Depression has many causes.1 These include poor diet, nutritional deficiencies, food allergies and intolerances, stress, trauma, social and lifestyle factors, chronic infections, and toxicants. One notable mechanism by which these may cause symptoms is inflammation. It’s well passed time to move beyond the paradigm of a single-drug intervention. Rather, the complexity of depression demands a holistic assessment of one’s entire life and subsequent intervention on multiple levels simultaneously. Numerous clinical trials have substantiated such a natural treatment approach.
This is part 2 of a 3-part series on depression. In part-1 of this series, we deconstructed the fallacious science behind antidepressants. We also made introductory remarks about environmental causes and natural treatments for depression. With the assumption that readers have already viewed that material, I now proceed with this review, which continues into part 3.
- Head-to-Head and Adjunctive Clinical Trials of Antidepressants and Natural Medicines
- Nutrients, Nutraceuticals, and Depression
Inflammation Associated with Depression
Inflammation is more frequently being discussed as a potential treatment target for depression.2–4 Three different meta-analyses have found differences in proinflammatory cytokines between patients with major depressive disorder and controls. These include interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1β, the soluble IL-2 receptor, the IL-1 receptor antagonist (IL-1ra), and C-reactive protein (CRP). It appears that there may be three causal pathways: depression to inflammation, inflammation to depression, and bidirectional relationships.5–7 In middle-aged men, high serum concentrations of homocysteine may be associated with depression.8
Depression is frequently associated with gastrointestinal inflammation, as well as a number of diseases in which inflammation plays a role. These include autoimmune, neurodegenerative, and cardiovascular diseases, as well as type-2 diabetes, cancer, and obesity.9–13 Hay fever, asthma, and urticaria have also been linked to depression, bipolar disorder, other mental disorders, and suicide. (See Appendix.) Depression, gastrointestinal permeability, and inflammation also seem to coincide.14
A case-control study found that major depression is associated with brain inflammation.15 Bipolar depressed patients have been found to have increased inflammatory markers which track linearly with symptoms. These include elevated CRP and elevated homocysteine, as well as accompanying lower levels of vitamin B12 and folic acid.16–18 Other kinds of immune dysfunction in bipolar depression have also been noted.19,20 A post-mortem study found significantly lower levels of reduced, oxidized, and total glutathione in all psychiatric conditions, suggesting a greater susceptibility to oxidative stress.21
Most importantly, inflammatory treatments such as cytokine therapy, multiple types of vaccines, and endotoxin administration have been shown to induce depressive symptoms, sometimes lasting several weeks. (See Appendix.) A systematic review and meta-analysis also found that anti-cytokine treatment improves depressive symptoms. They furthermore found that the effect was not associated with improvement in primary physical illness.22
So what does all this mean? It means depression can have actual physiological causes that you aren’t simply born with. The inflammation has to be caused somehow. It also means that anti-inflammatory effects may explain a part of the benefits of many dietary supplements I review in this series. However, we must take care to avoid a symptom management mindset, and instead seek to eliminate the root causes of inflammation. I will review many such underlying causes as well as therapies that have lead to documented improvements in both depression scores and inflammatory markers.
Head-to-Head and Adjunctive Clinical Trials of Antidepressants and Natural Medicines
A number of studies test natural medicines against antidepressants. These are called head-to-head trials. Other studies combine natural therapies with antidepressants and test the combination against either antidepressants alone, or placebo alone. These are called adjunctive trials.
In some instances head-to-head trials may actually underestimate the effectiveness of natural medicines due to unblinding bias. While there is an expectation of benefit within either group of a head-to-head trial, that expectation is probably greater within a drug group as compared to a dietary supplement group, owing to the side effects of drugs (see part-1). Though note that this only applies to trials where the patient is scoring their own depression. In trials where the physician is doing the scoring, it is not as clear cut how unblinding bias will affect them. Which treatment are they unconsciously rooting for?
In other instances, head-to-head trials at the very least further prove that antidepressants don’t work. For example, two studies found homeopathy is not any less effective than fluoxetine (Prozac).23 Some may interpret this as evidence that homeopathy works. A more biochemically plausible explanation is rather that Prozac doesn’t work.
Adjunctive trials should be viewed cautiously because often times the second intervention does not have an adequate control. If one group is receiving two interventions, and the other group is receiving only one intervention, the first group may have greater expectation of benefit, thus confounding results with a placebo effect. Ideally, the second group should receive the one intervention, plus a placebo. Or else, both groups should have all ingredients contained within a single capsule, so no one knows how many interventions they are receiving.
Although sometimes positive results of head-to-head or adjunctive trials might just be due to noise (small studies with small effect sizes), as a whole, these studies indicate that a number of natural therapies may be beneficial in the treatment of depression. This is especially the case when we consider that several of the interventions mentioned in this section also have standalone evidence from placebo-controlled trials, which I review later on.
Light therapy outperformed fluoxetine in a trial of 122 patients with major depressive disorder. 44% achieved remission in the light therapy only group, 30% in the placebo group, and only 19% in the fluoxetine group. Note that the drug failed to outperform placebo.24 A systematic review and meta-analysis found light therapy to be an effective adjunct to antidepressants in major depressive disorder and bipolar depression without a seasonal pattern.25
A Review of Adjunctive Trials
A review of 40 clinical trials that used natural supplements as an adjunct to antidepressants found primarily positive results for replicated studies testing S-adenosylmethionine (SAMe), methylfolate, fish oil, and vitamin D. It also found positive isolated studies for creatine, folinic acid, and an amino acid combination. No trials reported any major adverse effects.26 Some of these reviewed studies might have also had a third group which allowed for testing the nutrient head-to-head with the antidepressant, rather than only as an adjunct. It might be worth digging through their references to look for those. For example, in one adjunctive study of omega-3 fatty acids (EPA), there was also an EPA-only group which performed as well as the fluoxetine group.27 However, fish oil research should be interpreted with particular skepticism as previous authors have found no benefit in depression after adjusting for publication bias.28
It is worth noting that using SAMe to boost serotonin is still symptom management. Such supplements do little to address root causes of disease. The same goes for other serotonin-boosting supplements like L-typropthan, which performed as well as imipramine in one study.29
A more recent systematic review also suggested positive results for vitamin D as an adjunct.30
Saffron was found to be as effective as fluoxetine in three different trials. (See Appendix.) Another trial found saffron to be as effective as imipramine.31 A trial of 60 patients found no significant difference in the efficacy of curcumin when compared to fluoxetine (Prozac) in the treatment of major depression.32 Another trial found curcumin to be an effective adjunct to antidepressants.33 A trial tested a rhodiola extract against the drug sertraline. Both interventions outperformed placebo, although sertraline apparently did better. However, rhodiola was associated with less than half the risk of adverse effects as compared to the drug.34 A review of 29 studies testing St. John’s wort (hypericum) against depression was published in 2009. 18 trials tested against placebo, and 17 trials tested against various antidepressants drugs. The review concluded that hypericum is more effective than placebo and similar in effectiveness to antidepressants, but with fewer side effects.35 A 2015 review had similar conclusions, but gave more stress to the incompleteness of the research.36 Ayurvedic herbal treatment showed comparable results to clonazepam (Klonopin) in the treatment of generalized anxiety disorder with comorbid generalized social phobia.37
A 2008 trial found magnesium to be as effective as imipramine in treating depression in diabetics, without any of the side effects of the drug. (See Appendix.)
A 2014 review of acetyl-L-carnitine in the treatment of depression appeared favorable. It found four trials that demonstrated superiority over placebo in depression. Two trials showed superiority over placebo in dysthymic disorder. Two trials showed equal efficacy as fluoxetine and amisulpride in treatment of dysthymic disorder. Efficacy was also found for depressive symptoms in patients with fibromyalgia and minimal hepatic encephalopathy. It had equal tolerability to placebo and better tolerability than the drugs.38
One trial found that vitamin C appeared to be an effective adjunct to fluoxetine. The combination group had significantly greater improvements in two out of three depression scores compared to the fluoxetine-only group.39 A trial tested vitamin C in combination with individually prescribed antidepressants against only individually prescribed antidepressants. The vitamin C group showed improvements that were significantly larger than the antidepressant-only group. However, this study had a large dropout rate and there were multiple types of antidepressants used.40 Another trial in patients with major depression did not find a significant difference between one group that took a combination of vitamin C and citalopram and another group that took a combination of vitamin C and placebo.41
Both endogenous and found in some foods, palmitoylethanolamide (PEA) showed efficacy as an adjunct to citalopram in one trial.42
Exercise is effective as both an adjunctive and standalone therapy in the treatment of major depressive disorder.43 A Cochrane review which included four head-to-head trials comparing exercise to pharmacological therapy found no significant difference.44
Patients with depression or anxiety disorders who were receiving standard medication were either assigned to a control group or a study group which was additionally treated with whole-body cold therapy for 15 days. By three weeks, the percentage of patients experiencing more than 50% reduction in depression scores was 34.6% in the study group and 2.9% in the control group. For anxiety disorders, these percentages were 46.2% and 0%.45
Poor Diet as a Cause of Depression
Numerous studies – both observational and interventional – have implicated poor diet as a cause of depression.
A prospective study of 43,000 women found that an inflammatory dietary pattern is associated with a higher risk of depression.46 A study of 15,000 Spanish adults found that simply having a poor diet is associated with an increased chance of depression.47 Data from over 70,000 postmenopausal women suggest that a high glycemic index diet is also a likely risk factor for depression.48 Fruit and vegetable intake is inversely associated with depression. 49,50 A study of 281 young adults found that increasing intake of fruits and vegetables predicted improved emotional well-being on the following day.51 A study of over 263,000 people found that drinking 4 cans of diet soda a day is linked to a 30% higher chance of depression compared to non-drinkers. Drinking 4 cans of fruit punch was linked to a 38% higher risk compared to non-drinkers. On the other hand, drinking 4 cups of coffee was linked to a 10% lower chance compared to non-drinkers.52 Energy drink consumption has also been linked to depression, anxiety, and stress in young males.53 Intake of refined sugar and dairy predicted worse 2-year outcomes in schizophrenia.54 A prospective study found that sugar intake was associated with depression, with further evidence that there was no reverse causality.55 A study of 3,040 Australian adolescents found relationships between quality of diet and mental health. These results include a trend of mental health improving as diet quality was improved over the course over follow-up. There was also evidence that reverse causality was not the explanation.56 Dietary trans fatty acids are “strongly associated” with aggression.57
A 2014 systemic review selected 12 epidemiological studies to investigate the association between diet and mental health in children and adolescents. Overall, the review seems to support the notion that unhealthy dietary patterns may cause depression.58 Some of the studies the researchers chose to exclude from their review are still quite interesting. For example, in a study of 3486 middle-aged individuals, a processed food dietary pattern was associated with an increased risk of depression, whereas a whole food dietary pattern was associated with a decreased risk of depression.59
A randomized controlled trial found that a Mediterranean diet supplemented with nuts had an inverse association with depression compared to controls in elderly patients at high risk of cardiovascular disease. Though the association was not significant overall, it was significant when looking only at patients with diabetes.60 One small study found that reducing fat intake from 41% to 25% of the overall energy in a diet resulted in significant increases in ratings of anger-hostility, whereas controls saw a slight decrease.61 Conversely, a one-year RCT found that when obese people are placed on a low-fat, high-carbohydrate diet, their mood benefits relative to a high-fat, low-carbohydrate diet.62 Another RCT found that when people in a corporate setting are given either vegan dietary counseling or no counseling, the vegan diet is associated with a variety of improved outcomes, including mental health.63
A 2018 meta-analysis (Firth et al.) of RCTs testing dietary interventions found positive effects on depressive symptoms.64 However, most all studies were done in nonclinical populations (i.e. not diagnosed with depression). Overall, a relatively small benefit was found, and females appeared to benefit more than men. The only trial identified in the review that was done in a clinical population was the “SMILES” trial (Jacka et al. 2017). The authors tested dietary counseling versus a social support protocol in moderate to severe depression, and found greater improvements in the dietary counseling group relative to the controls, with an NNT of 4.1.65
In general, trials that use active controls are more believable, as they address the effects of unblinding bias. It is desirable to have patients in both groups have an “expectation” of benefit. This helps ensure that any reported benefit is not inflated by a placebo effect. Though Firth et al. found benefit whether trials were grouped by active or inactive controls, it is not surprising that trials that used inactive controls tended towards smaller benefit. The SMILES trial is thus doubly important in that it yielded a large benefit, while still employing an active control. This suggests the benefit of dietary interventions are likely to be much greater overall and that the reported lack of benefit in men may not apply to patients actually diagnosed with depression.
Many other studies, including at least four more meta-analyses or systematic reviews of observational studies, have found an association between poor quality diet and depression. (See Appendix.)
Overall, research suggests that a healthy diet with regards to mental health is one that emphasizes whole foods such as fruits, vegetables, and nuts, and that avoids all refined sugars, refined carbohydrates, processed foods, and trans fats. Raw fruits and vegetables appear to be better than processed. The role of a vegetarian versus an omnivore diet is not particularly clear and has some conflicting evidence. (See Appendix.) The best approach would probably be to consume flesh foods in moderation, and not in a processed form.
Nutrients, Nutraceuticals, and Depression
Related to poor diet, we now look at common nutritional deficiencies among depressed individuals, and at trials which have treated depression with nutrients and nutraceuticals. Note the overlap between the below interventions and those already discussed in the section on head-to-head and adjunctive trials.
A 2017 review found that low levels of vitamin B (B1, B2, B3, B6, B9, B12) are common in patients with depression, and that vitamin B supplementation has been shown to improve depression outcomes.66 I mention some select studies here: In a controlled trial, B-vitamins were found to improve symptoms of depression and reduce homocysteine in certain adults over 65.67 Folate levels may be a predictor of treatment response and may also be a useful adjunct to antidepressants.68,69 A population based study of over 2,800 people found that those with the highest folate intake had a 45% lower chance of melancholic depression compared to those with the lowest intake.70 A prospective study of 2,313 Finnish men found that those who fell below the median folate intake had 3 times the risk of being diagnosed with depression during the follow-up period.71
Curcumin and Saffron
A 2016 meta-analysis of six trials found that curcumin is effective in the treatment of depression.72 A 2017 systematic review concluded that curcumin is a promising natural agent for many neuropsychiatric conditions, most notably major depression.73 At least three systematic reviews and meta-analyses have found saffron is more effective than placebo. And at least two more positive RCTs have been published since then. (See Appendix.) A 2017 trial tested low-dose curcumin, high-dose curcumin, and the combination of low-dose curcumin and saffron against placebo in patients with major depressive disorder. All three treatment groups saw significant reduction in depression and anxiety symptoms compared to controls.74
Vitamin D and Sunlight
Research is increasingly suggesting that low vitamin D levels is an effect, rather than a cause of disease. Also, vitamin D technically does not meet the definition of a nutrient either, but I will discuss that some other time. And although sunlight is not a dietary nutrient and has many biological effects, for ease of discussion I include it here. Latitude correlates with suicide rate, suggesting lack of sunshine as a cause of depression.75,76 Lower levels of vitamin D appear to predict severity of depressive symptoms in young adult women.77 In one study low vitamin D was associated with an 11-fold increased risk of mood disorder in older adults.78 A study also found that there is a significant drop in Google searches relating to mental health during the summer, relative to the winter.79 A study in community-dwelling European men found the risk of depression was 70% higher across decreasing quartiles of vitamin D levels.80 A small study of 15 patients with seasonal affective disorder received either broad-spectrum phototherapy or a form of vitamin D. All patients receiving vitamin D improved in all measured outcomes, whereas no improvements were seen in the phototherapy group. Both groups saw increases in their vitamin D levels.81 Vitamin D deficiency is associated with anxiety and depression in fibromyalgia.82 In a study of 441 obese subjects with depression, one year of supplementation with vitamin D led to significant improvements in depression scores compared to baseline, whereas the placebo group saw no improvements compared to baseline.83 Vitamin D improved mood and blood pressure in diabetic women.84 A study of over 16,000 university students found that seasonal increases in sun time were associated with decreased mental health distress.85
A study found that young women who took a multivitamin plus 7 mg of zinc showed significant improvements in three different depression scores, whereas women who took only the multivitamin did not see any significant improvements.86 A meta-analysis found that lower levels of zinc are associated with depression.87 For example, one study found zinc deficiency was found in 36.6% of depressed geriatric patients, compared to only 14.4% of controls.88
A placebo-controlled trial of chromium supplementation in atypical depression found significant improvements compared to controls in diurnal variations of feelings, appetite increase, increased eating, and carbohydrate craving.89 Another small study of 15 patients with atypical depression showed responses in 70% of the chromium group, with zero responses in the placebo group.90
A meta-analysis of 8 studies found that supplementation with multivitamins/minerals improves measures of stress, mild psychiatric symptoms, anxiety, fatigue, and confusion, but not depression. The authors suggested that higher doses of nutrients may be called for.91
A trial in hospitalized acutely ill older patients found that oral nutritional supplementation led to a statistically significant benefit on depressive symptoms.92
In women over 50 supplementation with multivitamins/minerals and herbs led to acute improvements in mood compared to controls.93
A study of 492 patients with a range of mental illness were given “targeted nutrient therapy”. 382 patients complied for one year. 44.9% noted major improvement, 18.5% noted partial improvement, and 14.2% noted no improvement in three quality of life outcomes. In a group of 26 patients who did not receive the nutrient treatment, 19% noted major improvements, 19% noted partial improvement, and 62% noted no improvement. Hospital admission was lower in the treatment group.94
A study of 80 subjects found lower levels of vitamins A, C, and E in depressed patients compared to controls, and that supplementation led to improvements in depression scores.95
In the treatment of anxiety, naturopathic care involving a combination of dietary counseling, a multivitamin, ashwaganda, and deep breathing and relaxation techniques outperformed a control group which employed standardized psychotherapy, matched deep breathing and relaxation techniques, and a placebo.96
A study of 50 men found that supplementing with a multivitamin containing vitamins, minerals, antioxidants, and herbal extracts resulted in significant improvements in depression and anxiety scores, alertness, and general daily functioning compared to placebo controls.97
Magnesium and Calcium
A 2015 review and meta-analysis found that there may be an association between magnesium deficiency and depression.98 Another study of 5,708 community-dwelling adults found a significant relationship between magnesium intake and depression.99 The magnesium load test is considered by some to be more reliable than testing serum, red blood cell, whole blood, or white blood cell magnesium levels. One study found that these methods will miss deficiencies found by a magnesium loading test at least 40% of the time. The researchers furthermore found that a sample of 100 depressed patients revealed every single one of them had magnesium deficiency as determined by loading testing.100 A randomized open-label crossover trial suggests magnesium chloride supplementation may be beneficial.101 However, such results could be explained by placebo and nocebo effects experienced by the two respective groups.
Low dietary calcium is associated with self-rated depression in middle-aged Korean women.102
One study found that 51.4% of depressed patients had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value detected in the controls.103 A controlled study in multiple sclerosis patients showed CoQ10 improved depression scores.104 However, a controlled trial in breast cancer patients did not lead to significant improvements in depression scores.105
A study of 986 older adults found a significant association between depression and anemia. 15% of depressed patients had anemia, whereas only 8% of controls did.106 A study of nearly 3,000 children and adolescents found an association between iron deficiency anemia and depressive disorder (OR=2.34) , bipolar disorder (OR=5.78), anxiety disorder (OR=2.17), and a number of other psychiatric disorders.107
A 2002 paper reviewed 5 studies that found an association between low selenium intake and poorer mood.108 A number of studies have come out since then. Prenatal selenium supplementation is associated with significantly lower postpartum depression in women compared to controls.109 A study of 978 young adults found that serum selenium concentrations are associated with depressive symptoms and negative mood.110 A study in nursing home residents found that 8 weeks of supplementation with selenium, vitamin C, and folate significant improved depression compared to placebo controls. Furthermore, selenium levels were significantly associated with depression. Although 67% of patients had low serum vitamin C, those levels were not significantly associated with depression.111
Low plasma vitamin C has been associated with depression.112 Despite popular belief, vitamin C deficiency or depletion is common, with incidences ranging from 5% to 25% even in the United States and the UK. In other countries like India, it may be as high as 74%. (See Appendix.) A controlled trial in healthy young adults found 3000 mg of vitamin C improved depression scores, and increased frequency of sexual intercourse. Within just 2 weeks of supplementation, people who weren’t cohabiting with their partners reported having intercourse nearly 14 times per month, as compared to less than 4 times per month in the placebo group.113
Other Nutrients and Nutriceuticals
A systemic review looked at 21 controlled trials testing herbal and nutritional supplements in the treatment of mostly anxiety and depression. 71% of trials showed a positive direction of evidence. The authors concluded that there was strong evidence for the use of extracts of passionflower, kava, and combinations of L-lysine and L-arginine.114
Other nutraceuticals and interventions with controlled trials that suggest efficacy include dark chocolate, blue-green algae extract, goji berry juice, rhodiola extract, N-acetyl cysteine, ashwagandha extract, chlorella extract, chamomile extract, and aromatherapy.115–127
Food Allergies and Intolerances as a Cause of Depression
Food allergies and intolerances play a substantial role in depression and mental health in general.
A general population-based cohort study found an association with celiac disease and depression.128 A small double-blind cross-over study found that when irritable bowel syndrome patients that had celiac disease excluded were challenged with a gluten-containing diet, they reported higher depression scores compared to placebo. The authors suggest that patients with non-celiac gluten sensitivity may still feel better on a gluten-free diet, despite the continuation of gastrointestinal symptoms.129
Candida infection may actually be a trigger of celiac disease.130 I discuss the role of Candida and other chronic infections in depression in part-3.
A longitudinal study found increased levels of IgG antibodies to gliadin in patients hospitalized for acute mania compared to controls, but not so with other markers of celiac disease. No significant difference compared to controls was found at six month follow-up. Elevated antibody levels at follow-up were associated with re-hospitalization during the six month follow-up period.131
Intake of refined sugar and dairy predicted worse 2-year outcomes in schizophrenia.54
Anti-Saccharomyces cerevisiae antibodies (ASCA) is a marker of GI inflammation. In one study, an elevated ASCA conferred a 3.5-4.4 fold risk of bipolar disorder. ASCA also correlated with food antibodies in bipolar patients, and with antibodies to measles and T. gondii in patients with recent onset psychosis bipolar disorder.132
The Microbiome and Depression
A systematic review and meta-analysis found that probiotics are associated with a significant reduction in depression in both a healthy population and patients with major depressive disorder.133 One study found that consuming fermented foods (a source of probiotics) is associated with lower levels of social anxiety.134
As we saw earlier, gluten sensitivity may be a significant cause of depression. And gut bacteria may play a role in determining how sensitive individuals are to gluten.135
There are many environmental factors that lead to a distorted microbiome. Antibiotics are a prominent example, with history of antibiotic use being associated with depression.136 Though I will review this in more detail in the future, Selhub et al. provide a good start. Probiotics have pleiotropic effects that provide many potential ways in which they may positively affect mental health.137
Thyroid Disorders and Depression
A link between thyroid disorders and depression has been known for a long time.
For example, one study found that subclinical hypothyroid patients have symptoms of depression 45.6% of the time, where as only 20.9% of euthyroid patients did.138 Fifty-two percent of treatment resistant cases of depression appear to have subclinical hypothyroidism.139 Perhaps 20% of depressed patients carry thyroid antibodies, as compared to 5 to 10% of the general population.140
Some associations that have been found with depression are elevated T4 levels, low T3, elevated rT3, a blunted TSH response to TRH, antithyroid antibodies, and elevated CSF TRH concentrations.141–146 Overall, these authors suggest that using T3 as an adjunct, especially in treatment resistant cases, might improve outcomes. However, I would still call this symptom management and would rather that people investigate root-causes for the thyroid dysfunction, of which there could be many. Interestingly, in patients with subclinical hypothyroidism and depression, levothyroxine does not appear to improve symptoms.147
It should also be noted that I have already described the use of selenium in the treatment of depression. Selenium is required for the synthesis of thyroid hormone. Hence there could be a relation.
Continue to Part 3 – Chronic Infection, Toxicants, Stress, Trauma, and Lifestyle
In the third and final part of this series we review the roles of chronic infection, toxicants, stress, trauma, and lifestyle in depression. We also close with some treatment suggestions.