Depression has serious impacts on health and is a common condition seen in clinical practice. The initial therapy for depression may include both psychotherapy and medication, with selective serotonin reuptake inhibitors considered first-line treatment. For those with a partial or incomplete response to treatment, additional medications may also be utilized. In some individuals with treatment-resistant depression, there may be a need for adjuvant therapies in addition to such medications. This article reviews the adjuvant use of natural substances in people with depression. Evidence for the use of curcumin, methylfolate, omega-3 fatty acids, zinc, probiotics, and vitamin D in this context is discussed.
Substance Abuse and Mental Health Services Administration. Table 9, DSM-IV to DSM-5 Major Depressive Episode/Disorder Comparison. 2016;Jun.
3.
NewsonJJ, PastukhV, ThiagarajanTC. Poor separation of clinical symptom profiles by DSM-5 disorder criteria. Front Psychiatry, 2021; 12:775762.
4.
TolentinoJC, SchmidtSL. DSM-5 criteria and depression severity: Implications for clinical practice. Front Psychiatry, 2018; 9:450.
5.
SajatovicM, ChenP, YoungRC. Rating scales in bipolar disorder. In Clinical Trial Design Challenges in Mood Disorders. Elsevier; 2015, pp. 105–136.
6.
KroenkeK, StumpTE, ChenCX, et al.Responsiveness of PROMIS and Patient Health Questionnaire (PHQ) Depression Scales in three clinical trials. Health Qual Life Outcomes, 2021; 19(1):1–14.
7.
Substance Abuse and Mental Health Services Administration. Impact of the DSM-IV to DSM-5 Changes on the National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration (US): Rockville, MD; 2016.
8.
WeissmanMM, MarkowitzJC, KlermanGL. Persistent depressive disorder. In The Guide to Interpersonal Psychotherapy. Oxford Academic; 2023, pp. 160–166.
9.
CurleyLE, LinJC, ChenTF. Major depressive disorder. Encyclopedia of Pharmacy Practice and Clinical Pharmacy, 2023; 1–3:V3A-672–V3A-685.
10.
GautamS, JainA, GautamM, et al.Clinical practice guidelines for the management of depression. Indian J Psychiatry, 2017; 59:S34.
11.
KennedySH. Beyond response: Aiming for quality remission in depression. Adv Ther, 2022; 39(9):4391.
ZhdanavaM, PilonD, GhelerterI, et al.The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry, 2021; 82(2).
14.
YoonRSY, RavindranN, RavindranA. Complementary and alternative therapies for treatment-resistant depression: A clinical perspective. In Complex Clinical Conundrums in Psychiatry: From Theory to Clinical Management. Springer; 2018, pp. 123–142.
15.
ZhangY, LiL, ZhangJ. Curcumin in antidepressant treatments: An overview of potential mechanisms, pre-clinical/clinical trials and ongoing challenges. Basic Clin Pharma Tox, 2020; 127(4):243–253.
16.
SchmidtFM, KirkbyKC, LichtblauN. Inflammation and immune regulation as potential drug targets in antidepressant treatment. Curr Neuropharmacol, 2016; 14(7):674–687.
17.
NguyenHD, KimMS. The protective effects of curcumin on depression: Genes, transcription factors, and microRNAs involved. J Affect Disord, 2022; 319:526–537.
18.
BergmanJ, MiodownikC, BersudskyY, et al.Curcumin as an add-on to antidepressive treatment: A randomized, double-blind, placebo-controlled, pilot clinical study. Clin Neuropharmacol, 2013; 36(3):73–77.
19.
YuJJ, PeiLB, ZhangY, et al.Chronic supplementation of curcumin enhances the efficacy of antidepressants in major depressive disorder: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. J Clin Psychopharmacol, 2015; 35(4):406–410.
20.
PanahiY, BadeliR, KaramiGR, et al.Investigation of the efficacy of adjunctive therapy with bioavailability-boosted curcuminoids in major depressive disorder. Phytother Res, 2015; 29(1):17–21.
21.
KanchanatawanB, TangwongchaiS, SughondhabhiromA, et al.Add-on treatment with curcumin has antidepressive effects in Thai patients with major depression: Results of a randomized double-blind placebo-controlled study. Neurotox Res, 2018; 33(3):621–633.
22.
Al-KarawiD, Al MamooriDA, TayyarY. The role of curcumin administration in patients with major depressive disorder: Mini meta-analysis of clinical trials. Phytother Res, 2016; 30(2):175–183.
23.
Calderón-OspinaCA, Nava-MesaMO. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther, 2020; 26(1):5–13.
24.
KennedyDO. B vitamins and the brain: Mechanisms, dose and efficacy—a review. Nutrients, 2016; 8(2):68.
GrauletB, GirardCL. B vitamins in cow milk: their relevance to human health. In Dairy in Human Health and Disease across the Lifespan. Academic Press; 2017, pp. 211–224.
27.
RogersLM, CorderoAM, PfeifferCM, et al.Global folate status in women of reproductive age: A systematic review with emphasis on methodological issues. Ann N Y Acad Sci, 2018; 1431(1):35–57.
28.
YoungLM, PipingasA, WhiteDJ, et al.A systematic review and meta-analysis of B vitamin supplementation on depressive symptoms, anxiety, and stress: Effects on healthy and ‘at-risk’ individuals. Nutrients, 2019; 11(9):2232.
29.
WuY, ZhangL, LiS, et al.Associations of dietary vitamin B1, vitamin B2, vitamin B6, and vitamin B12 with the risk of depression: A systematic review and meta-analysis. Nutr Rev, 2022; 80(3):351–366.
30.
SheltonRC, Sloan ManningJ, BarrentineLW, et al.Assessing effects of L-methylfolate in depression management: Results of a real-world patient experience trial. Prim Care Companion CNS Disord, 2013; 15(4).
31.
PapakostasGI, SheltonRC, ZajeckaJM, et al.L-methylfolate as adjunctive therapy for SSRI-resistant major depression: Results of two randomized, double-blind, parallel-sequential trials. Ajp, 2012; 169(12):1267–1274.
32.
ZajeckaJM, FavaM, SheltonRC, et al.Long-term efficacy, safety, and tolerability of l-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: A 12-month, open-label study following a placebo-controlled #05#. J Clin Psychiatry, 2016; 77(5):654–660.
33.
AltafR, GonzalezI, RubinoK, et al.Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis. Complement Ther Med, 2021; 61:102770.
34.
Al MarufA, PoweleitEA, BrownLC, et al.Systematic review and meta-analysis of L-methylfolate augmentation in depressive disorders. Pharmacopsychiatry, 2022; 55(03):139–147.
35.
MacalusoM. L-methylfolate in antidepressant non-responders: The impact of body weight and inflammation. Front Psychiatry, 2022; 13:840116.
36.
JainR, ManningS, CutlerAJ. Good, better, best: Clinical scenarios for the use of L-methylfolate in patients with MDD. CNS Spectr, 2020; 25(6):750–764.
37.
RobinsonS, MillerJ. L-Methylfolate: Augmenting agent may contribute to agitation and mania. Psychiatric Times, 2020.
38.
AlmeidaOP, FordAH, HiraniV, et al.B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: Results from the B-VITAGE randomised, double-blind, placebo-controlled trial. Br J Psychiatry, 2014; 205(6):450–457.
39.
KelaiditisCF, GibsonEL, DyallSC. Effects of long-chain omega-3 polyunsaturated fatty acids on reducing anxiety and/or depression in adults; A systematic review and meta-analysis of randomised controlled trials. Prostaglandins Leukot Essent Fatty Acids, 2023; 192:102572.
40.
LiaoY, XieB, ZhangH, et al.Efficacy of omega-3 PUFAs in depression: A meta-analysis. Transl Psychiatry, 2019; 9(1).
41.
GuuTW, MischoulonD, SarrisJ, et al.International society for nutritional psychiatry research practice guidelines for Omega-3 fatty acids in the treatment of major depressive disorder. Psychother Psychosom, 2019; 88(5):263–273.
42.
Anonymous. Omega-3 Fatty Acids. National Institute of Diabetes and Digestive and Kidney Diseases; 2017.
43.
AzargoonjahromiA. A systematic review of the association between zinc and anxiety. Nutr Rev, 2023.
44.
LiZ, LiB, SongX, et al.Dietary zinc and iron intake and risk of depression: A meta-analysis. Psychiatry Res, 2017; 251:41–47.
45.
Machado Da SilvaLE, Portela De SantanaL, Ribas De Farias CostaP, et al.Zinc supplementation combined with antidepressant drugs for treatment of patients with depression: A systematic review and meta-analysis. Nutr Rev, 2021; 79(1):1–12.
46.
YosaeeS, ClarkCCT, KeshtkaranZ, et al.Zinc in depression: From development to treatment: A comparative/dose response meta-analysis of observational studies and randomized controlled trials. Gen Hosp Psychiatry, 2022; 74:110–117.
47.
RafaloA, Sowa‐KucmaM, PochwatB, et al.Nutritional Deficiency. IntechOpen; 2016.
48.
Rafało‐UlińskaA, PochwatB, MisztakP, et al.Zinc deficiency blunts the effectiveness of antidepressants in the olfactory bulbectomy model of depression in rats. Nutrients, 2022; 14(13):2746.
49.
SwardfagerW, HerrmannN, MazereeuwG, et al.Zinc in depression: A meta-analysis. Biol Psychiatry, 2013; 74(12):872–878.
50.
LiuL, WangH, ChenX, et al.Gut microbiota and its metabolites in depression: From pathogenesis to treatment. EBioMedicine, 2023; 90:104527.
51.
DinanK, DinanT. Antibiotics and mental health: The good, the bad and the ugly. J Intern Med, 2022; 292(6):858–869.
52.
AppletonJ. The gut-brain axis: Influence of microbiota on mood and mental health. Integrative Medicine: A Clinician’s Journal, 2018; 17:28.
53.
BarandouziZA, LeeJ, del Carmen RosasM, et al.Associations of neurotransmitters and the gut microbiome with emotional distress in mixed type of irritable bowel syndrome. Sci Rep, 2022; 12(1):1611–1648.
54.
ChudzikA, OrzyłowskaA, RolaR, et al.Probiotics, prebiotics and postbiotics on mitigation of depression symptoms: Modulation of the brain–gut–microbiome axis. Biomolecules, 2021; 11(7):1000.
55.
LiuRT, WalshRFL, SheehanAE. Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev, 2019; 102:13–23.
56.
HuangR, WangK, HuJ. Effect of probiotics on depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients, 2016; 8(8).
57.
LinJ, ZhangY, WangK, et al.The effect and safety of probiotics on depression: A systematic review and meta-analysis of randomized controlled trials. Eur J Nutr, 2023; 62(7):2709–2721.
58.
KliglerB, CohrssenA. Probiotics. Am Fam Physician, 2008; 78(9):1073–1078.
59.
SchaubAC, SchneiderE, Vazquez-CastellanosJF, et al.Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: A randomized controlled trial. Transl Psychiatry, 2022; 12(1):210–227.
60.
SpeddingS. Vitamin D and depression: A systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients, 2014; 6(4):1501–1518.
61.
VellekkattF, MenonV. Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials. J Postgrad Med, 2019; 65(2):74–80.
62.
EylesDW, SmithS, KinobeR, et al.Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat, 2005; 29(1):21–30.
63.
NevilleJJ, PalmieriT, YoungAR. Physical determinants of vitamin D photosynthesis: A review. JBMR Plus, 2021; 5(1):e10460.
64.
AnglinRES, SamaanZ, WalterSD, et al.Vitamin D deficiency and depression in adults: Systematic review and meta-analysis. Br J Psychiatry, 2013; 202(2):100–107.
65.
XieF, HuangT, LouD, et al.Effect of vitamin D supplementation on the incidence and prognosis of depression: An updated meta-analysis based on randomized controlled trials. Front Public Health, 2022; 10.
66.
AkpınarŞ, KaradağMG. Is Vitamin D important in anxiety or depression? What is the truth? Curr Nutr Rep, 2022; 11(4):675–681.
67.
CuomoA, MainaG, BolognesiS, et al.Prevalence and correlates of vitamin D deficiency in a sample of 290 inpatients with mental illness. Front Psychiatry, 2019; 10:167.
68.
SarrisJ, RavindranA, YathamLN, et al.Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry, 2022; 23(6):424–455.
69.
SarrisJ, MurphyJ, MischoulonD, et al.Adjunctive nutraceuticals for depression: A systematic review and meta-analyses. Ajp, 2016; 173(6):575–587.
