Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed treatments for major depressive disorder (MDD) and related mood disorders. While they offer substantial benefits for many individuals, a significant subset of patients experience partial or inadequate response, persistent depressive symptoms, or undesirable side effects. This has prompted growing interest in evidence-based integrative strategies that may enhance SSRI efficacy, improve tolerability, and support broader aspects of patient health. (Chu 2023)

This template outlines a targeted adjunctive approach incorporating folate, vitamin D3, and omega-3 fatty acids—nutrients that have demonstrated promising effects in enhancing antidepressant outcomes.

Folate/Folic Acid

Dosing: 500 mcg per day of L-methylfolate for 1–2 months adjunctive to current SSRIs

Supporting evidence:

  • In an RCT of patients with MDD, women who received 500 mcg of folic acid alongside SSRI therapy experienced greater improvements in depressive symptoms, higher plasma folate, lower homocysteine, and fewer side effects compared to SSRI alone, with no significant effects observed in men. (Coppen 2000)
  • In patients with SSRI-resistant MDD, adjunctive L-methylfolate at 15 mg per day showed significant improvement of depression outcomes compared to placebo in a second randomized trial. (Papakostas 2012)
  • Compared to antidepressant monotherapy, initiating treatment with L-methylfolate plus SSRIs/serotonin-norepinephrine reuptake inhibitors (SNRI) resulted in significantly greater and faster clinical improvement in depressive symptoms and functional outcomes, especially in more impaired patients, and was associated with better tolerability and lower discontinuation rates. (Ginsberg 2011)
Folate in the Fullscript catalog

Vitamin D

Dosing: 1,500 IU vitamin D3 daily

Supporting evidence: 

  • In an RCT, combining vitamin D3 with fluoxetine significantly enhanced the reduction of depressive symptoms compared to fluoxetine alone, demonstrating superior efficacy beginning at week four of treatment in patients with MDD. (Khoraminya 2012)
  • A meta-analysis of 12 observational studies found that SSRI use is associated with a significantly increased risk of fractures. (Eom 2012)
  • A 2022 meta-analysis found that daily supplementation of 800–1,000 IU of vitamin D significantly reduced the risk of osteoporotic fractures and falls, particularly in deficient individuals. (Kong 2022)
Vitamin D in the Fullscript catalog

Omega-3 Fatty Acids

Dosing: >500 mg combined EPA/DHA daily, taken with food (Mehdi 2023)

Supporting evidence:

  • In individuals with mild-to-moderate depression, combination therapy with omega-3 fatty acid supplements and antidepressants led to significantly greater improvement in depressive symptoms compared to either treatment alone, supporting the potential benefit of integrative management strategies. (Mehdi 2023)
  • In adolescents with SSRI-resistant MDD, significant baseline docosahexaenoic acid (DHA) deficiencies were observed, and adjunctive high-dose fish oil supplementation (16.2 g per day) effectively improved omega-3 status and depressive symptoms without notable adverse effects. (McNamara 2014)
  • In individuals with bipolar disorder type I experiencing a depressive episode, adjunctive treatment with omega-3 fatty acids alongside fluvoxamine significantly improved depressive symptoms over 12 weeks compared to fluvoxamine alone, supporting omega-3’s potential as a safe and effective complementary therapy. (Safa 2013)
Omega-3 fatty acids in the Fullscript catalog

Disclaimer

The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

View protocol on Fullscript
References
  1. Chu A, Wadhwa R. Selective Serotonin Reuptake Inhibitors. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554406/
  2. Coppen, A., & Bailey, J. (2000). Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. Journal of Affective Disorders, 60(2), 121–130. https://doi.org/10.1016/s0165-0327(00)00153-1
  3. Eom, C., Lee, H., Ye, S., Park, S. M., & Cho, K. (2012). Use of selective serotonin reuptake inhibitors and risk of fracture: A systematic review and meta-analysis. Journal of Bone and Mineral Research, 27(5), 1186–1195. https://doi.org/10.1002/jbmr.1554
  4. Khoraminya, N., Tehrani-Doost, M., Jazayeri, S., Hosseini, A., & Djazayery, A. (2012). Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Australian & New Zealand Journal of Psychiatry, 47(3), 271–275. https://doi.org/10.1177/0004867412465022
  5. Kong, S. H., Jang, H. N., Kim, J. H., Kim, S. W., & Shin, C. S. (2022). Effect of vitamin D supplementation on risk of fractures and falls according to dosage and interval: A Meta-Analysis. Endocrinology and Metabolism, 37(2), 344–358. https://doi.org/10.3803/enm.2021.1374
  6. McNamara, R. K., Strimpfel, J., Jandacek, R., Rider, T., Tso, P., Welge, J. A., Strawn, J. R., & DelBello, M. P. (2014). Detection and treatment of long-chain omega-3 fatty acid deficiency in adolescents with SSRI-resistant major depressive disorder. PharmaNutrition, 2(2), 38–46. https://doi.org/10.1016/j.phanu.2014.02.002
  7. Mehdi, S., Manohar, K., Shariff, A., Kinattingal, N., Wani, S. U. D., Alshehri, S., Imam, M. T., Shakeel, F., & Krishna, K. L. (2023). Omega-3 fatty acids supplementation in the treatment of Depression: an observational study. Journal of Personalized Medicine, 13(2), 224. https://doi.org/10.3390/jpm13020224
  8. Papakostas, G. I., Shelton, R. C., Zajecka, J. M., Etemad, B., Rickels, K., Clain, A., Baer, L., Dalton, E. D., Sacco, G. R., Schoenfeld, D., Pencina, M., Meisner, A., Bottiglieri, T., Nelson, E., Mischoulon, D., Alpert, J. E., Barbee, J. G., Zisook, S., & Fava, M. (2012). L-Methylfolate as adjunctive therapy for SSRI-Resistant major depression: results of two randomized, Double-Blind, Parallel-Sequential trials. American Journal of Psychiatry, 169(12), 1267–1274. https://doi.org/10.1176/appi.ajp.2012.11071114
  9. Safa, M., Tafti, S. F., Boroujerdi, F. G., & Talischi, F. (2013). Clinical trial in the treatment of 80 Iranian patients with major depression disorder by the combination of omega 3 fatty acid and a selective serotonin reuptake inhibitor. Therapeutic Advances in Psychopharmacology, 3(4), 186–190. https://doi.org/10.1177/2045125312471667