Fatigue and Depression

These two complex symptoms have a terrifyingly circular relationship, often blending seamlessly into each other, making it impossible to tell where one ends and the other begins. I have so many clients with depression, but the main symptom isn't sadness. It's a lack of energy, a lack of motivation, a lack of interest. It is depression, but it's also fatigue. Many people who say they are fatigued look the same, and many of them report an accompanying sadness or loss of interest because they're just too tired to be bothered doing things.

Even for your doctor, it can be difficult to find the dividing line, and many people are being treated for one without truly addressing the other. Depression and fatigue dovetail into each other, and looking at them as two intermixed problems can be helpful in terms of finding solutions from different angles.

Why Fatigue Is a Symptom of Depression

We tend to think of the mind as one thing and the body as another, but in truth, the environment of your mind and body are intermixed. We think of depression as a neurotransmitter problem, but it's bigger than that. Neurotransmitters are involved, but so are cytokines, inflammatory molecules, oxidative stress, and much more.

The most common conventional drug-based therapies for depression center around neurotransmitters, but none of the other physiological changes are typically addressed. Some antidepressants, like desipramine and fluoxetine, do have anti-inflammatory activity, but it isn't their primary focus.

In the first episode of this season, we talked about something called "sickness behavior," which is the group of symptoms your body generates in response to a pathogen or major injury. These symptoms are intended to force you to act like a sick person and go to bed. In the context of a virus, this makes complete sense. In a longer-term scenario, however, this starts to look like depression. It turns out that depression and sickness behavior have a lot in common on a molecular level.

Many of the cytokines, or signaling molecules, your body releases during sickness behavior are also elevated in depression, which helps account for the massive symptom overlap. Both states involve deep fatigue, listlessness, lack of interest in social activities, slower thinking, less activity, reduced exploration, less grooming, lack of enjoyment, and sleepiness. The fact that the chemistry of the two states is similar may give us new treatment targets for depression in the future.

Symptoms of depression that are not linked to these inflammatory cytokines include actual sadness, feelings of guilt or low self-esteem, and suicidal thoughts or ideation. So clearly, depression and fatigue are not the same; there are distinctions. Still, shared immuno-inflammatory pathways may underpin both states.

Why Depression is a Symptom of Fatigue

Fatigue is also taxing on mental and emotional health, possibly through the cytokines we mentioned before, but possibly also because feeling unable for long periods is actually crippling to the human psyche. It is easy to interpret your own lack of energy or clarity as a personal failure, to feel guilty, unworthy, or sad because of it.

Sickness behavior does have the hallmark symptom of fever, which is not present in typical depression, although studies have shown that those with depression are likely to have higher resting body temperatures than those without, possibly due to the same inflammatory molecules.

To make things more complicated, inflammatory cytokines have been shown to affect the levels of different neurotransmitters, including serotonin and norepinephrine. So when inflammation or other markers of illness are increasing, neurotransmitters are changing in response, again feeding into this vicious cycle.

Your Resting Normal Neurotransmitter Level

I believe there is a resting normal neurotransmitter level for most people that also influences this conversation, and gene SNPs have a profound impact on that level. For example, many people, like myself, with slow COMT polymorphisms could be described as terminally cheerful. Depression in this group is likely to look very different from depression in a group with fast COMT function, who tend to have lower resting neurotransmitters and less general chirpiness.

Resting normal neurotransmitter levels are part of the reason why I think so many people try antidepressants, go through the adjustment reaction, feel amazing for a few months, then slowly sink back to where they were. The natural consequence is to keep chasing that amazing feeling with dosage changes, medication changes, etc, but their body always seems to bring them back to their baseline eventually. For a more detailed discussion of why chasing neurotransmitters doesn't often work, read more about neurotransmitters working as a web rather than a tug of war.

What You Can Do About Fatigue and Depression

It is all well and good to say fatigue and depression overlap significantly, but what do we actually do about it? Well, this is still a question, but research in this area gets nested under "treatment resistant depression," which is what doctors call depression when antidepressants don't work. Some of the therapeutic strategies for this include ketamine, which has become controversial because of its misuse as a street drug, and new drug candidates that are being researched that inhibit the glutamate, an excitatory neurotransmitter.

My own opinion, unbacked by research though it is, is that depression and fatigue treatments should also overlap, with some attention paid to both the inflammatory process in the body and mind as well as the changes to neurotransmitters.

Many natural substances that have shown promising effects for depression are also powerful antioxidants, which suggests they might also have effects on the inflammation and oxidative status of the body. Some of these include:

• Saffron—this bright yellow spice has been well documented for depression, but it is also an incredibly potent antioxidant.

• Fish oils—Fish oils are a commonly used natural remedy for depression and inflammation.

• Vitamin D—Low levels of vitamin D have been implicated in depression, and vitamin D has a strong antioxidant function.

• St John's Wort—This herbal medicine has long been used for depression, but studies show it also inhibits inflammatory signaling.

• Creatine—This common supplement for exercise performance and muscle development has also shown promise in reducing depression, inflammation, and oxidative stress.

• NAC—I have spoken a million times about the benefits of NAC as a precursor to glutathione, your master antioxidant. It therefore lowers inflammation and oxidative stress. However, it is also a glutamate inhibitor, which means research is ongoing about the use of NAC for depression.

While I don't suggest that you rush out and start taking all of these supplements, it is important to consider your whole body in the treatment of depression, and your mind in the treatment of fatigue, and to potentially include some support that overlaps with both.

Research is also investigating novel drug therapies based on plant medicines or other existing drugs that don't target the more conventional neurotransmitter pathways. I want to mention some other therapies currently being researched.

Two of the studies currently ongoing are on plant medicines, including psilocybin from hallucinogenic mushrooms, and ayahuasca from the plant medicine of the same name. I have enormous respect for traditional plant medicines and have heard and witnessed incredible stories of transformation. These plant medicines have been used for centuries for people suffering from mental health disorders, spiritual and emotional crises, and grief, and even with our cultural fear of what we think of as recreational drugs, it is hard to deny their centuries of success.

Nitrous oxide, or laughing gas, is also being studied as a treatment for depression and is the subject of several ongoing phase I and II clinical trials. Remember, MTHFR folks, this one is not a great option for us, or for people with the MTR or MTRR mutations, because nitrous oxide is known to raise histamine levels and drop B12 sharply and can be dangerous with MTHFR.