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Complement Ther Med. 2018 Feb;36:38-45. doi: 10.1016/j.ctim.2017.09.011. Epub 2017 Nov 23.

Adjunctive Vitamin D in the treatment of non-remitted depression: Lessons from a failed clinical trial.

Author information

Canadian College of Naturopathic Medicine, Canada. Electronic address:
Canadian College of Naturopathic Medicine, Canada; Australian Research Centre in Complementary and Integrative Medicine, University of Technology, Sydney, Australia.
START Clinic for Mood and Anxiety Disorders, Canada.
Chatham-Kent Health Alliance, Canada.
Eden Mental Health Centre, Canada.
START Clinic for Mood and Anxiety Disorders, Canada; Department of Psychology, Adler Graduate Professional School, Canada; Northern Ontario School of Medicine, Canada; Department of Psychology, Lakehead University,Canada.



Many patients with depression fail to achieve remission after several consecutive treatments. Vitamin D deficiency is prevalent and new research suggests that it may have an impact on mood, primarily through an effect on neurotransmitters. Numerous observational studies suggest a relationship between low levels of vitamin D and increased incidence and severity of mood disorders. A small number of pilot studies have been undertaken but lack rigorous methodology required to draw conclusions about a clinical role for this nutrient in treatment resistant depression.


This study was designed as a randomized, double-blind, placebo controlled intervention study administering a weekly (bolus) dose of 28 000IU of Vitamin D3 or placebo to 125 patients with non-remitted depression adjunct to current antidepressant medication. Patients were followed weekly for eight weeks plus a one month follow up. Outcomes measured included depression severity, serum vitamin D levels and safety. Due to slow recruitment during the first season, amendments were made. These included extending the age range to 18-75 and removing the requirement for failing to respond to one pharmacologic antidepressant agent. The protocol was amended to reduce the burden on participants by changing the in-office visits to bi-weekly. Three additional tertiary psychiatric clinics were also added as trial sites.


Over three recruitment period years (fall/winter), a total of 148 participants completed screening, 24 (16.2%) of whom qualified to participate in the study. Use of too many or no psychiatric medications, comorbid exclusionary psychiatric conditions, current use of a vitamin D supplement, and lack of participant compensation were the predominant reasons for ineligibility or unwillingness to participate. 9 participants were successfully enrolled in the study, 7 (77.8%) of whom completed the trial as per the protocol. After the third season, futility was declared based on inability to enroll participants. The sample size of enrolled participants (7/125, 5.6%) lacks power to conduct a full assessment of findings.


High accessibility of vitamin D, as well as a growing lack of equipoise in patients and clinicians about the potential ubiquitous benefits of vitamin D for Canadians, not just for mood disorders, resulted in a large proportion of ineligible potential participants. Limited funding provided to studies on natural health products hampered recruitment. The labile and fluctuating nature of non-remitted depression as well as frequent co-morbid conditions creates additional challenges for conducting trials in this population. Future studies assessing vitamin D in depression should consider our experiences in design and conduct of research. Innovations in clinical trial design such as preference trials or accepting patients already using vitamin D but not achieving an optimal target value are potential solutions to some of these challenges.


Clinical trial design; Depression; Obstacles; Vitamin D

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