My father was old school. For one, he wasn’t interested in sports cars.  He liked big Cadillacs, and always bought his, versus leasing it.  He would drive those old cars into the ground rather than ever parting with one.  But it isn’t like he babied them, spending weekend afternoons applying endless layers of wax.  I recall exactly one time in my life that he spent the money to go to a car wash, and I never saw him wash his car.  In his opinion, a car was a machine that took you from one place to another.  It needed to be safe, efficient, and reliable.  Dirt and style didn’t affect those qualities, and so, for my father, washing a car was a waste of time.

Maybe it was genetic, because as much as I though he was crazy or cheap as a kid, the apple didn’t fall too far from the tree.  I prefer big vehicles too, and I’m still driving the 2006 SUV I bought new almost eighteen years ago, even though it has close to 150,000 miles on it.  My kids are embarrassed to drive in it, and they used to leave countless “wash me” messages in the dust layer, that is until my wife steps in and has my truck detailed every time I leave town for a trip.  I can hear my father’s voice in my head when I tell my kids, “why would I get rid of the Joe-mobile?  It still works, and I still like it.”

He also listened to Count Basie and Glenn Miller, in mono, as they were recorded, on AM radio.  I definitely do not listen to the Hit Parade, but now my kids think I’m an “old head” for preferring Billy Joel to Billie Eilish.  One of his favorite sayings, that I use now with my kids is, “the older you get, the smarter I get.”  Hear that Tommy?

My dad passed in the Fall of 2022.  It was a good life, well lived, and if there is a God, as my dad certainly believed, He gave my father a graceful exit from this world.  On the day he died, he woke up at home in his own bed, with my mother there beside him, experienced no real pain, and passed a few hours later in the hospital, knowing he lived a good life.

He spent most of that life as an OB-GYN, helping to bring healthy infants into the world, and making sure their mothers survived the process.  He trained to be a physician during an age when looking for a root cause or a problem was something physicians had to do themselves, rather than relying on the internet for an answer.  Even though he was in practice long before his younger colleagues, he was humble enough to recognize that he didn’t have all the answers.  That led him to accept that, sometimes, the prevailing way of looking at things could just be wrong.  Knowing when to release your grip on the old way of thinking and grab ahold of the new is an art form that each person has to master for himself.  Do you want to be the heretic out in front of the pack, the early adopter, the skeptic who is fashionably late to the party, or the curmudgeon who curses the new-fangled ways until forced?  Everyone has to choose for himself when to jump ship from the old and embrace the new, but who’d have believed that liking Van Halen and Aerosmith makes me curmudgeonly!

You’d think that my father, who listened to big band jazz music from the 1920s and drove old Cadillacs with fins would have been an Archie Bunker when it came to medicine, but you’d be wrong.  It turns out that his allegiances weren’t to that status quo or to status symbols.  He just thought about things and figured it out for himself what he wanted, almost always based on what made sense to him.  He thought and held opinions based on what went on in his own mind, and he was highly skeptical of what went on in other people’s heads.  I hope that healthy skepticism is a family trait I inherited from him.  Maybe the propensity for holding onto high-mileage vehicles and listening to the music we grew up on are the ways we both subconsciously balance out our willingness to make “impulse purchases” of relatively immature ideas that just make sense and feel right.  Let’s spend a few minutes talking about one of those iconoclastic concepts because it is one that just might just change the world.

Mood is a funny thing.  What makes a person feel down on one day and happy the next?  Life events certainly play a big role, but are there reasons why people feel down that go beyond the ordinary things like watching their favorite basketball team blow a 12-point lead and lose the biggest game in the school’s history on a last second shot the opposing team never should have gotten the chance to shoot? (Any similarity to actual events is purely coincidental … yeah, right!)  Sure, and being sick makes you feel down.  Being stressed about something can depress your mood.  Being sleep deprived can sap you of your enthusiasm and flatten your mood.  All of these things have a biological component to them.  In the extreme, when it becomes debilitating and/or chronic, we call it clinical depression, which rises to the level of being a medical condition.  But what about just being down more than your friends and family, or even you think is normal?

It stands to reason that the less severe mood-altering biological conditions might actually be related to the more serious ones.  Since we all want to feel happy and energized as we go through life, and being in a generally good humor is a great way to have the resilience to overcome life’s obstacles, getting to understand the ways to deal with clinical depression might give us some insights as to how we can achieve the goal of being happier people.

Clinical depression, or Major Depressive Disorder (MDD), is defined by the Mayo Clinic as “a mood disorder that causes a persistent feeling of sadness and loss of interest.”  As our understanding of the brain evolved from 1900 to the 1970s and 80s, the general understanding among scientists and medical professionals was that mental health problems stemmed from neurons not functioning properly.  Since neurons have a primary task of firing and releasing neurotransmitters onto one another, the assumption was that the dysfunction involved neurons failing to release the neurotransmitters in the amounts they were supposed to.

Neurotransmitters of the class called “monoamines” include serotonin, dopamine and norepinephrine, each of which have been categorized by their general effects.  Serotonin has been tied to mood, dopamine to motivation, and norepinephrine to both alertness and as an important trigger for the release of the other two neurotransmitters.

As mentioned above, neurotransmitters are released from neurons when they fire, and afterwards they can be broken down by an enzyme known as monoamine oxidase, or MAO.  Alternatively, the neurotransmitters can be recycled through reuptake mechanisms.  The reuptake process involves transport proteins that grab and shuttle the corresponding neurotransmitter from the synapse into the cell.  Fairly obviously, these reuptake proteins, the primary one for serotonin is called SERT – an abbreviation for SERotonin Transporter – reside on the outside of cells (which include neurons and astrocytes, the support cells that wrap around synapses to control their activity).  The name MAO suggests that the enzyme uses oxygen to break down the monoamines, which is exactly what it does.  MAO, and there are two different types, A and B, typically reside on the surfaces of mitochondria.  If you are a reader of my other blogs, you won’t be surprised when it turns out that mitochondria play a role in depression.

Given that serotonin level is related to mood, the assumption has been that serotonin levels are lower in folks with depression. Thus, one of the earliest pharmaceutical approaches to treating depression came in the form of monoamine oxidase inhibitors (MAOIs), which turned out to be an extremely strong class of antidepressants.  MAOIs treat depression by preventing the breakdown of the monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, through the normal function of monoamine oxidase.

Of course, no medicine works for everyone, and all medicines have some degree of toxicity or side effects (MAOIs certainly do), and so a need arose for a different type of antidepressant.  This led to the manufacture of a new pharmaceutical type (actually, two related classes) called, you probably guessed it, reuptake inhibitors.  Two major types are selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).  As the names suggest, these medicines prevent the corresponding transporter proteins from doing their job of quickly and effectively cleaning up the synapse of the serotonin that has been released from prior neuronal firing.

These medicines “work” in the sense that folks with depression often experience a reduction in the symptoms they are experiencing while taking the drug.  The problem is, in order to maintain the benefits, you have to stay on them, because they work by preventing the natural activity of MAO and/or SERT.  If you are a frequent reader of my blogs, a question might be percolating up from your subconscious: Wouldn’t it be a better strategy to figure out why the serotonin levels are low and fix that, rather than use MAOIs, SSRIs, and SNRIs to inhibit the normal activity of monoamine oxidase and SERT?

Yes … it would!

If we’re going to figure out why serotonin levels might be low, we need to understand serotonin synthesis.  Serotonin is produced in nearly every cell in the same way.  It starts with a couple of enzymes that convert the amino acid tryptophan into the neurotransmitter.  (For those of you who are interested, these enzymes are tryptophan hydroxylase and tryptophan-5 monooxygenase, but there is no quiz at the end of this blog.  I promise!)  It turns out, however, that there is another enzyme, called indolamine 2,3 dioxygenase, that is also present in cells and it uses tryptophan as a precursor.  It is called indolamine 2,3 dioxygenase, and it makes kynurenine, the first of a series of toxic compounds that are free radical promoters.

Why, you might ask, does the cell make a series of toxic compound like kynurenine, and why would it want to make free radicals?  The answer is, it does so when triggered to react to a possible microbial assault.  Those free radicals are dangerous to microbes and form a part of the intracellular defense of the cell if there is an infective agent attacking it. Even when there is no sign of an infection, indolamine 2,3 dioxygenase and kynurenine are always present at low levels because the end product of the kynurenine pathway is a form of nicotinamide adenine dinucleotide, NAD, that is used in many metabolic processes.

Would you be surprised to know that high kynurenine levels have been measured in depressed patients?

So, we’re on to something. Serotonin production competes with kynurenine production.  Under healthy normal situations, the balance of the two heavily favors serotonin because only a little activity along the kynurenine pathway is needed to produce the necessary levels of NAD.  In depressed folks, however, the levels are off, which happens when there is too much indolamine 2,3 dioxygenase around.  What causes indolamine 2,3 dioxygenase levels to go up.  If you bet that it was inflammatory cytokines because you thought about the need for free radicals to fight microbes and how inflammation signals rise dramatically during an infection, well, you’re 2-for-2!

There is a lot of evidence that this line of reasoning makes sense, and interestingly, those same inflammatory cytokines cause an increase in the serotonin transporter levels. This means that inflammation signals (like TNF-  and IL-1 ) cause the serotonin levels to go down and the SERT expression to rise.  It’s a double-whammy, as my grandmother would say, and makes inflammatory cytokines the exact opposite of an SSRI.  In fact, that means that if those cytokines are floating around, pharmaceuticals that try to inhibit reuptake are fighting an uphill battle against the natural processes of inflammation?  Maybe preventing inflammation is the better way to treat depression?

Before we complete that thought, let’s go back to the kynurenine pathway for a minute.  Inflammation causes the increase in indolamine 2,3 dioxygenase, which reduces serotonin levels and causes the production of free radicals.  On both levels, this is bad for mitochondria.  First, the free radicals cause damage to organelles within the cell in an attempt to kill microbes, and since mitochondria actually originated as distinct microbes that came to live within our cells symbiotically, they have a lot of microbe-like characteristics and are targeted by free-radicals.  Free-radical damage is particularly problematic for mitochondria, given the fact that they are the oxidative phosphorylation centers of the cell, meaning they already have high free radical risk from their job.

The second problem for mitochondria arises from the fact that they have evolved the ability to use melatonin that is produced by the cell as a key free-radical scavenger.  Unfortunately, melatonin is produced from serotonin, and the lack of serotonin means that the mitochondria are even more at risk.

Mitochondrial dysfunction, which is also highly correlated with depression, means that the cells start to rely on glycolysis versus oxidative phosphorylation.  This is far less efficient.  Systemically, this can lead to metabolic issues, including fatigue and organ damage, and not surprisingly, physical and mental fatigue are common complaints among depression patients.  This dysfunction among the mitochondria triggers more inflammation through several pathways, some of which can actually trigger the cell to commit suicide through programmed cell death!

Along the way, the immune cells in the brain become pro-inflammatory also, and that means cognitive dysfunction.  Guess what?  Cognitive dysfunction has recently been identified as a significant co-morbidity of depression.  To really understand the mechanism that cause that to happen, you should start by reading a couple of my other blogs about inflammation, learning, memory formation, and intelligence. 

So, let’s review.  Inflammation causes serotonin (and melatonin) production to drop and serotonin transporter expression to rise.  The transporters may rise to recapture previously released serotonin that does exist so it can be converted into melatonin, which is in short supply but needed to protect the mitochondria.  If mitochondria can’t protect themselves from the reactive oxygen species they create and the other free radicals being made by the kynurenine pathway products, they start to fail.  Mitochondrial dysfunction leads to fatigue, altered metabolism, more inflammation, and even cell death.  So, it seems like inflammation and inflammation signaling is a pretty important root cause of depression.

How can we stop that inflammatory signaling from causing this cascade of trouble?

One way is to reduce the triggers of inflammation that occur as a result of our own actions.  These include sleep deprivation, eating too many overly processed foods, being sedentary to an extreme, and living a stressed-out life.  All of these things are extremely hard to accomplish in modern society.  Some of the things we can do to reduce inflammation include deep breathing exercises, meditation, and just getting up and moving.  It doesn’t have to be extremely athletic, in fact walking is a great way to take a break from stress, breathe, and get the muscles and blood moving enough to remind your immune system and nervous systems that you aren’t dead!  It also helps to be engaged with others socially, so grab a friend and go for a walk.  Maintaining a healthy body weight is very important for reducing systemic inflammation that can trigger all the problems laid out above.

There are other ways to reduce inflammation, but one way that I have spent a lot of time blogging about is vagus nerve stimulation, or VNS.  In fact, a lot of the things I just suggested are natural ways to stimulate your vagal tone.  Another way that can be extremely useful to people looking to enhance, maintain, or even restore themselves to the state of health they used to have is VNS using electricity. There are a number of other blogs in which I explain how VNS reduces inflammation (and protects and restores mitochondrial function), so I won’t go through the details again, but understand that undergoing a surgical procedure used to be the only way you could get vagus nerve stimulation, and one of those devices was actually FDA approved for treating medically refractive (i.e., really difficult to treat with drugs) for the treatment of depression.

That was then, and this is now.  I might like my old truck and enjoy listening to Led Zeppelin, but I also like medical advances that are safer and less invasive.  That is why I am so proud of the work I was part of to develop VNS devices that are non-invasive and can do the job of activating the vagus nerve whenever you want.  Truvaga is an example of one of these devices.  A similar technology was actually FDA cleared for the treatment of very serious headaches (see my blog on gammaCore), but the same VNS is now available through Truvaga, which is a wellness device designed to help you with your stress … and for all the reasons I discussed above, and previous blogs, stress can certainly drive inflammation and impact how happy and resilient you are feeling.

Truvaga delivers what I call 2-minute “doses” of stimulation, and my recommendation is to use it twice per day – once in the morning and once in the evening.  In my house, Truvaga is what we do when we brush our teeth.  Try it and let me know how it’s working for you.  My bet is, you’ll get to sleep more easily and wake up more refreshed than you have in years.  That will help you feel better, think more clearly, and be happier.  

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