 1 (very much improved) to 7 (very much worse) (Guy, 1976). As such, CGI-I scores were measured from Week 2 to Week 24 and were not assessed at baseline.

EORTC QLQ-C30
This scale is a widely used clinical scale measuring the cancer-specific quality of life. It contains five functioning scales (physical, social, role, cognitive, and emotional functioning), eight symptom scales (fatigue, nausea/ vomiting, pain, dyspnea, sleep disturbances, appetite loss, constipation, and diarrhoea), financial impact, and overall quality of life. All scale scores are linearly converted to a range from 0 to 100. Higher scores indicate better functioning for the functioning scales and global QOL; for the symptom scales, higher scores indicate higher symptom burden (Aaronson et al., 1993).

Antidepressant Side-Effect Checklist (ASEC)
The Royal College of Psychiatrists developed

Efficacy Primary Efficacy Outcomes
Although there was variability in the patient dosing, data revealed (Table 2) a statistically significant difference in total MADRS from baseline starting from Week 2, this improvement in scores was maintained throughout the 24 weeks of the study. Patients experienced a reduction of 18 points in total MADRS scores from 29.89 ± 5.997 at baseline to 11.59 ± 4.629 by Week 24 (Figure 2). Furthermore, the PDQ-5 scores started to show significant change from baseline by Week-4; this significance in change was maintained for the rest of the study duration except for Week-8.

Secondary Efficacy Outcomes
Table 2 summarises the differences in scores of the secondary outcomes from baseline at Week 2 until Week 24; these include the CGI, EORTC quality of life, EORTC Asian Pacific Journal of Cancer Prevention, Vol 24 2587 DOI:10.31557/APJCP.2023.24.8.2583 Vortioxetine in Cancer with MDD   Figure 3 illustrates changes in the EORTC quality of life, EORTC physical functioning, EORTC role functioning, EORTC emotional functioning, EORTC social functioning, and EORTC cognitive functioning scores throughout the six months of therapy.There appears to be an overall increase in the EORTC scores from baseline as early as week 2, this increase has been sustained till week 16 despite the appararent fluctuation in scores across the study duration.

Tolerability and Safety Adverse Events (AE)
During the 24 weeks of therapy with variable doses of vortioxetine, around three-quarters of the patients (73.3%) had one or more adverse events. Out of the included 45 patients, 22 withdrew from the study, of which 16 patients (35.55 %) were due to Treatment-Emergent Adverse Events (TEAE). The most frequently reported TEAEs were dry mouth, insomnia, somnolence, and headache, with more than a 30% incidence rate. The frequency of TEAD reported by the patients is detailed in Table 3.

Serious Adverse Events (SAE)
Three deaths occurred during the study. The first was a 51-year-old woman with advanced rectosigmoid carcinoma involving lung and liver metastasis; the patient was in the study for around 20 Weeks. The second patient was a 70-year-old woman with intrahepatic cholangiocarcinoma; she died two weeks after inclusion in the study. The last case was a male, 80 years old with prostate carcinoma, who passed away two weeks following his entry to the trial. The investigator evaluated all the patients and assessed their death as a natural disease progression and not related to vortioxetine medication.

Discussion
Depressive symptoms are frequent among cancer patients, and their frequency has been well documented in the literature. However, given that depression is linked to poorer cancer outcomes, decreased patient quality of life, and non-compliance with chemotherapy, the coexistence of these two conditions can be particularly problematic. Accordingly, we conducted a study to assess the efficacy and tolerability of a novel multimodal antidepressant on cancer patients diagnosed with depression. To our knowledge, this is the first assessment of the effects of vortioxetine in this patient cohort. This research provides supporting evidence that vortioxetine has a positive impact on cancer patients' depressive symptoms, The findings of our study demonstrate a significant improvement in the mean total MADRS score as early as week 2; this change was maintained until week 24. This pattern of results is consistent with and extends the body of evidence on the positive impact of vortioxetine on adults with MDD previously reported (Alvarez et al., 2012;Boulenger et al., 2014). Both randomized, double-blinded placebo-controlled studies demonstrated a statistically significant change in MADRS total scores from baseline that is superior to placebo. Another key finding is the enhancement in the baseline patient-reported cognitive function scores set out from week four and maintained until week 8. Similar results were mirrored in a randomized, double-blind study on adults with recurrent MDD; the vortioxetine group showed significant improvement in objective and subjective cognitive function measures compared to the placebo (McIntyre et al., 2014). Furthermore, our results are highly consistent with the REVIDA study that demonstrated the efficacy of vortioxetine in reducing depressive symptoms and enhancing cognitive function among South-East Asian patients in clinical settings (Chin et al., 2018).
The enhancement in physician-reported CGI scales further supports the positive impact of vortioxetine on depression; both the improvement and severity scores showed significant change from baseline by week 24. The reduction in CGI scores is congruous with data from research and clinical settings related to vortioxetine use among adults with Major Depressive Disorder (Alvarez et al., 2012;Boulenger et al., 2012;Boulenger et al., 2014;Chin et al., 2018;McIntyre et al., 2014). The current study also highlighted the effect of vortioxetine on cancer patients' quality of life, which was assessed using the EORTC QLQ-C30 scale. The findings showed that the domains of role, emotional, and cognitive functioning improved significantly from Week 2. These results are corroborated by six short-term, placebo-controlled studies analyzed for the impact of vortioxetine on the healthrelated quality of life of adults with MDD (Florea et al., 2015). Vortioxetine demonstrated significantly better results than placebo in the vitality, social functioning, emotional role functioning, and mental health domains of the Short Form 36 Health Survey. Furthermore, it separated from the placebo on the European Quality of Life Scale and the Quality of Life Enjoyment and Satisfaction Questionnaire.
During the 24-week study period, around threequarters of the patients reported one or more adverse events. Although this proportion is slightly higher than in past research, the medical history of our patient cohort provides a compelling explanation for these findings (Alvarez et al., 2012;Boulenger et al., 2014). In addition, side effects were actively assessed via the ASEC scale at all time points of this study. As such, this could induce a higher adverse event reporting than in real-life clinical practice, where patients spontaneously report adverse events. The most common adverse events during treatment, including dry mouth, insomnia, somnolence, and headache, are consistent with studies on treatmentrelated adverse events of vortioxetine (Alvarez et al., 2012;Boulenger et al., 2012;Boulenger et al., 2014). The withdrawal rate in this study is significantly higher than in other real-life studies of vortioxetine in Asia (Alvarez et al., 2012;Boulenger et al., 2012;Boulenger et al., 2014) and could be due to cancer exacerbating some of the adverse events.
This six-month open-label clinical trial was conducted to evaluate the efficacy and tolerability of vortioxetine in a small sample of cancer patients with depressive symptoms, however its findings are subject to several limitations. The first limitation concerns patient adherence; it was not possible for the investigators to confirm the reported patient adherence, especially since they were not required to stay on-site throughout the study duration. Another potential limitation, notwithstanding the positive study results, is the small sample size and the absence of a placebo/ comparator arm rendering the findings exploratory in nature. Additionally, the use of questionnaires that have not been validated within the population of interest exposed the data to potential measurement error, thereby the results are to be interpreted with caution. Another major source of uncertainity is the impact of confounding variables, this study had no restrictions on concomitant psychotherapy, and hence its effect on the research outcomes cannot be ruled out. Furthermore, almost half of the subjects enrolled in the study were breast cancer patients, thereby affecting the potential pertinency of its findings to other types of cancers, including advanced or palliative cases. These limitations affect the potential  Table 3. Reported Incidence of Treatment-Emergent Adverse Events (TEAE) during the 24 Week Treatment Period generalizability of the study findings beyond the clinical trial setting and suggest the need for future research to evaluate the effect of vortioxetine on depression, cognitive function, and quality of life of depressed cancer patients. The current study fills the gap in research on the effect of multimodal antidepressants on cancer patients with depression. Despite its limitations, the results suggest that vortioxetine is efficacious in reducing depressive symptoms and enhancing this patient cohort's cognitive function and quality of life. Future randomized controlled clinical trials evaluating the efficacy and safety of vortioxetine in larger cancer populations are warranted.
In conclusions, the present study supports the growing body of evidence on the efficacy of vortioxetine, 5-20 mg/ day, in the management of depression, enhancement of cognitive function, and quality of life of cancer patients with Major Depressive Disorder. Findings from this research suggest that vortioxetine at the earlier mentioned doses can be utilized in future clinical trials to evaluate its comparative efficacy among cancer patients with depression.