Serotonin, Dopamine, Norepinephrine SSRI/SNRI | Episode 197

There's a whole list of indications with contemporary MDD drugs. That's really mixed. Depressive disorder or significant depressive disorder or major depressive disorder, situational depression, anxiety. Maybe it's PTSD. 

Evolution from MAOIs to SNRIs

The MAOIs, monoamine oxidase inhibitor. Then tricyclic antidepressants and the follow up, quatra -cycle antidepressants. Next, in the 1970s and 1980s,  we saw the evolution of tricyclics to the serotonin selective reuptake inhibitors. That was followed by serotonin norepinephrine reuptake inhibitors. These are now the most common antidepressants. They take a little while to work. SNRIs are a little faster. The SNRIs followed the timeline after SSRIs, and they use two mechanisms. SSRIs use more of a singular, but really it's a little bit of a gray area. So this is the situation. We needed some drugs with less side effects.

The SSRIs evolved into a really good option over MAOIs and TCAs, and some of the later evolutions of the TCA. But when they came along, there was a lot of trepidation. People didn't know exactly what they would do. They didn't seem to work because it took them so long to work, sometimes up to five weeks. Only about 40 to 60% were significant responders. 

SSRIs and SNRI Side Effects

Definitely we could say they're probably safer. The ultimate problem you can get with these SSRIs and SNRIs is serotonin syndrome. That is rapid heartbeat, very dry mouth. Sexual dysfunction was reported, both male and female. There was good and bad, a tradeoff, as there is always with any drug. The traditional, or most everybody’s side effects: dizziness, headache, nausea, vomiting. And weight gain was seen, probably due to dietary alterations and changes. 

But these drugs blocked the reuptake of serotonin. What does that mean? Well, the TCA's, MAOIs, et cetera, they blocked serotonin reuptake. They probably had an increase in dopamine. TCAs are kind of understood. No one really still has a good grasp on exactly what they do.

And we started noticing over time these SSRIs were associated with some types of bleeding. So you had to be careful with the anticoagulants clopidogrel gel like Plavix and warfarin, NSAIDs, aspirin, et cetera. You had to kind of be careful. The Warfarin is Coumadin.

Depression and Suicidal Ideation and other Side Effects

And there was this other odd thing that seemed to show up that I think was important. I don't know what it was. Was at the depression that led to suicidal ideation, especially at risk adolescents, 25 year olds, 30 year olds, et cetera, or was it the drug? Well, I don't know.

We found as clinicians, we were moving drugs around. So citalopram was really the first one around, and in younger people you could take up to 40 milligrams a day, probably undivided doses, and it was recommended by the FDA. Anybody over 60, cut it back to 20. Well, I think most people push it a little further than that.

And then we started noticing that there were probably some abnormal arrhythmias or heart rate changes that had to do with sodium, potassium channels, and that sort of thing. 

And also a lot of people were taking over the counter drugs. These herbs and the like, and they are drugs, if they have bioactive effects, they are drugs. So we had to kind of be careful of those. 

SNRIs came around, in the seventies and like, so the timeline with the fifties there was MAOI. And then in the sixties, seventies, TCA, et cetera, evolved into SSRIs, SNRIs, serotonin norepinephrine reuptake inhibitors. That would be the Effexor, venlafaxine.

And we found that if you had problems with one SSRI, you could kind of switch to another, and a number were in evolution and same with SNRIs. 

And then along came, I have to say, one of my favorites and that being Cymbalta. It changed people's lives. I think what was recognized early on is norepinephrine had a lot of pain modulating effects. So did dopamine, probably serotonin. And so these drugs had potential for fibromyalgia-like symptoms, situational depression, anxiety, PTSD.  Cymbalta got labeled by the FDA, fibromyalgia, headache, et cetera. Cymbalta Is a trade name. 

An Early Drug Used to Treat Tuberculosis was an Antidepressant

So in the early 1950s, it had to do with antibiotics. Iproniazid came along and it was to treat TB. It was an antibacterial, but it was found to have psychoactive effect because it was a mood alternator. These people became kind of happy, they had enhanced mood effects when they were taking it, they became more gleeful. What it did is it inhibited the enzyme MAOI monoamine oxidase, and hence monoamine oxidase inhibitors.

The breakdown of serotonin and dopamine was felt to be effective to treat situational depression, anxiety. And then there was a big push in the eighties and nineties about norepinephrine, which led to SNRIs. The phenylethylamines, and it was less so with dopamine, but it really did help serotonin and norepinephrine.

So we have these drugs that are very effective. I think that we have to look beyond just the very straightforward effects, and we have to look at receptor technology. Understanding the physiology of receptors, that being the histamine receptor, H1, and others, that these drugs are effective on. 

For example, the sodium channels that affect the heart. That's how something as simple as sodium can impact. It has to do with how you handle sodium in your body and these things called alpha one and alpha two adrenergic receptors. 

So it gets kind of complicated, but that's how the effects of these drugs go. They're in evolution and we're understanding them more and more.

This thing that makes stuff happen at the cellular level is called a G Protein. It starts a cascade of events that causes transcription of messenger RNA and the like, and then elaboration of these physiologic active chemicals. So they affect certain parts of the brain. 

You can take somebody that's using cocaine and slug them in the face (don’t do this)  and it doesn't hurt them at all because of the locus coeruleus, a part of that brain, or the lateral tegmentum. The locus coeruleus is full of norepinephrine and with cocaine and other drugs. It is a mood enhancer, but it blunts pain and it blunts the response to pain.

There's lots of places where these drugs work. We've got to be very mindful of these drugs working at multiple places in the brain. But to the best effect, therefore, we're going to say that SSRIs and SNRIs are not only effective for us to treat situational depression and anxiety, but they probably have a spillover effect on pain.

Consider Which Medications Really Work to Treat Depression

That's an important thing to know with pain, addiction and depression. What works outside of the box? What works kind of in the gray area where we can kind of bend it a little, bend It like beckham and get a response even, you know, if it's off label. 

I've heard that 50% of drugs are used off-label. Tricyclic antidepressants were used in fibromyalgia and sleep for a long time, and for musculoskeletal pain, for a long time. They weren't necessarily approved for that type of indication, but they were used and they were effective and they helped with sleep. 

Restorative sleep capacity is key to not only incorporating memory, getting certain parts of the brain working there, but also to get you to stage four sleep and keep you out of alpha intrusion. Otherwise you will have interference with your ability to feel good, when you wake up and you get kinda like in that funk, that fibro fog that most people with fibromyalgia describe. It's because they don't sleep well. You need that sleep study. 

SSRIs and SNRIs are key drugs. Talk it over with your healthcare provider. Do not stop these drugs abruptly. They have to be appropriately managed in a healthcare delivery system somewhere by ER, outpatient, primary care, or somebody that knows these drugs and understands their side effects. 

If you're having side effects, it doesn't necessarily mean they're a failure, it just means you must take the global presentation of healthcare problems into account.

Talk it over with your healthcare provider. Take in your notes, take in your side effects and understand you must give them a chance. They are going to take a little bit of time. So we are constantly reviewing different drugs that I think are important. They're going to come along, and get more effective, and have more rapid onset. 

They're going to be more targeted toward certain types of depression and better understood. They will help situational depression and anxiety mechanisms, ptsd, and help with sleep and ultimately pain, addiction, and depression. 

I don't think I've ever met anybody that has had chronic, longstanding pain that hasn't had some situational depression and anxiety. Drugs have an effect on pain probably because they treat globally. 

Pain and chronic pain is not one thing, they are a response to an important physiologic mechanism, be it one or be it many, and it is manifest in what you are, how you feel, and it's completely individualized.

Don't think that one person has the same pain as another. Be careful with comparing, although it is important to get a common language. You're a unique individual and be that person. So keep good notes, talk it over to your healthcare provider and patient with these drugs.

This whole thing is working itself out, but as you can see, it's taken decades to get where we are. Not a bad thing. I'm happy to use these medications to treat pain. I think that they really do help minimize escalation and controlled substances. They really do help with sleep, and they really do help people get around and think better.

People are able to do more from a functional standpoint. Remember rule five,don’t chase pain. These drugs are embraced by many folks and used as one of the most common prescriptions in the world. I think they're in the top 20 in the United States. I know SSRIs sit in the top 10 a lot, but I think it's also a testament to their utility, usefulness and safety.

Please send any questions to us. We'll be happy to answer them and jump on different podcasts. I think the best thing that we're doing here is continuing the awareness about pain. And we're going to advance further into the understanding of addiction and brain processes and take it one step at a time, because that's what it always is, one step at a time.