David Scheiderer, MD, MBA, DFAPA – Specialty: Integrative psychiatry – Company Affiliation: Clinical Advisory Board Member for NeuroScience, Inc. 
What controls our mood? Is it our brain, our gut… more specifically neurotransmitters? Over the years, I’ve come to recognize an epidemic of patients presenting with fatigue, apathy, weight gain, brain fog and a host of other symptoms indicating a lack in activity throughout the body. I’ve found that the source of this systemic hypoactive state is a combination of imbalances in neurotransmitters and an active immune system. Going one step further, I’ve found that the immune system is controlling the mood and lives of many of the patients I see in my practice.
Here’s a case I see all too often. Sound familiar?
Linda came to me in her mid-40s, with a history of anxiousness and sleep difficulties early in life. She was put on multiple mainstream interventions, primarily targeting serotonin, which helped with the anxiousness and sleep. While she saw improvement in some of her symptoms, others popped up or worsened. She’d begun to feel down and numb. When interventions targeting norepinephrine were used to boost her mood, the anxiousness would return. It was a constant teeter-totter.
By the time I saw her, she was also fatigued, had gained weight, had less sex drive, no orgasms, brain fog, and general apathy. She’d tried all the interventions, and they just weren’t effective. She simply wanted what all patients want- to feel better, to not constantly be fighting some complaint.
Given her age, there could be some hormonal factors, and her history indicates nervous system involvement. But, here’s another piece of information: her regular doctor found her blood sugar was beginning to fluctuate and hs-CRP was elevated. This confirms what I suspected; there is an immune aspect to her symptoms.
How does the immune system contribute to mood issues?
Research has found a correlation between increased cytokine activity and symptoms like poor mood, social withdrawal, fatigue, anxiousness, brain fog and more.1 As part of the immune system’s surveillance activities, it activates cytokines such as interferon-gamma (IFN-gamma), interleukin- 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in the presence of foreign substances. Once these cytokines are activated, the nervous system, especially serotonin, begins to pay the price.
NSgraph_092415During the adaptive immune response, IFN-gamma,   IL-6, and TNF-alpha become elevated. This triggers a shift in the activity of the enzyme indoleamine 2,3-deoxygenase (IDO) that has the effect of reducing the production of serotonin in favor of kynurenic acid (Figure 1).2,3 The resulting imbalances in serotonin and melatonin, present as anxiousness, poor sleep, low mood, lack of interest, etc. (The first stage of Linda’s presentation.)
The increase in IDO is meant to be an adaptive response that results in the production of kynurenic acid, which is neuroprotective. However, this shift also results in production of neurodegenerative quinolinic acid which generates reactive oxygen species (ROS). ROS activity can further reduce serotonin levels by upregulating activity of monoamine oxidase (MAO).4 This also leads to a reduction in energy, mood, and cognitive function as norepinephrine and dopamine levels drop from MAO upregulation. Eventually, symptoms more indicative of immune activity, like achiness, start to pop up.
The yin and yang of treating these patients
While serotonin is clearly impacted by immune activity, supporting just serotonin, as Linda’s case demonstrates, isn’t the answer. These patients need a multi-system, balanced approach. The immune system activity needs to be managed, balance has to be restored to the nervous system, and ROS must be addressed.  Adrenal support wouldn’t hurt either.
Although not easily visible, immune activity can be the driving factor. Ingredients like Boswellia serrata and Curcuma longa (Turmeric) are known to regulate cytokines to support a healthy immune response.*5-7 This may help to downregulate the activity of IDO, stopping the serotonin depleting effects of its activity. B. serrata and C. longa along with L-cysteine also provide support for antioxidant activity, helping to clean up the effects of ROS.*5,6,8
To restore balance in the nervous system, start with supporting serotonin and GABA to help with anxiousness and sleep, but norepinephrine and dopamine support must be added once symptoms are under control to keep the mood and energy up or they’ll soon feel like Linda, numb and fatigued.
The next time you have a patient that is unresponsive to your interventions or develops new symptoms to replace the old, or symptoms including unstable blood sugar, sympathetic fatigue, estrogen dominance and the widespread achiness and discomfort consider incorporating an immune approach while taking a balanced approach to the nervous system.
Article provided by NeuroScience


  1. Schiepers, O., et al. (2005). Progress in Neuro-Psychopharmacology and Biological Psychiatry; 29: 201-217.
  2. Dantzer, R., et al. (2008). Nature Reviews Neuroscience, 9(1): 46–56.
  3. Leonard, B., Maes, M. (2012) NeuroScience and Biobehavioral Reviews. 36: 764-785.
  4. Wichers, M., Maes, M. (2004). J Psychiatry Neurosci; 29(1): 11-17.
  5. Ammon, HT. Phytomedicine. 2010;17: 862-67.
  6. Abdel-Tawab, AM, et al. Clin Pharmacokinet. 2011;50(6): 349-369.
  7. Aggarwal, B., Harikumar, K. Int J Biochem. 2009;41(1): 40-59.
  8. Rai, B., et al. Journal of Oral Science. 2010;52(2): 251-256.

    *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.