Adjunct Therapies for Depression: More Treatment Options

White Feather resting on a black stone
Read Time: 4 Minutes

The percentage of US adults with depression increased significantly from 8.7% to 10.6% in March 2020 and 14.4% in April 2020.1 Young adults (aged 18-34) experienced a marked increase in depression of 13.4 percentage points, which was larger than any other age group. Additional analyses of depression trends in NHANES from 2007/2008–2017/2018 showed that the substantial increase in depression in April 2020 was unlikely to be due to typical year-to-year variation, suggesting that the COVID-19 pandemic may have adversely affected mental health.1 Yet despite these numbers, a major study published in 2018 found that only about a third of patients diagnosed with depression actually start treatment.2

For those who adhere to antidepressant therapies, treatment of the acute phase of major depressive disorder (MDD) leads to a greater number of adverse events in patients 65 and over, according to a 2019 systematic review.1 Antidepressants included in the study were selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine. Specifically, the reports found that SSRIs and SNRIs led to a greater number of study withdrawals due to adverse events, and duloxetine increased the risk of falls.1

Non-adherence to antidepressants is also common.3 A 2017 study found that 68% of the females surveyed were non-adherent to their prescribed antidepressant therapy.3 Forgetfulness was the main reason for missing doses. Another study showed that antidepressant non-adherence is common among veterans, with ineffectiveness and avoidance of side effects frequently reported as reasons.4

With the general ineffectiveness of prescriptions and the additional tendency of patients to not adhere to the prescribed treatment, if prescriptions are all you can offer, the clinical encounter can seem as hopeless as the patient feels. Depression is a multi-factorial condition with a large number of potential antecedents and triggers. How can you get to the root cause for an individual patient, and what adjunct therapeutic interventions might improve outcomes?

The Path Forward: Complementary Therapies

The functional medicine model emphasizes a multi-pronged approach to health and wellness, engaging patients in a therapeutic partnership that recognizes that the current conventional paradigm does not optimally address the needs of patients with depressive symptoms. In the following video, IFM educator Patrick Hanaway, MD, IFMCP, talks about how a clinician might unravel the root cause of depression by looking at several factors, including levels of vitamin D and other vitamins, amino acids, and minerals—as well as the gut microbiome.

[Video Time: 4:00] IFM educator Patrick Hanaway, MD, IFMCP, is a board certified family physician who works in clinical practice at Family to Family: Your Home for Whole Health Care in Asheville, NC. He has served on the executive committee for the American Board of Integrative Medicine, is past president of the American Board of Integrative Holistic Medicine, and is the former director of research at Cleveland Clinic Center for Functional Medicine

Clearly, variable reports on the efficacy of antidepressants,5,6 combined with the high prevalence of depression,7,8 have left many clinicians challenged about how to help patients. According to one report, 42% of doctors had a hard time differentiating between unhappiness and clinical depression.9 What’s more, clinicians differ greatly in how they diagnose depression—from using checklists to using “gut sense.”10 Perhaps due to lack of time or the inherent difficulties of diagnosis, some clinicians are not inquiring much or at all about depression.11 But there is a wealth of medical research on the topic, and studies continue to point to the effectiveness of non-pharmacological therapies for depression.

For patients who have tried several different antidepressants to no avail, other therapeutic interventions such as diet may yield better results. Although epidemiological studies do not establish causality, some have suggested an association between diet and mental health.12 A 2019 study found that long-term adherence to a healthy diet may offer protection against recurrent depressive symptoms.13 Analyses were conducted on a sample of 4,949 men and women, and diet scores were calculated using data collected from food frequency questionnaires repeated over 11 years of exposure. Higher scores on the Alternative Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension, and transformed Mediterranean diet were associated with a lower risk of recurrent depressive symptoms.13

Evidence suggests that dietary or supplemented intake of other nutrients, such as those listed below, can be protective against depression or reduce depressive symptoms:

  • Vitamin K14
  • Fatty acids15-17
  • Zinc (postpartum depression)18
  • Magnesium19,20

Exercise and movement are also not to be overlooked. Research suggests that physical activity alone can treat mild to moderate depression symptoms.21-23 A 2015 cross-sectional national data study found that higher physical activity levels were associated with fewer self-reported days of poor mental health.24 Another large cohort study found that regular leisure-time exercise is associated with reduced incidence of future depression; it was predicted that 12% of future cases of depression could have been prevented if all participants had engaged in at least one hour of physical activity each week.25 Accumulating evidence also suggests that tai chi and yoga can significantly regulate emotion and relieve the symptoms of depressive disorders.26,27

Depression is a common and complex mood disorder that can severely affect a patient’s quality of life and even their family dynamic. The source can be biological, psychological, and/or social, and in the functional medicine model, it is incumbent upon the clinician to unravel the root cause of depression in order to address it effectively. Functional medicine tools like the timeline, as well as other resources, can help the patient cope, manage, and navigate a path to recovery.

Gain new tools to more effectively evaluate and personalize treatments for depression and other disorders at the Bioenergetics Advanced Practice Module.

Learn More About Mitochondrial Function

Read more about the Functional Medicine approach to treating depression and improving health outcomes in the following IFM-authored articles:




  1. Daly M, Sutin AR, Robinson E. Depression reported by US adults in 2017-2018 and March and April 2020. J Affect Disord. 2021;278:131-135. doi:10.1016/j.jad.2020.09.065
  2. Waitzfelder B, Stewart C, Coleman KJ, et al. Treatment initiation for new episodes of depression in primary care settings. J Gen Intern Med. 2018;33(8):1283-1291. doi:10.1007/s11606-017-4297-2
  3. Shrestha Manandhar J, Shrestha R, Basnet N, et al. Study of adherence pattern of antidepressants in patients with depression. Kathmandu Univ Med J. 2017;15(57):3-9.
  4. Zivin K. Antidepressant non-adherence is common among veterans, with ineffectiveness and side effects as commonly reported reasons. Evid Based Ment Health. 2011;14(4):91. doi:10.1136/ebmh.2011.100177
  5. Barbui C, Cipriani A, Patel V, Ayuso-Mateos JL, van Ommeren M. Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis. Br J Psychiatry. 2011;198(1):11-16. doi:10.1192/bjp.bp.109.076448
  6. Jakobsen JC, Katakam KK, Schou A, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis [published correction appears in BMC Psychiatry. 2017;17(1):162]. BMC Psychiatry. 2017;17(1):58. doi:10.1186/s12888-016-1173-2
  7. Lara Muñoz Mdel C, Jacobs EA, Escamilla MA, Mendenhall E. Depression among diabetic women in urban centers in Mexico and the United States of America: a comparative study. Rev Panam Salud Publica. 2014;36(4):225-231.
  8. Inglis AJ, Hippman CL, Carrion PB, Honer WG, Austin JC. Mania and depression in the perinatal period among women with a history of major depressive disorders. Arch Womens Ment Health. 2014;17(2):137-143. doi:10.1007/s00737-013-0408-1
  9. Botega NJ, Silveira GM. General practitioners’ attitudes towards depression: a study in primary care setting in Brazil. Int J Soc Psychiatry. 1996;42(3):230-237. doi:10.1177/002076409604200307
  10.  Thomas-MacLean R, Stoppard J, Miedema BB, Tatemichi S. Diagnosing depression: there is no blood test. Can Fam Physician. 2005;51(8):1102-1103.
  11.  Keeley RD, West DR, Tutt B, Nutting PA. A qualitative comparison of primary care clinicians’ and their patients’ perspectives on achieving depression care: implications for improving outcomes. BMC Fam Pract. 2014;15:13. doi:10.1186/1471-2296-15-13
  12.  Nakamura M, Miura A, Nagahata T, Shibata Y, Okada E, Ojima T. Low zinc, copper, and manganese intake is associated with depression and anxiety symptoms in the Japanese working population: findings from the Eating Habit and Well-Being study. Nutrients. 2019;11(4):E847. doi:10.3390/nu11040847 
  13.  Recchia D, Baghdadli A, Lassale C, et al. Associations between long-term adherence to healthy diet and recurrent depressive symptoms in Whitehall II Study. Eur J Nutr. 2020;59(3):1031-1041. doi:10.1007/s00394-019-01964-z
  14.  Bolzetta F, Veronese N, Stubbs B, et al. The relationship between dietary vitamin K and depressive symptoms in late adulthood: a cross-sectional analysis from a large cohort study. Nutrients. 2019;11(4):E787. doi:10.3390/nu11040787
  15.  Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584. doi:10.4088/JCP.10m06634
  16.  Mozaffari-Khosravi H, Yassini-Ardakani M, Karamati M, Shariati-Bafghi SE. Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: a randomized, double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2013;23(7):636-644. doi:10.1016/j.euroneuro.2012.08.003
  17.  Carney RM, Steinmeyer BC, Freedland KE, Rubin EH, Rich MW, Harris WS. Baseline blood levels of omega-3 and depression remission: a secondary analysis of data from a placebo-controlled trial of omega-3 supplements. J Clin Psychiatry. 2016;77(2):e138-143. doi:10.4088/JCP.14m09660
  18.  Roomruangwong C, Kanchanatawan B, Sirivichayakul S, Mahieu B, Nowak G, Maes M. Lower serum zinc and higher CRP strongly predict prenatal depression and physio-somatic symptoms, which all together predict postnatal depressive symptoms. Mol Neurobiol. 2017;54(2):1500-1512. doi:10.1007/s12035-016-9741-5
  19.  Derom ML, Sayón-Orea C, Martínez-Ortega JM, Martínez-González MA. Magnesium and depression: a systematic review. Nutr Neurosci. 2013;16(5):191-206. doi:10.1179/1476830512Y.0000000044
  20.  Yary T, Aazami S, Soleimannejad K. Dietary intake of magnesium may modulate depression. Biol Trace Elem Res. 2013;151(3):324-329. doi:10.1007/s12011-012-9568-5
  21.  Hallgren M, Kraepelien M, Öjehagen A, et al. Physical exercise and internet-based cognitive-behavioural therapy in the treatment of depression: randomised controlled trial. Br J Psychiatry. 2015;207(3):227-234. doi:10.1192/bjp.bp.114.160101
  22.  McCurdy AP, Boulé NG, Sivak A, Davenport MH. Effects of exercise on mild-to-moderate depressive symptoms in the postpartum period: a meta-analysis. Obstet Gynecol. 2017;129(6):1087-1097. doi:10.1097/AOG.0000000000002053
  23.  Josefsson T, Lindwall M, Archer T. Physical exercise intervention in depressive disorders: meta-analysis and systematic review. Scand J Med Sci Sports. 2014;24(2):259-272. doi:10.1111/sms.12050
  24.  Fluetsch N, Levy C, Tallon L. The relationship of physical activity to mental health: a 2015 behavioral risk factor surveillance system data analysis. J Affect Disord. 2019;253:96-101. doi:10.1016/j.jad.2019.04.086
  25.  Harvey SB, Øverland S, Hatch SL, Wessely S, Mykletun A, Hotopf M. Exercise and the prevention of depression: results of the HUNT Cohort Study. Am J Psychiatry. 2018;175(1):28-36. doi:10.1176/appi.ajp.2017.16111223
  26.  Kong J, Wilson G, Park J, Pereira K, Walpole C, Yeung A. Treating depression with tai chi: state of the art and future perspectives. Front Psychiatry. 2019;10:237. doi:10.3389/fpsyt.2019.00237
  27.  Capon H, O’Shea M, Evans S, McIver S. Yoga complements cognitive behavior therapy as an adjunct treatment for anxiety and depression: qualitative findings from a mixed-methods study. Psychol Psychother. Published online April 8, 2021. doi:10.1111/papt.12343

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