Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo-controlled pilot study

The prevalence of depression in community settings has been estimated to be between 0.4% and 2.5% in children and 0.4% and 8.3% in adolescents [1]. However, in a more recent community study of children without depression who were initially assessed between the ages of 9 and 13 years, more than 7% of boys and almost 12% of girls developed a depressive disorder by the age of 16 [2].

While the diagnosis of major depressive disorder (MDD) in younger patients generally follows the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) [3], the treatment of pediatric depression presents many challenges. Not only do children with MDD have multiple co-morbid disorders [4, 5], psychosocial and academic problems, and are at increased risk for suicide attempts, self-harm, and substance abuse [1, 6‐10], treatment options are often limited and ineffective, poorly tolerated, and generally present long delays in delivering a therapeutic benefit [11‐14].

One of the few antidepressants approved for use in children is the selective serotonin reuptake inhibitor (SSRI) fluoxetine [15]. The first study that demonstrated the positive effects of using fluoxetine to treat depression in child and adolescent patients was published in 1997 [16], following a small trial in which no difference was observed between fluoxetine treatment and placebo [17]. Overall, five clinical trials have been conducted which show the positive effects of using fluoxetine to treat pediatric depression [16, 18‐21]. In addition, the improvement response rate on the Clinical Global Impressions (CGI) for antidepressant use was found to be between 52% and 61% for fluoxetine patients versus 33% to 37% for patients treated with placebo [22]. The CGI measures whether or not depressive symptoms have improved after treatment.

Despite being one of the most popular treatments for pediatric patients, in 2004 the use of prescription medication such as fluoxetine as well as other antidepressant medications declined by approximately 20% in the United States [23]. This shift in prescription patterns is likely due to warnings issued by regulatory agencies, initially in the United Kingdom [24] and later in the United States [25], against the use of SSRIs to treat depression in pediatric populations due to the possible link between antidepressant usage and an increased incidence of suicidal ideations or attempts. Subsequently, there is a compelling need for better understanding of the pathophysiology of MDD as well as the development of novel treatment methods that can be used to improve the current clinical management of pediatric depression.

Nutrients like vitamin C (ascorbic acid) have become of interest in adjuvant therapy settings for the management of depressive symptoms due to the fact that psychological abnormalities are among the characteristics of vitamin C deficiency [26‐29]. A recent population-based survey revealed that 60% of the patients in the acute medical wards of a Montreal teaching hospital were vitamin C deficient, while this deficiency was only detected in 16% of people attending the hospital’s outpatient center [30]. There is also preliminary evidence that the administration of vitamin C may be able to reduce the severity of MDD in both children [31] and adults [32], as well as improve mood in healthy individuals [33‐35]. In addition, a recent study reported a 35% reduction in average mood disturbance in hospitalized patients following treatment with vitamin C (1000 mg/day) [36]. In one particular study that investigated mood, patients who were acutely hospitalized were either treated with vitamin C or vitamin D as a deficiency in both of these vitamins has been associated with psychological abnormalities [32]. The results showed that only vitamin C led to an improved mood. More specifically, treating the vitamin C deficiency led to a decrease in mood disturbance while vitamin D supplementation had no effect on mood. Similar findings were observed in non-critically ill hospitalized patients who were treated with vitamin C for hypovitaminosis C [36]. Moreover, an animal study showed that the co-administration of vitamin C was found to potentiate the action of subeffective doses of fluoxetine (1 mg/kg) [37]. This synergistic antidepressant effect of vitamin C and fluoxetine suggests that this vitamin could be helpful in improving conventional pharmacotherapy for pediatric MDD and potentially reduce side effects.

This study would be the first to examine the efficacy of vitamin C as an adjunct to SSRIs in the treatment of pediatric depression. In addition, the low potential toxicity, inexpensiveness, and over-the-counter availability, we sought to investigate whether oral supplementation of vitamin C would improve clinical depressive symptoms. Therefore, the present study was designed to measure the effect of vitamin C on the Children’s Depression Rating Scale (CDRS), the Children’s Depression Inventory (CDI), and the CGI scores in pediatric patients with depression taking fluoxetine.

These results show that orally administered vitamin C as an adjunct to fluoxetine treatment leads to significantly greater decreases in depressive symptoms in comparison to fluoxetine treatment alone. This was demonstrated by the decrease in depressive symptoms, which was observed in the improved CDRS and CDI scores. A significant effect was not observed for the CGI, but this may be related to the response items for this instrument. For instance, symptoms were scored according to whether “much improvement” or “very much improvement” was observed [49]. Although there may have been a slight increase in CGI scores, response items such as these may have made it difficult to detect a significant improvement of symptoms. The differences between the scores may have also been related to the individuals who supplied the ratings for each instrument. More specifically, the scores for the CDRS were based on parent ratings, the scores for the CDI were based on children ratings, and the scores for the CGI were based on clinician ratings. The scores from the CGI were computed based on clinical criteria such as that which is listed in the DSM-IV-TR as well as semi-structured interviews. Therefore, the clinician’s rating and score interpretations adhered to strict guidelines and training, whereas the ratings from parents and children may have been more subjective leading to significantly different scores. Nonetheless, these preliminary findings, including the results of ANOVA suggest that vitamin C may be an effective adjuvant agent for the treatment of depression in pediatric patients. Furthermore, the results support the notion that vitamin C has antidepressant-like properties and are in accordance with previous animal research that demonstrated vitamin C’s ability to potentiate the action of conventional antidepressants [37].

Despite the lack of research investigating the effects of vitamin C in pediatric patients with MDD, previous studies have suggested that vitamin C improves clinical symptoms in other psychiatric disorders [51‐53], and that vitamin C supplementation can be used to positively modulate mood [33‐35]. Furthermore, Khanzode et al., (2003) showed that plasma levels of vitamin C were decreased in depressive patients [54]. In a more recent study, Chang et al., (2007) described a case in which a patient with depression developed scurvy, suggesting that reduced plasma levels of vitamin C due to inadequate vitamin C intake could be associated with the pathophysiology of depression [29]. Other studies have also shown that depressive symptoms are associated with scurvy [55‐57].

While the exact role of vitamin C in the etiology of MDD is not well understood, a growing body of evidence suggests that oxidative stress, characterized by an accumulation of free radicals due to an organism’s inhibited antioxidant capacity, may play a primary or secondary role in the pathogenesis of neurological and psychiatric diseases like MDD [58, 59]. The brain is much more vulnerable to oxidative free radicals than other tissues since it utilizes 20% of the oxygen consumed by the body, contains large amounts of polyunsaturated fatty acids and iron, and typically has low concentrations of antioxidant enzymes [60]. Previous studies have shown that MDD may be accompanied by disturbances in the balance between pro- and anti-oxidative processes, demonstrated by decreased blood plasma levels of the antioxidants enzymes superoxide dismutase, catalase, and glutathione peroxidase and an increased level of lipid peroxidation by-products in patients with depression versus healthy controls [54, 61, 62].

While antidepressant drugs may affect the oxidative or antioxidative systems [54], partly due to their effects on the immune [63] and P450 systems [64], adjunctive therapy with vitamin C may provide additional protection as it is the brain’s most abundant antioxidant and plays an important role in preventing free radical-induced damage [65, 66]. In addition to its neuroprotective properties, vitamin C has also been identified as a neuromodulator in the brain, modulating both dopamine- and glutamate-mediated neurotransmission [67‐69]. As there is a considerable amount of pharmacological evidence demonstrating the efficacy of antidepressants with dopaminergic effects in the treatment of depression [70], vitamin C’s complex interaction with the dopaminergic system may be another potential mechanism of action. However this effect appears to be dose-dependent. Wambebe and Sokomba (1986) showed that administering 50–200 mg/kg of vitamin C to rats enhanced dopamine-mediated behavioral effects [71], while higher dosages have been shown to antagonize such effects [68].

There are a number of other potential biological substrates that underlie vitamin C’s effects on depression and mood. For example, Binfaré et al. [37] identified the involvement of 5-HT_1A receptors in the antidepressant-like effect of vitamin C. Additionally, adjuvant administration of vitamin C may also prove useful in decreasing the risk of suicidal thoughts and behaviors linked to antidepressant therapy in pediatric patients [72]. Meta-analyses of placebo-controlled studies have indicated that antidepressants may cause a significant, although small and short-term, risk of self-harm or suicide-related events in children and adolescents with MDD, no completed suicides were reported in any trial included in the analysis [73, 74]. Li et al. [75] reported that a history of attempted suicide was shown to be associated with a low level of antioxidant vitamins and carotenoids. Therefore, increasing plasma vitamin C levels in children and adolescents who are being treated with antidepressants may help mitigate some of this risk. However, as suicidal thoughts and behaviors were not measured in the present study, future clinical research is needed to test this hypothesis.

Treatment with 1000 mg/day of vitamin C potentiated the efficacy of fluoxetine in pediatric patients being treated for MDD. Furthermore, vitamin C was shown to be a particularly attractive therapeutic adjuvant due to the absence of substantial side effects and its inexpensive cost. The observed improvements in CDRS and CDI scores also imply that this type of treatment effectively increases blood plasma levels of vitamin C as it has been shown that ascorbic acid deficiency is associated with psychological abnormalities [26‐29]. Future, large-scale clinical trials are warranted to evaluate the therapeutic efficacy of vitamin C for the treatment of depression in pediatric patients as well as its effectiveness as an adjuvant treatment to antidepressants.