Identify and synthesize the studies that have assessed depression levels in patients receiving IVC treatment for cancer, identify gaps and put forward recommendations for further research.
Vitamin C for the treatment of depression in cancer patients: A literature review
Abstract
Introduction:
One in two Canadians will be diagnosed with cancer in their lifetime and one in four will experience depression during their diagnosis. The cause of depression during cancer could be related to psychological, social, inflammatory, or immunological factors. Vitamin C can exert an effect on oxidative stress levels, adrenal function, and immune function and may have a role in the treatment of both cancer and depression. Vitamin C levels can affect neurotransmitter levels and its ability to increase quality of life in cancer patients, as well as relieve other cancer-related symptoms such as pain, has been documented.
Methods:
A systematic literature search was completed to identify all studies that assessed changes in depression symptom severity in patients receiving intravenous vitamin C treatment. The databases utilized include Pubmed, Medline Complete, CINAHL Plus, Web of Science, Cochrane, and PMC. The criteria of inclusion were the following: human participants with confirmed cancer of any type and stage, intravenous vitamin C (IVC) treatment, with or without conventional treatment and with or without additional oral vitamin C dosing, and assessment of depression. Studies were excluded if they were preclinical studies (e.g., animal or in vitro), non-English publications, and literature reviews and/or opinion articles.
Results:
Out of 152 unique articles analyzed, four observational studies were identified which assessed depression symptoms as part of an assessment of quality of life in cancer patients undergoing intravenous vitamin C treatment. All four studies reported improvement in mood.
Conclusion:
The present findings are limited by a lack of a control group and the lack of a validated questionnaire for the measurement of depression symptoms. While these results suggest that vitamin C may be a useful adjunctive therapy in the treatment of depression in patients with cancer, more research is needed.
Keywords
Vitamin C; Cancer; Depression; Intravenous; Ascorbic acid; Mental health; Mood; Naturopathic medicine; Naturopathy
Introduction
-One in two Canadians will receive a diagnosis of cancer in their lifetime and one in four of them will experience depression during their diagnosis [1]. The cause of depression during cancer is often multifactorial and may include psychological, social, and immunological factors as well as inflammation related to cancer or treatments [2]. Chronic stress is common in cancer patients, leading to increased levels of catecholamines, which are associated with higher rates of depression [2]. Although depression in cancer patients is common, it is underdiagnosed [2]. Not only does depression in cancer patients significantly reduce quality of life (QoL), it is also associated with higher levels of anorexia, fatigue/sleep issues as well as an increased number of days in the hospital and numbers of resources used, leading to greater health-related expenses [2, 3]. Cancer patients with depression are more than two times more likely than people without cancer to commit suicide [4]. Studies have associated increased depression with increased metastasis and worse survival outcomes [5, 6]. Vitamin C deficiencies have significant implications in the synthesis of the neurotransmitters serotonin, norepinephrine, and dopamine, which play an important role in the setting of depression and mental health [7-9].
-The antioxidant effects of vitamin C in non-cancerous cells are a potential mechanism of action for a possible antidepressant effect [3, 10]. Khanzode et al. showed that individuals with major depression have significantly increased levels of oxidative stress markers, such as serum superoxide dismutase (SOD), and increased serum malondialdehyde (MDA) and decreased plasma vitamin C levels [10]. Multiple studies have been conducted that show patients with depression have significantly decreased vitamin C levels [11-13]. In a double-blind, experimental study, Zhang et al. demonstrated that oral vitamin C administration to acutely hospitalized patients significantly improved depression[14]. In the double-blind, placebo-controlled pilot study, Amr. et al found that 1 g of oral vitamin C per day alongside fluoxetine significantly reduced depression as compared to fluoxetine with placebo [15].
-Nutritional deficiencies are frequently observed in cancer patients due to a variety of reasons, ranging from lack of appetite, changes in taste, to increased biological demands associated with cancer and chemo/radiotherapy [16-21]. These nutritional deficiencies have dramatic implications in disease progression with some studies citing an approximated 30% increase in mortality in malnourished cancer patients [16]. In a 2019 study of palliative cancer patients, authors Vollbracht et al. sought to determine nutritional status and found vitamin C deficiency (defined as serum below 4.5mg/L) in 45.2% of patients, as well as deficiencies of vitamin D3 (93.5%), B6 (48.4%), and B1 (25.8%) [11]. When a patient undergoes surgery, chemotherapy, or radiation, there is an increased demand by the body for vitamin C as it plays an integral role in several different biological mechanisms [19, 21-25].
-Cancer and depression share some common pathophysiologic characteristics, such as decreased immune function and altered adrenal function and vitamin C could possibly alleviate both [2, 26]. Not only are cancer patients at an increased risk for depression, but depression can cause chronic stress, which may be implicated in the pathogenesis and progression of cancer [26-28]. Chronic stress increases epinephrine, which is known to suppress the immune system and high enough levels for a long enough time may potentially contribute to carcinogenesis [26]. Studies have been completed in-vitro and in-vivo that show vitamin C decreases chronic stress-induced cancer cells, indicating that vitamin C possibly plays a role in tumour growth via this mechanism [26]. Vitamin C is also vital for adrenal function, which plays a crucial role in depression via the hypothalamic-pituitary-adrenal (HPA) axis, therefore it is important to have sufficient levels for emotional wellbeing [29, 30].
-Vitamin C is a versatile nutrient in the body which was first isolated in 1928 and has since been subject to many different studies to explore its various applications and mechanisms [7]. Humans lack the enzyme gulonolactone oxidase, which is integral to endogenous vitamin C synthesis; as such, deficiency is common in humans when demands are not met through dietary sources or supplementation [7]. Linus Pauling was the first to provide intravenous vitamin C (IVC) to cancer patients in the 1970’s and in the following 50 years to help reduce tumour growth as well as cancer-related symptoms, and a significant amount of research has been undertaken on this therapy [31]. Studies have shown that high dose IVC is safe and has beneficial cancer-related effects such as increased survival times, decreased tumour growth, increased QoL, increased efficacy of conventional treatment, decreased cancer symptoms, and decreased side effects from conventional cancer treatment [31].
IVC administration results in increased serum levels 25 to 100 times higher than with oral administration for a minimum of 4 hours; this is largely due to the limitations of oral route administration, such as the limited capacity for enteric absorption coupled with renal excretion rates [32-34]. IVC produces an exponentially higher serum status of vitamin C for a sustained period of time as compared to oral route administration [33]. The resulting increase in serum vitamin C is utilized by GLUT glucose transporters, which are upregulated in tumour cells and lead to substantially higher concentrations within tumours than non-cancerous tissue [31]. This upregulation of vitamin C intake in tumour cells accounts for some of the increased metabolic demand for vitamin C in cancer patients; this is why achieving substantially higher serum status is necessary through IVC application as it bypasses the limitations of enteric absorption rates [31]. The pro-oxidant effects of high cellular levels of vitamin C increases hydrogen peroxide, which has been demonstrated to be oncolytic while being neutral to non-cancer cells due to the presence of catalase [31, 35-37]. This capacity of catalase is demonstrably reduced in cancer cells with some studies noting a two-fold difference in metabolism [38]. In short, several authors have suggested that there is an increased metabolic demand for vitamin C in people with cancer; this may have implications in mental health due to vitamin C’s role in neurotransmitter synthesis.
Despite preliminary evidence and possible mechanisms, no efforts have been made to synthesize the research related to the effects of IVC on depression levels in patients with cancer. The purpose of this literature review is to identify and synthesize the studies that have assessed depression levels in patients receiving IVC treatment for cancer, identify gaps and put forward recommendations for further research.
Methods
This literature review analyzed all available studies on the effect of IVC on depression in cancer patients. The search strategy was executed using the PubMed, MedLine Complete, CINAHL Plus, Web of Science, Cochrane, and PMC databases in May 2020. The “IVC,” “Intravenous Vitamin C,” “Vitamin C” and “Ascorbic Acid” search terms were used in conjunction with “Depression” and “Cancer.” Both prospective and retrospective observational studies were included. Bibliographies of relevant articles were searched for additional publications not identified in the search.
The criteria of inclusion were the following: human participants with confirmed cancer of any type and stage, intravenous vitamin C (IVC) treatment, with or without conventional treatment (chemotherapy, radiation, and/or surgery) and with or without additional oral vitamin C dosing, and assessment of depression. Studies were excluded if they were preclinical studies (e.g., animal or in vitro), non-English publications, and literature reviews and/or opinion articles.
Results
The search strategy identified 152 scholarly articles. Of these, four observational studies met criteria for inclusion. These four studies have been summarized in Table 1.
The populations of the included studies were all adults with a variety of different kinds of malignant cancer diagnoses and stages, including stage IV terminal cancer and stages IIa-IIb breast cancer (refer to Table 1). In all four studies, researchers found a benefit of IVC on depressive symptoms associated with cancer and/or cancer therapy. All four studies excluded information on whether or not supplemental professional mental health support was provided to patients. In the Yeom et al. study, authors examined the impact of IVC and oral vitamin C supplementation on 39 patients with terminal cancer diagnoses (less than six months life expectancy) where the treatment goal was improvement of QoL[39]. Two doses of 10 g IVC per day for three days with concurrent 4 g oral route per day vitamin C for one week was found to significantly improve the scores of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)[39]. Analysis revealed significant improvement in all five functional scales (physical, role, emotional, cognitive, social) and significant improvement in several symptom scores such as fatigue, nausea/vomiting, and appetite loss; and other symptom improvement was observed in pain and sleep disturbance [39].
Similarly, Takahashi et al. used a combination of oral and intravenous vitamin C and reported a significant improvement in EORTC QLQ-C30 scores at two weeks compared to baseline and an even greater improvement at 4 weeks in 60 patients [40]. This study also reported significant improvements in all five functional scales, which includes emotional function as well as fatigue, insomnia, pain, and constipation [40].
Two retrospective studies were included in our review, Bazzan et al. and Vollbracht et al [3, 41]. In the Bazzan et al. study, authors identified cases where patients had either received IVC alone, IVC and chemotherapy, or chemotherapy alone [41]. Bazzan et al. reported significant improvement in pain and fatigue and six out of seven patients reported improved mood (the last remained unchanged) [41]. In the Vollbracht et al. study, authors sought to explicitly examine the impact of IVC on symptoms caused by chemotherapy and radiotherapy with regards to depression as well as fatigue, sleep disorders and loss of appetite [3]. As a result, Vollbracht et a. found a significant reduction in depression scores (p=0.017) in patients with stages 2a-3b breast cancer undergoing IVC with concomitant conventional treatments [3].
Table 1: Human studies of high-dose vitamin C in the treatment of cancer-associated depression.
| Author and Year | Methodology | Sample size | Cancer Type(s) | Dose of vitamin C | Concomitant Therapy | Depression Scale Used | Outcome for Depression | Other Outcomes |
| Yeom 2007 [39] | Prospective Observational Study | 39 | Stage IV terminal cancer (estimated survival less than 6 months) | Two doses of 10 g IVC per day for three days with concurrent 4 g oral route per day vitamin C for one week | None; however, all had previously completed standard of care treatment | EORTC QLQ-C30 | Patients had significantly increased scores in emotional function after IVC therapy (p<0.005). | Significant improvements in QoL/global health scale as well as improvements in sleep, fatigue, N/V, pain, appetite loss and cognitive function (p<0.005). Patients had significantly increased scores for physical, cognitive and social function post-IVC therapy (p<0.005). No patients ceased IVC due to adverse effects.
|
| Takahashi 2012 [40] | Prospective Observational Study | 60 | Any cancer with malignant tumours | Riordan IVC protocol:
1st dose 12.5-15 g; |
No limitations were placed (i.e., patients were allowed to engage in ongoing standard of care therapy) | EORTC QLQ-C30 | There was a significant improvement in emotional function at four weeks (p<0.05). | Significant QoL improvements were observed from baseline where an average 8.6-point increase was observed at weeks 2 (p<0.05) and a 16.8-point improvement at week 4 (p<0.01). There were significant improvements in physical, role, cognitive, and social function at four weeks (p<0.05). There were significant reductions in fatigue and insomnia at 4 weeks compared to baseline (p<0.01) by nearly 50%; as well as significantly decreased pain and constipation (p<0.05). No patients ceased IVC due to adverse effects. |
| Vollbracht 2011 [3] | Retrospective Observational Study | 125 | Breast cancer (stages IIa-IIIb) | Standard therapy + IVC (7.5 g Pascorbin once weekly) | Standard chemotherapy and radiation | 3-point scale to assess the intensity of complaints
(0=no complaints, 1=mild complaints, 2=severe complaints). |
The IVC (n=53) treatment group had significantly reduced scores of depression (p=0.017). | There were significant reductions in cancer- and chemo/radiation- associated side effects during the adjuvant stage, such as fatigue (p=0.004), sleep disorders (p=0.005), and loss of appetite (p=0.046). No adverse effects associated with IVC were documented and there were no significant interactions between IVC and adjuvant therapy (p=0.255 for chemotherapy and p=0.905 for radiotherapy). |
| Bazzan 2018 [41] | Retrospective Observational Study | 86
(32 IVC only; 54 had IVC and chemotherapy)
|
Variety of different kinds and stages | At least 5 doses of 50-150 g of IVC given over 2-3 hours | Chemotherapy (different kinds) | 3-point scale to assess the efficacy of IVC
(improved, stable or worse) during the adjuvant therapy and aftercare phases. |
6 of the 7 patients that had mood disturbances* reported significant improvement and the last patient reported mood stability. | The most common adverse events related to IVC were temporary nausea and local discomfort at the site of injection. All adverse events reported in the IVC alone group were associated with less than 3% of the total number of infusions. Patients also reported improvements in fatigue and pain while receiving IVC. |
Table made using Microsoft Word. *Mood Disturbances are not the same as depression. QoL: Quality of life. IVC: Intravenous vitamin C. EORTC QLQ-C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30. N/V: Nausea/vomiting. 152 scholarly articles were reviewed to get these four included studies.
Discussion
This literature review is a natural progression to the current studies, unifying what has been explored so far on the effects of vitamin C for depression in cancer patients. Other nutrients have been shown to potentially improve mood in adult cancer patients as well, including isoquercetin and omega-3 fatty acids, using the PHQ-9 and EORTC QLQ-C30, respectfully, but much larger and higher quality studies need to be done [42, 43].
Low levels of vitamin C (e.g. scurvy) have been observed in adults with depression [44-48]. That being said, not all of the research done on vitamin C deficiency and mood reflected these same results [49, 50]. Oral vitamin C supplementation has been shown to possibly improve mood in acutely hospitalized patients, healthy young adults [14, 51]. It seems that most studies measuring the effects on mood with vitamin C supplementation show at least a trending improvement, a small 2015 clinical trial did not show any significant changes in major depressive disorder and suicidal behaviour when treated with oral vitamin C adjuvant with citalopram versus citalopram alone [52]. Considering the Yeom 2007 study where cancer patients took oral vitamin C in addition to IVC, it would be helpful for future studies to assess the effects of depression using the PHQ-9 by comparing IVC in cancer patients with and without oral supplementation [39].
In terms of dosing, the included studies use varying doses of IVC ranging from 7.5 g to 100 g per administration with several studies using additional oral dosing. Previous clinical research has found tolerability of IVC dosages up to 1.5 g per kg of body weight [3, 53]. There is no definitive guideline that sets apart high-dose from low-dose vitamin C, however a review of the literature reveals a common understanding that low-dose vitamin C refers to dosages typically in the 1-5 g range as these are the general limitations on enteral administration due to bowel tolerance; while high-dose vitamin C refers to dosages over 5 g and are synonymous with serum status levels that are only achievable through parenteral administration [22, 31]. Alternative distinguishing characteristics could be related to the safety implications of dosing, such as the requirement for glucose-6-phosphate dehydrogenase testing in dosages greater than 15 g as a deficiency in this enzyme with high doses of vitamin C can result in hemolytic anemia [31]. Other contraindications include renal failure, hemochromatosis, and oxalate calculus [3].
Four observational studies assessed the role of IVC for depression in cancer patients. These studies confirmed previous research in reporting improved QoL and other cancer-related benefits (i.e., decreasing fatigue and pain) [3, 39-41]. All four studies noted a decrease of depression in cancer patients [3, 39-41]. In the Takahashi et al. study, 5% of the IVC patients experienced a transient worsening in QoL scores which were graded as “minimally worse”, while adverse events were minimal and did not result in patients withdrawing from the study [40]. The included studies all evaluated safety of IVC and reported no significant adverse effects associated with IVC, which is critical when considering any intervention as a proposed treatment. These findings of safety have been replicated in numerous trials and have been summarized in several meta-analyses and systematic reviews [3, 13, 14, 31, 39-41, 54]. The consistency of these findings further supports the feasibility of future studies into IVC and cancer, including its role in the treatment of depression.
One strength of this review is that a systematic search strategy was implemented to ensure it identified all relevant studies. Another strength is that the validated questionnaire, EORTC QLQ-C30, was used in two studies, which aids in comparison of the findings [39, 40]. It is important to note, however, key differences between the studies such as cancer staging and timing of IVC interventions with conventional therapies. One limitation of using the EORTC QLQ-C30 is that it was designed to capture overall QoL and while a subdomain assesses emotional function, it is not validated for the assessment of depression. Research does exist, however, that draws an association between EORTC scores and depression, such as a 2009 study of colorectal cancer patients that correlates those who scored over 17 points on the Beck Depression Inventory with substantially lower EORTC scores [55]. Another limitation of this review is that two of the four studies were retrospective and only one study had a control group; which can make direct comparison of findings difficult [3, 39-41]. In future studies, it is important that a validated tool, such as the PHQ-9, Hamilton Depression Rating Scale, and the Beck Depression Inventory, is used in order to adequately assess the impact treatment has on depression symptoms [56].
Conclusions
The results presented suggest that IVC could potentially have a beneficial effect on levels of depression in patients with cancer; however, more research is needed. The studies completed to date lacked an assessment tool designed to capture changes in depression severity. Prospective clinical trials using validated assessment tools and control groups are needed to further study the potential role of this therapy in the treatment of this highly prevalent and disabling condition.
