medicines Article
Study Protocol for a Randomized Double Blind, Treatment Control Trial Comparing the Efficacy of a Micronutrient Formula to a Single Vitamin Supplement in the Treatment of Premenstrual Syndrome Hannah Retallick-Brown *, Julia Rucklidge and Neville Blampied Department of Psychology, College of Science, University of Canterbury, Private Bag 4800, Christchurch 8041, New Zealand; [email protected] (J.R.); [email protected] (N.B.) * Correspondence: [email protected]; Tel.: +03-364-2987 (ext. 7705); Fax: +03-364-2181 Academic Editor: James D. Adams Received: 12 August 2016; Accepted: 15 November 2016; Published: 7 December 2016
Abstract: Background: The recent addition of Premenstrual Dysphoric Disorder (PMDD) to the Diagnostic and Statistical Manual (5th ed.) has highlighted the seriousness of this disorder. Many alternatives to psychoactive medication in the form of vitamins, minerals, and plant extracts have been trialled by women seeking a natural treatment approach. We plan to explore whether a well validated micronutrient formula, EMPowerplus Advanced, can outperform a recognized single nutrient treatment, vitamin B6, for the treatment of Premenstrual Syndrome (PMS). Methods: This will be a randomized treatment control study. Eighty women will be recruited and assigned to one of two treatment groups; EMPowerplus Advanced or vitamin B6. Baseline daily data will be collected for an initial two cycles, followed by three months of active treatment. A natural follow up will take place three cycles post treatment. Results: The primary outcome measure will be PMS change scores as based on results from the Daily Record of Severity of Problems (DRSP). The number of treatment responders for each of the two groups will yield a comparison score between the two treatments, with participants deemed as a responder if they show a total PMS score improvement of 50% from their baseline scores on the DRSP. Conclusion: If a micronutrient formula proves more effective for treating PMS, not only does it give women suffering from the condition a viable treatment option, but it may also suggest one cause of PMS; that is insufficient minerals and vitamins. Keywords: premenstrual syndrome; premenstrual dysphoric disorder; treatment; vitamins; minerals
1. Introduction The average woman will experience 13 menstrual cycles per year, corresponding to roughly 451 cycles over her lifetime and nearly 35 years of menstruation [1]. As many as 90% [2] of women will experience mild physical or mental symptoms in the week leading up to menstruation, and for some the symptoms are severe. Approximately 20% to 40% of ovulating women will suffer from numerous symptoms, collectively termed; premenstrual syndrome (PMS) [3]. An even more symptomatic form of PMS, known as Premenstrual Dysphoric Disorder (PMDD) is found in 1.8%–5.8% of women [4]. For women meeting criteria for either PMS or PMDD the symptoms include: affective lability, irritability, anger, increased interpersonal conflict, depressed mood, anxiety, difficulty concentrating, fatigue, change in appetite, sleep disturbance, feelings of being out of control, less interest in normal activities as well as physical symptoms such as bloating, breast swelling, and joint pain [4]. The hormonal induced changes affect all women regardless of ethnicity or socio-economic status and place a burden on interpersonal relationships, mental health, and work productivity [3]. Medicines 2016, 3, 32; doi:10.3390/medicines3040032
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The American College of Obstetricians and Gynecologists (ACOG) recommend pharmacological treatment should be used as a first line intervention for PMDD [5]. Selective serotonin reuptake inhibitors (SSRIs) have demonstrated a small effect size in PMS change scores (standardized mean difference= −0.36, 95% CI −0.2 to −0.51) [6], although they are more effective in women with severe PMS/PMDD; showing a moderate effect size in overall symptom reduction in this population of women (standardized mean difference= −0.53, 95% CI 0.68 to −0.39) [7]. However, the use of anti-depressants in the treatment of PMS can, at times, cause significant side effects including nausea, loss of libido, fatigue, insomnia, dry mouth, gastrointestinal complaints, and tremors (among other problems) [8], which can cause many women to terminate treatment. Women are far more likely to terminate participation when in an active treatment group compared to women on placebo, with higher frequencies of side effects observed in the former group. However, results from SSRI trials have produced incomplete side effect results, with many studies neglecting to specify side effects [8]. The second line of pharmacological treatment, hormone replacement therapies, interrupt the process of sex hormone production, causing anovulation. Due to serious side effects including reduction in mineral bone density, induction of postmenopausal symptoms and induction of symptoms similar to those seen in PMS such as headaches, lowered mood, and muscle tenderness [9,10], gonadotropin-releasing hormones (GnRH) agonists are used sparingly. Meanwhile, oral contraceptives have shown poor treatment efficacy and are not a recommended treatment [11]. Women with less severe symptoms are advised to try lifestyle changes such as dietary alterations, exercising regularly, improving sleep length and quality, and alleviating stress [12]. As current frontline medical treatments for PMS can have significant side effects, there is a need for new forms of treatment. Vitamins and minerals have a long history of being studied for the treatment of mental illness, usually one nutrient at a time [13]. A lack of specific vitamins and minerals (micronutrients) has been thought to be a causal factor in PMS and therefore their supplementation provides a possible treatment avenue [14]. Vitamin B6 (pyridoxine) has received much attention for its use in alleviating premenstrual symptoms. It has been hypothesized that B6 works, at least in part, through synthesizing serotonin, a neurotransmitter implicated in depression [15]. Numerous randomized controlled trials (RCTs) have studied the vitamin, finding promising results. For example, in a randomized crossover trial Doll, et al. [16] found pyridoxine to be effective in a dose as little as 50 mg per day on the emotional symptoms of depression and irritability and on tiredness. Kashanian, et al. [17] in a placebo controlled trial showed that at 80 mg per day pyridoxine exerted a significantly stronger effect on psychiatric symptoms compared to placebo, while both significantly reduced somatic symptoms. Wyatt, et al. [18] carried out a systematic review of the literature involving vitamin B6 and its use in the treatment of premenstrual syndrome. They noted that a number of studies were of poor quality but they did find evidence in support of the use of vitamin B6. In particular, the odds ratio for active treatment over placebo in alleviating overall premenstrual symptoms was 2.32 (95% confidence interval 1.95 to 2.54). While a number of other nutrients including calcium, vitamin E, magnesium have shown some evidence of efficacy in treating PMS [15,19], the overall results are generally modest, suggesting that the one disease one treatment model fails to take in the complexities of human nutrient requirements [20]. 1200 mg of calcium a day over three menstrual cycles produced a 48% reduction in PMS symptoms compared to 30% in the placebo group [21]. Vitamin E has been indicated as a possible treatment, yet results have failed to reach significance [22]. Magnesium has shown variable results in treating the symptoms of PMS [23]. When combined with 50 mg of vitamin B6, magnesium at a dose of 200 mg/day was effective on multiple PMS symptoms despite a relatively short treatment duration of one month [24]. Given that micronutrients are implicated in a range of essential brain functions from neurotransmitter synthesis to powering brain metabolism [25] and work synergistically, there is a growing body of literature exploring a much greater combined approach. Indeed, broad spectrum micronutrient formulas have been found to be effective in treating a multitude of symptoms typically seen in PMS such as irritability, low mood, poor sleep and anger [26]. There is a
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growing body of literature demonstrating the benefit of using broad spectrum micronutrients in the treatment of a variety of psychological/psychiatric conditions such as anxiety, depression, bipolar, attention-deficit/hyperactivity disorder, and obsessive compulsive disorder in both adults and children and this approach is proving to be far more successful than any single nutrient alone [26]. Previous research has already explored the use of a multi-ingredient formula in the treatment of PMS [27–29]. However, the formula, “Optivite”, contained high doses of both magnesium (250 mg/day) and vitamin B6 (300 mg/day) when taken at the full recomme

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