Depression is an increasingly common issue in the United States. The Centers for Disease Control in 2010 estimated that 11.1 percent of the American population suffers from significant depression — a whopping 35 million individuals — and this figure seems to be steadily rising. Prescribed mood modifiers are everywhere, starting as early as elementary school and continuing on into old age. How successful are these pharmacologic approaches? Not very. Optimistic estimates maintain that such interventions are reasonably successful in only one half of those treated. Less optimistic observers note that in those currently taking an SSRI (selective serotonin reuptake inhibitor) antidepressant drugs such as Prozac, despite a host of side effects, most do not attain relief. Nearly two-thirds of elderly patients treated for depression fail to achieve symptomatic remission and functional recovery with first-line pharmacotherapy; they obtain better results with, for instance, tai chi.¹ For major depressive disorder, a condition for which one would think that pharmacological treatments would win out over nonpharmacological therapy, it turns out that nonpharmacological therapy not only is just as effective, but also involves far fewer adverse events.^2,3

The causes of depression and mood disorders remain an area of controversy. Human beings are prepared to react to vastly varied environmental factors. Not surprisingly, many biological and psychological factors cut in more than one direction. Metabolic factors (inflammation, insulin resistance, and oxidative stress) are not necessarily one-direction in terms of causation, for example, with regard to emotional and physical stress and the resulting stress hormones (glucocorticoids). Sex hormones (testosterone, estrogen), likewise, both influence and are influenced by emotional and physical factors.

Is Inflammation the Central Issue?
The concept of inflammation in the last few years has been stretched to cover more and more forms of illness and dysfunction. One reason is that inflammation is actually a set of responses that occur naturally all the time, yet each of which can itself escape proper regulation. You get a sense of this from the article on inflammation available online from Wikipedia: “Inflammation is a protective response that involves immune cells, blood vessels, and molecular mediators. The purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair.” Inflammation thus involves both destruction and repair.

A number of researchers are looking into the issue of neuroinflammation outside of the traditional medical areas of concern, such as stroke. For instance, psychological stress has been demonstrated to increase neuroinflammation in animal models.⁴ Similarly, there is evidence to support the position that links chronic depression to chronic brain inflammation and acute depression to stress-triggered neuronal microdamage.⁵ Another line of argument is that the “metabolic syndrome and its individual components induce a proinflammatory state that damages blood vessels. This condition of chronic inflammation may damage the vasculature of the brain or be directly neurotoxic.”⁶

Countering Depression without Drugs
Inflammation and the metabolic syndrome are closely linked in physiology and biochemistry. Therefore, it should not come as a surprise that studies on obesity, diet and exercise habits often turn up implications for preventing and treating depression. For example, a large study of 15,093 people published in 2015 indicated that depression could be linked with nutrient deficits. The best results were found with two essentially Mediterranean-style diets. These diets overlapped in terms of foods such as omega-3 fatty acids, vegetables, fruits, legumes, nuts and moderate alcohol intake. Another finding was that there apparently is a threshold effect, meaning that a certain level of protective foods needed to be in the diet, but that benefits in terms of reduced risk of depression plateaued after this threshold was passed.⁷

It is difficult to find many nutrients that can be given as dietary supplements that cross the blood-brain barrier. Many of the nutrients that are of use are from berries. Pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease.⁸ “Blueberry, strawberry, blackberry, grape and plum juices or extracts have been successfully tested in cognitively impaired rodents. Published trials of the benefits of grape and blueberry juice in the treatment of small numbers of cognitively impaired persons have recently appeared.”⁹ Another potentially useful item in this regard is the Chinese herb known as blue dogbane, Apocynum venetum. This interesting item, virtually unknown outside of Asia, exerts proven anti-depressant effects, in part, via brain monoamine levels and the dopaminergic system. The latter, again, is influenced by pterostilbene, but not resveratrol.¹⁰ Of importance regarding the impact of Apocynum venetum on inflammation is its high content of the potent antioxidant / anti-inflammatory, isoquercitrin.¹¹

A complementary option to the foregoing nutrients is to reduce the impact of stress. Phosphatidylserine (PS) supports the brain’s physiological processing of stress and promotes neuronal communication by its effect on cell membrane fluidity. It is a natural phospholipid that is an essential component of cell membranes. PS promotes brain function by increasing neuronal membrane fluidity (cell-to-cell communication), resulting in improved cognition. Also, PS protects against stress by mitigating the actions of cortisol (catabolic stress hormone.) Human research routinely demonstrates these benefits and suggests the usefulness of a combination with DHA, e.g., “The results demonstrate that consumption of 100 mg/day of PS-DHA might be associated with improving or maintaining cognitive status in elderly subjects with memory complaints.”¹²

Finally, there is the issue of the relation between Alzheimer’s and sugar consumption. In old age, there tends to be an increasingly significant association between forms of cognitive impairment and depression. Some believe there’s a connection between sugar intake and Alzheimer’s disease. There are a number of theories as to why this might be. One argument is that increased consumption of simple carbohydrates leads to blood brain barrier degradation and subsequently to damage to the hippocampus.¹³ A related argument is that increased consumption of simple carbohydrates leads to elevations of specific advanced glycation end products (AGEs), especially the neurotoxic methyl-glyoxal derivatives (MG). High levels of AGEs also are correlated with reduced insulin sensitivity in older human adults. These factors promote chronic oxidant stress and inflammation in the brain.¹⁴

Endnotes:

1. Lavretsky H, Alstein LL, Olmstead RE, Ercoli LM, Riparetti-Brown M, Cyr NS, Irwin MR. Complementary use of tai chi chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. Am J Geriatr Psychiatry. 2011 Oct;19(10):839–50.
2. Gartlehner G, Gaynes BN, Amick HR, Asher G, Morgan LC, Coker- Schwimmer E, Forneris C, Boland E, Lux LJ, Gaylord S, Bann C, Pierl CB, Lohr KN. Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Dec.
3. Gartlehner G, Gaynes BN, Amick HR, Asher GN, Morgan LC, Coker- Schwimmer E, Forneris C, Boland E, Lux LJ, Gaylord S, Bann C, Pierl CB, Lohr KN. Comparative Benefits and Harms of Antidepressants, Psychological, Complementary, and Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016 Feb 9. [Epub ahead of print]
4. Barnum CJ, Pace TW, Hu F, Neigh GN, Tansey MG. Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS challenge. J Neuroinflammation. 2012 Jan 16;9:9.
5. Wager-Smith K, Markou A. Depression: a repair response to stress-induced neuronal microdamage that can grade into a chronic neuroinflammatory condition? Neurosci Biobehav Rev. 2011 Jan;35(3):742–64.
6. Cherniack EP. A berry thought-provoking idea: the potential role of plant polyphenols in the treatment of age-related cognitive disorders. Br J Nutr. 2012 Sep;108(5):794–800.
7. Sánchez-Villegas A, Henríquez-Sánchez P, Ruiz-Canela M, Lahortiga F, Molero P, Toledo E, Martínez-González MA. A longitudinal analysis of diet quality scores and the risk of incident depression in the SUN Project. BMC Med. 2015 Sep 17;13:197.
8. Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt- Hale B, Smith MA, Joseph JA, Casadesus G. Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease. Neurobiol Aging. 2012 Sep;33(9):2062–71.
9. Cherniack EP. A berry thought-provoking idea: the potential role of plant polyphenols in the treatment of age-related cognitive disorders. Br J Nutr. 2012 Sep;108(5):794–800.
10. Zheng M, Fan Y, Shi D, Liu C. Antidepressant-like effect of flavonoids extracted from Apocynum venetum leaves on brain monoamine levels and dopaminergic system. J Ethnopharmacol. 2013 May 2;147(1):108–13.
11. Butterweck V, Nishibe S, Sasaki T, Uchida M. Antidepressant effects of apocynum venetum leaves in a forced swimming test. Biol Pharm Bull. 2001 Jul;24(7):848–51.
12. Vakhapova V, Cohen T, Richter Y, Herzog Y, Kam Y, Korczyn AD. Phosphatidylserine containing omega-3 Fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: results from an open-label extension study. Dement Geriatr Cogn Disord. 2014;38(1–2):39–45.
13. Hsu TM, Kanoski SE. Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia. Front Aging Neurosci. 2014 May 9;6:88.
14. Cai W, Uribarri J, Zhu L, Chen X, Swamy S, Zhao Z, Grosjean F, Simonaro C, Kuchel GA, Schnaider-Beeri M, Woodward M, Striker GE, Vlassara H. Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans. Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4940–5.

Phosphatidylserine (PS) is quite literally a “brain nutrient.” As a matter of fact, this phospholipid is an integral component in the structure of the brain and spinal cord, and is active at cell membranes (including synaptic membrane zones). A significant amount of published clinical research has demonstrated that PS supplementation supports various cognitive parameters in adults and in children.¹

Age-related memory impairment
Kato-Kataoka et al² conducted a double-blind, randomized controlled study to investigate the effects of PS on the cognitive functions of elderly Japanese subjects with memory complaints. Seventy-eight elderly people with mild cognitive impairment (50–69 years old) were randomly allocated to take PS (100 mg, 300 mg/day) or placebo for six months. In the subjects with relatively low score at baseline, the memory scores in PS treated groups were significantly increased against the baseline, while those of the placebo group remained unchanged. And the memory improvements in PS treated groups were mostly attributed to the increase in delayed verbal recall, a memory ability attenuated in the earliest stage of dementia.