Neurological - Depression


The Problem
Depression is commonly thought of being due to decreased serotonin levels.  However, depression is strongly associated with both increased inflammation (1,2) and insulin resistance (3)

The Traditional Medical Approach
The primary approach to treating depression has been the use of drugs that enhance serotonin levels in the brain.  Before such drug therapy was introduced, the primary treatment for depression was electroshock therapy.  Recent research indicates that electroshock therapy increases AMPK levels (3)

The Metabolic Engineering™ Approach
Both inflammation and insulin resistance are reduced by Metabolic Engineering™ because it activates AMPK.  As an example, both bipolar and unipolar depression respond well to high-dose omega-3 fatty acids (4,5).  In treating unipolar depression, the improvement in symptoms were correlated with an increase in resolvins formation (6).  Finally, there is an association between depression and increased oxidative stress (7).

The goal of Metabolic Engineering™ is to activate AMPK in the brain.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces neuroinflammation and promotes its resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to reduce neuroinflammation. 

This suggests that Metabolic Engineering™ may play a significant role in the reduction of the symptoms associated with depression.  These benefits would include the reduction of insulin resistance, an increase in the production of resolvins (the hormones that turn off neuroinflammation) and decreased oxidative stress.  All these benefits are mediated by increased activation of AMPK (8).

1. Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: Depression fans the flames and feasts on the heat. Am J Psychiatry. 2015; 172:1075-91. doi: 10.1176/appi.ajp.2015.15020152.

2. Beurel E, Toups M, Nemeroff CB. The bidirectional relationship of depression and inflammation:  Double trouble.  Neuron. 2020; 107:234-256.doi: 10.1016/j.neuron.2020.06.002.

3. Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression:  A large meta-analysis of metabolic parameters and variation.  Neurosci Biobehav Rev. 2022;139: 104758. doi: 10.1016/j.neubiorev.2022.104758.

4. Kim SH, Yu HS, Huh S, Kang UG, Kim YS. Electroconvulsive seizure inhibits the mTOR signaling pathway via AMPK in the rat frontal cortex.  Psychopharmacology.  2022; 239: 443-454. doi: 10.1007/s00213-021-06015-2.

5. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial.  Arch Gen Psychiatry. 1999; 56:407-12.doi: 10.1001/archpsyc.56.5.407.

6. Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, Lamon-Fava S, Rakofsky JJ, Nierenberg AA, Clain AJ, Mletzko Crowe T, Wong A, Felger JC, Sangermano L, Ziegler TR, Cusin C, Fisher LB, Fava M, Rapaport MH.  Omega-3 fatty acids for major depressive disorder with high inflammation:  A randomized dose-finding clinical trial. J Clin Psychiatry. 2022; 8:21m14074. doi: 10.4088/JCP.21m14074.

7. Lamon-Fava S, Liu M, Dunlop BW, Kinkead B, Schettler PJ, Felger JC, Ziegler TR, Fava M, Mischoulon D, Rapaport MH. Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators.  Neuropsychopharmacology. 2023; 48:929-935. doi: 10.1038/s41386-022-01527-7.

8. Sipahi H, Mat AF, Ozhan Y, Aydin A. The interrelation between oxidative stress, depression, and inflammation through the kynurenine pathway.  Curr Top Med Chem. 2023; 23:415-425. doi: 10.2174/1568026623666221223111309.

9. Sears B and Saha AK.Dietary control of inflammation and resolution.Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435.