Adjunct Therapies for Depression: More Treatment Options

Cheerful young Black couple laughing while sitting on floor and eating salad in living room, happy to be utilizing functional medicine therapies to treat depression.
Read Time: 5 Minutes

Mental health disorders, including depression and anxiety, continue to be leading causes of health-related burdens worldwide.1 According to the World Health Organization, an estimated 5% of adults worldwide experience depression.2 While depression is most acutely seen in females and young adults (aged 18-34),3 the prevalence among children and adolescents has significantly increased in recent years.4

Depression is a multifactorial condition that may have several different antecedents and triggers unique to each individual; as such, a singular focus on antidepressant medication therapy may not be the optimal approach. In fact, a major study published in 2018 found that only about a third of patients diagnosed with depression actually start treatment.5 Nonadherence to antidepressants is also common among different populations.6 A 2017 study found that 68% of the females surveyed did not follow their prescribed antidepressant therapy.7 Forgetfulness was the main reason for missing doses. A 2019 observational study of 278 older veterans with depression found that nearly a third were nonadherent to their antidepressant medication.8 Nonadherence was significantly associated with veterans who were Black, those who were unmarried, and those with greater medical comorbidity, level of functional impairment, and self-reported side effects.8

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.9 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.9

Many factors can impact the efficacy of a given treatment, but with lower rates of patient engagement to medication therapy, it may not be as effective as standalone treatment. When the cycle of depression continues for your patients and they still do not find relief, the clinical encounter can seem as hopeless as the patient feels. How can you get to the root cause for an individual patient, and what adjunct therapeutic interventions may 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, Patrick Hanaway, MD, IFM educator and senior advisor to IFM’s CEO, 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 minutes) Dr. Hanaway is a board-certified family physician who teaches on the clinical application of nutritional biochemistry, with an emphasis on digestion, immunology, mitochondrial function, and wellness. He is also the former medical director of the Center for Functional Medicine at the Cleveland Clinic.

Clearly, variable reports on the efficacy and acceptability of antidepressants,10,11 combined with the high prevalence of depression,12,13 have left many clinicians challenged about how to help patients. Research continues to point to the effectiveness of non-pharmacological approaches as adjunctive treatments for depression.

Diet and Nutrients

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.14 A recent study found that long-term adherence to a healthy diet may offer protection against recurrent depressive symptoms.15 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.15

Evidence suggests that if appropriate for an individual patient, the dietary or supplemented intake of other nutrients, such as those listed below, may be protective against depression development risk or reduce depressive symptoms:

  • Vitamin K16
  • Zinc (postpartum depression)17
  • Magnesium18,19
  • B vitamins20
  • Vitamin D21
Physical Activity and Movement Routines

Exercise and movement are also not to be overlooked. Research suggests that physical activity improves mental health and lowers the risk of depression22 and is an effective approach to treating mild to moderate depression symptoms among different patient populations.23-26 A 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.27

Accumulating evidence also suggests that tai chi and yoga can significantly regulate emotion and relieve the symptoms of depressive disorders.28,29 A 2021 systematic review (n=19 randomized controlled trials; 1,080 total participants) and meta-analysis found that among adults with a diagnosed mental disorder, yoga interventions were associated with a greater reduction in depressive symptoms compared to controls.30 Researchers noted that a higher frequency in yoga sessions per week resulted in greater reductions in symptoms.30

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 (APM).

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  1. Arias D, Saxena S, Verguet S. Quantifying the global burden of mental disorders and their economic value. EClinicalMedicine. 2022;54:101675. doi:1016/j.eclinm.2022.101675
  2. World Health Organization. Depressive disorder (depression). Published March 31, 2023. Accessed April 18, 2023.
  3. 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:1016/j.jad.2020.09.065
  4. Racine N, McArthur BA, Cooke JE, Eirich R, Zhu J, Madigan S. Global prevalence of depressive and anxiety symptoms in children and adolescents during COVID-19: a meta-analysis. JAMA Pediatr. 2021;175(11):1142-1150. doi:1001/jamapediatrics.2021.2482
  5. 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:1007/s11606-017-4297-2
  6. González de León B, Del Pino-Sedeño T, Serrano-Pérez P, Rodríguez Álvarez C, Bejarano-Quisoboni D, Trujillo-Martín MM. Effectiveness of interventions to improve medication adherence in adults with depressive disorders: a meta-analysis. BMC Psychiatry. 2022;22(1):487. doi:1186/s12888-022-04120-w
  7. 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.
  8. Gerlach LB, Chiang C, Kales HC. The start predicts the finish: factors associated with antidepressant nonadherence among older veterans during the acute and maintenance treatment phases. J Clin Psychiatry. 2019;80(3):18m12476. doi:4088/JCP.18m12476
  9. Sobieraj DM, Martinez BK, Hernandez AV, et al. Adverse effects of pharmacologic treatments of major depression in older adults. J Am Geriatr Soc. 2019;67(8):1571-1581. doi:1111/jgs.15966
  10.  Kishi T, Ikuta T, Sakuma K, et al. Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis. Mol Psychiatry. 2023;28(1):402-409. doi:1038/s41380-022-01824-z
  11.  Zhou X, Teng T, Zhang Y, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(7):581-601. doi:1016/S2215-0366(20)30137-1
  12.  Hu T, Zhao X, Wu M, et al. Prevalence of depression in older adults: a systematic review and meta-analysis. Psychiatry Res. 2022;311:114511. doi:1016/j.psychres.2022.114511
  13.  Shorey S, Ng ED, Wong CHJ. Global prevalence of depression and elevated depressive symptoms among adolescents: a systematic review and meta-analysis. Br J Clin Psychol. 2022;61(2):287-305. doi:1111/bjc.12333
  14.  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:3390/nu11040847
  15.  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:1007/s00394-019-01964-z
  16.  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. 2019;11(4):E787. doi:10.3390/nu11040787
  17.  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:1007/s12035-016-9741-5
  18.  Botturi A, Ciappolino V, Delvecchio G, Boscutti A, Viscardi B, Brambilla P. The role and the effect of magnesium in mental disorders: a systematic review. Nutrients. 2020;12(6):1661. doi:3390/nu12061661
  19.  Ljungberg T, Bondza E, Lethin C. Evidence of the importance of dietary habits regarding depressive symptoms and depression. Int J Environ Res Public Health. 2020;17(5):1616. doi:3390/ijerph17051616
  20.  Wu Y, Zhang L, Li S, Zhang D. 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. doi:1093/nutrit/nuab014
  21.  Xie F, Huang T, Lou D, 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;10:903547. doi:3389/fpubh.2022.903547
  22.  Pearce M, Garcia L, Abbas A, et al. Association between physical activity and risk of depression: a systematic review and meta-analysis. JAMA Psychiatry. 2022;79(6):550-559. doi:1001/jamapsychiatry.2022.0609
  23.  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:1097/AOG.0000000000002053
  24.  Watt JA, Goodarzi Z, Veroniki AA, et al. Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis. BMJ. 2021;372:n532. doi:1136/bmj.n532
  25.  Miller KJ, Areerob P, Hennessy D, Gonçalves-Bradley DC, Mesagno C, Grace F. Aerobic, resistance, and mind-body exercise are equivalent to mitigate symptoms of depression in older adults: a systematic review and network meta-analysis of randomised controlled trials. F1000Res. 2020;9:1325. doi:12688/f1000research.27123.2
  26.  Dauwan M, Begemann MJH, Slot MIE, Lee EHM, Scheltens P, Sommer IEC. Physical exercise improves quality of life, depressive symptoms, and cognition across chronic brain disorders: a transdiagnostic systematic review and meta-analysis of randomized controlled trials. J Neurol. 2021;268(4):1222-1246. doi:1007/s00415-019-09493-9
  27.  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:1176/appi.ajp.2017.16111223
  28.  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:3389/fpsyt.2019.00237
  29.  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. 2021;94(4):1015-1035. doi:1111/papt.12343
  30.  Brinsley J, Schuch F, Lederman O, et al. Effects of yoga on depressive symptoms in people with mental disorders: a systematic review and meta-analysis. Br J Sports Med. 2021;55(17):992-1000. doi:1136/bjsports-2019-101242

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