Depression Treatment Should Be Multi-Factorial

The Medication Reality

If medication didn't really work for you, you are probably right. Large meta-analyses of antidepressant randomized controlled trials show drug-placebo differences are small, with more impact in very severe depression and small to modest mean differences overall. [1] Minimal clinical improvement on global ratings corresponds to an effect size nearer 0.8, and typical antidepressant-placebo differences fall short of that threshold (0.3-0.4).

Irving Kirsch has been particularly vocal in this area, arguing that analyses of both published and unpublished clinical trial data consistently show that most of the benefits of antidepressants in treating depression and anxiety are due to the placebo response. [2]

Some people do have a positive response to antidepressants. For them, the problem is solved and the rest of this newsletter doesn't really apply unless they want a stronger effect, are concerned about a lasting effect, or want to stop medication.

The Numbers for Medication Alone:

If we're targeting 50% symptom reduction, placebo produces results in around 35-40% of people, while medication achieves 40-47% depending on symptoms. [3] For remission (where symptom scores drop below a certain level): placebo works for 20-25% of people, while medication works for 25-28%. [3]

For those who do respond, relapse rates over 6-12 months tell an interesting story: about 40% of people relapse on placebo, compared to 20% continuing medication. [4] The problem is that most medications cause side effects so people usually know if they are on placebo.

Exercise: The Most Robust Intervention

A 2023 meta-analysis of 41 randomized controlled trials involving 2,264 participants found a large effect of exercise versus non-active controls on depressive symptoms, with a difference of about -0.95 and a number needed to treat to get a benefit of approximately 2 (When people start exercising, roughly half of them will likely see a difference in mood). [5] Both aerobic and resistance training showed large effects, especially when supervised and at moderate intensity.

A 2024 network meta-analysis of 218 RCTs with approximately 14,000 participants reported moderate reductions in depression for walking/jogging, yoga, strength training, mixed aerobic exercise, and tai chi/qigong versus active controls, with dose-response relationships by intensity and good tolerability for yoga and strength work. [6]

And think of all the other benefits you get from exercise!

Dance: Movement Plus Connection

Dance-specific interventions have shown significant reductions in depressive symptoms versus no-intervention controls in adults and older adults across multiple randomized controlled trials and meta-analyses. [7] Effect sizes are typically small to moderate, and the group/social components may account for part of the benefit.

Sleep: A Critical Target

A 2024 meta-analysis in major depressive disorder patients with insomnia found that cognitive behavioral therapy for insomnia (CBT-I) increased depression response rates from about 17% in controls to approximately 32% in CBT-I groups, beyond the sleep improvements alone. [8]

Gratitude Practices

A 2023 systematic review of 64 randomized controlled trials found that gratitude interventions—including journaling, letters, and apps—improved gratitude, mental health, and reduced anxiety and depressive symptoms versus controls, with small to moderate effects. [9] Individual RCTs using digital gratitude programs report small to moderate reductions in repetitive negative thinking and depressive symptoms, with effects maintained at follow-up.

EFT (Emotional Freedom Techniques)

A 2024 meta-analysis of randomized controlled trials reported a large pooled effect size of approximately 1.27 for depression reduction, with group formats and moderate baseline depression showing the greatest benefit. [10]

HeartMath and HRV Biofeedback

A meta-analysis of randomized controlled trials with approximately 794 participants reports a medium effect size (0.38) of heart rate variability biofeedback on depressive symptoms across clinical and nonclinical samples. [11] A separate RCT adding HRV biofeedback to psychotherapy for major depressive disorder found greater improvement in heart rate variability and superior depression outcomes compared with psychotherapy alone. [12]

Expressive Writing

In community samples, expressive writing (Pennebaker journaling) has been associated with modest short-term reductions in depressive symptoms and mental/physical complaints, though effects often attenuate by 4-6 months. [13]

Diet Matters

In postmenopausal women, higher dietary glycemic index (too many simple carbs) was prospectively associated with greater odds of developing depression over 3 years, even after adjusting for multiple lifestyle and dietary factors. [14]

A 2025 systematic review and meta-analysis suggests ketogenic diets are associated with modest improvements in depressive symptoms, particularly when biochemical ketosis is confirmed, though the review emphasizes heterogeneity, small samples, and short follow-up, calling for well-powered randomized controlled trials. [15]

Supplements: Selective Benefits

A 2016 meta-analysis restricted to adults with major depressive disorder found an overall difference of approximately 0.40 favoring omega-3 polyunsaturated fatty acids over placebo— comparable in magnitude to effect sizes reported for antidepressants. [16] Higher EPA doses and concurrent antidepressant use showed larger benefits. With the right formulation and context (EPA-heavy, approximately 1 gram per day, as add-on therapy), omega-3 can approximate antidepressant-like effect sizes.

Of course if there is a specific deficiency, such as low B12, or iron, or sometimes low methylfolate in a susceptible patient, this should be addressed.

Hormone Therapy for Perimenopausal Depression

Two out of three double-blind randomized controlled trials showed that transdermal 17β-estradiol (about 0.1 mg/day, with cyclic progesterone when uterus intact) can significantly reduce depressive symptoms in women with confirmed perimenopause compared with placebo, even when they meet criteria for major depressive disorder. [17]

For men, low testosterone (also test free testosterone) is a reversible cause of depression.

Thyroid hormone levels should be optimized.

Therapy: All Roads Lead to Rome

A network meta-analysis of 331 randomized controlled trials involving 34,285 patients compared cognitive behavioral therapy, interpersonal therapy, psychodynamic therapy, behavioral activation, problem-solving, third-wave therapies, life-review, and non-directive counseling. [18] All major therapies outperformed care-as-usual and wait-list (standardized mean difference roughly -0.3 to -0.8 versus usual care), with very small differences between active modalities. Non-directive counseling was somewhat less efficacious.

The Power of Integration

One study combined multiple elements: addressing the relationship between cognitive, behavioral, emotional, somatic and environmental factors proposed to maintain the self-perpetuating cycle of symptoms; a focus on psychosomatics (the reciprocity of body and mind); and attention to associations between unhealthy lifestyle behaviors and symptoms/disability. [19] Physical therapists focused mainly on the somatic symptoms and bodily dysfunctions associated with diagnosed mental disorders. This approach led to roughly 2/3 of patients improving—similar to coordinated care models where someone is responsible for keeping track of patients, their interventions, and their ongoing symptoms.

The Healing Depression Project offers a similar type of multi-modal intervention, in addition to a therapeutic diet and functional medicine expertise.



REFERENCES

[1] Pigott HE, Kim T, Xu C, Kirsch I, Amsterdam J. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study's patient-level data with fidelity to the original research protocol. BMJ Open. 2023.
https://bmjopen.bmj.com/content/13/7/e063095

[2] Kirsch I. Placebo Effect in the Treatment of Depression and Anxiety. Front Psychiatry. 2019.
https://pubmed.ncbi.nlm.nih.gov/31249537/

[3] Pigott HE, Kim T, Xu C, Kirsch I, Amsterdam J. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study's patient-level data with fidelity to the original research protocol. BMJ Open. 2023.
https://bmjopen.bmj.com/content/13/7/e063095

[4] Kato M, Hori H, Inoue T, Iga J, Iwata M, Inagaki T, Shinohara K, Imai H, Murata A, Mishima K, Tajika A. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2021.
https://www.nature.com/articles/s41380-020-0843-0

[5] Heissel A, Heinen D, Brokmeier LL, Skarabis N, Kangas M, Vancampfort D, Stubbs B, Firth J, Ward PB, Rosenbaum S, Hallgren M, Schuch F. Exercise as medicine for depressive symptoms? A systematic review and meta-analysis with meta-regression. Br J Sports Med. 2023.
https://bjsm.bmj.com/content/57/16/1049

[6] Noetel M, Sanders T, Gallardo-Gómez D, Taylor P, Del Pozo Cruz B, van den Hoek D, Smith JJ, Mahoney J, Spathis J, Moresi M, Pagano R, Pagano L, Vasconcellos R, Arnott H, Varley B, Parker P, Biddle S, Lonsdale C. Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2024.
https://www.bmj.com/content/384/bmj-2023-075847

[7] Moratelli JA, Veras G, Lyra VB, Silveira JD, Colombo R, de Azevedo Guimarães AC. Evidence of the Effects of Dance Interventions on Adults Mental Health: A Systematic Review. J Dance Med Sci. 2023.
https://pubmed.ncbi.nlm.nih.gov/37287281/

[8] Furukawa Y, Nagaoka D, Sato S, Toyomoto R, Takashina HN, Kobayashi K, Sakata M, Nakajima S, Ito M, Yamamoto R, Hara S, Sakakibara E, Perlis M, Kasai K. Cognitive behavioral therapy for insomnia to treat major depressive disorder with comorbid insomnia: A systematic review and meta-analysis. J Affect Disord. 2024.
https://pubmed.ncbi.nlm.nih.gov/39242039/

[9] Diniz G, Korkes L, Tristão LS, Pelegrini R, Bellodi PL, Bernardo WM. The effects of gratitude interventions: a systematic review and meta-analysis. Einstein (Sao Paulo). 2023.
https://pubmed.ncbi.nlm.nih.gov/37585888/

[10] Seok JW, Kim JU. The Effectiveness of Emotional Freedom Techniques for Depressive Symptoms: A Meta-Analysis. J Clin Med. 2024.
https://pubmed.ncbi.nlm.nih.gov/39518619/

[11] Schumann A, Helbing N, Rieger K, Suttkus S, Bär KJ. Depressive rumination and heart rate variability: A pilot study on the effect of biofeedback on rumination and its physiological concomitants. Front Psychiatry. 2022.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9452722/

[12] Caldwell YT, Steffen PR. Adding HRV biofeedback to psychotherapy increases heart rate variability and improves the treatment of major depressive disorder. Int J Psychophysiol. 2018.
https://pubmed.ncbi.nlm.nih.gov/29307738/

[13] Sloan DM, Feinstein BA, Marx BP. The durability of beneficial health effects associated with expressive writing. Anxiety Stress Coping. 2009.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4842937/

[14] Gangwisch JE, Hale L, Garcia L, Malaspina D, Opler MG, Payne ME, Rossom RC, Lane D. High glycemic index diet as a risk factor for depression: analyses from the Women's Health Initiative. Am J Clin Nutr. 2015.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4515860/

[15] Janssen-Aguilar R, Vije T, Peera M, Al-Shamali HF, Meshkat S, Lin Q, Lou W, Laviada-Molina H, Phillips ML, Bhat V. Ketogenic Diets and Depression and Anxiety: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2025.
https://pubmed.ncbi.nlm.nih.gov/41191382/

[16] Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl Psychiatry. 2016.
https://pubmed.ncbi.nlm.nih.gov/26978738/

[17] Xiang X, Palasuberniam P, Pare R. Exploring the Feasibility of Estrogen Replacement Therapy as a Treatment for Perimenopausal Depression: A Comprehensive Literature Review. Medicina (Kaunas). 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11279181/

[18] Cuijpers P, Quero S, Noma H, Ciharova M, Miguel C, Karyotaki E, Cipriani A, Cristea IA, Furukawa TA. Psychotherapies for depression: a network meta-analysis covering efficacy, acceptability and long-term outcomes of all main treatment types. World Psychiatry. 2021.
https://onlinelibrary.wiley.com/doi/10.1002/wps.20860

[19] Wijnen J, Gordon NL, van 't Hullenaar G, Pont ML, Geijselaers MWH, Van Oosterwijck J, de Jong J. An interdisciplinary multimodal integrative healthcare program for depressive and anxiety disorders. Front Psychiatry. 2023.
https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1113356/full