common mechanisms of action / pharmacodynamics

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Common and not-so common uses of Antidepressants | AD Topic Index | Antidepressant Dosage Equivalents

1.  It’s All About Chemistry, Baby. Maybe.

As with all crazy meds, if you look at the Clinical Pharmacology section of the PI sheet of any antidepressant (AD) you’ll see something along the lines of “The mechanism of action of Fixitol (panacea HCl) in humans is unknown, but is believed to be associated with its potentiation of neurotransmitter activity in the CNS.” In English: “We don’t know exactly how it works, but we think it has to do with making your brain juices work better.” This is better known as the Chemical Imbalance Theory of mental illness, which is incredibly easy to understand: you have too much or too little of something somewhere in your body. While the traditional chemical imbalance theory is based on neurotransmitters, especially, but not limited to, serotonin, norepinephrine, and dopamine, if you broaden it to include hormones, enzymes, and whatever else is produced by genetic expression triggered or suppressed by the meds in your brain, liver, and just about anywhere else the receptors affected by the drugs exist, it simplifies things greatly.

Unfortunately, most researchers don’t like the Chemical Imbalance Theory. They have all sorts of evidence to back them up.

There is a much easier, and probably more accurate explanation for psychiatric and neurological problems: The Communications Interference Hypothesis.

2.  Communications Breakdown

Your brain is the hub of the vast communications network that controls everything from abstract thought to keeping your heart beating. This network uses a combination of electrical and chemical signals to transmit messages to, from, and within your brain. The Communications Interference Hypothesis is: All psychiatric, neurological, and assorted other conditions treated with crazy meds are manifestations of disruptions in the network. It doesn’t care why there are disruptions. Not enough serotonin? Dopamine receptors that barely function? Too few neurons in your hippocampus?

Let the people with impressive strings of letters after their names figure out the actual sources of the problems and develop better tools to fix them. All that matters is the tools we now have to correct the problem primarily work with the chemical signalling part of the network. If you have too few or marginally-functional serotonin receptors, raising the amount of serotonin they get is the functional equivalent of correcting how many receptors you have or how sensitive they should be, isn’t it? So if you have a screw loose you need a screwdriver, right? But if you don’t have a screwdriver or a dime, then a pair of pliers is better than a hammer or leaving the damn thing alone until the entire machine falls to pieces.

For a more detailed look at pharmacodynamics in general and the Communications Interference Hypothesis, see the page on Pharmacodynamics Basics.

3.  Methods to undo Madness

With a few exceptions every AD on the planet does the same thing: it enhances the effects of one or more neurotransmitters, thus strengthens the signal in the communications network. It does so in one or more of the following ways:

  • As a reuptake inhibitor, to increase the time, and often the amount of brain juice that stays on a neuron.
  • As an antagonist. To decrease excess neurotransmitters at “bad” neurons and focus them at “good” neurons.
  • As an agonist. To fine tune the sensitivity of a neurotransmitter receptor.

The biggest exception is Stablon (tianeptine), a reuptake enhancer, which speeds up the process of a neuron absorbing serotonin.

3.1  Quick on the Reuptake

All but a few antidepressants do some form of reuptake inhibition. Serotonin-Selective Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), Norepinephrine-Selective Reuptake Inhibitors (NSRIs), Tricyclic Antidepressants, Serotonin Antagonist and Reuptake Inhibitors (SARIs - AKA trazodone and nefazodone), Wellbutrin (bupropion), Viibryd(vilazodone), along with some meds under development and some more available outside of the US all have some form of reuptake inhibition as part of their mechanism of action.

Reuptake inhibitors prevent a neurotransmitter from being absorbed further into the neuron, broken down and recycled. This allows your synapses to marinade in whatever the target brain juice is for a longer period of time, as well as increases the amount since the method of transporting the neurotransmitter is being slowed down. This enhances the transmission of the signal through the CNS’ communications network.

Monoamine oxidase inhibitors (MAOIs) create an effect similar to reuptake inhibitors, in that they slow down not the transportation mechanism, but the chemical that breaks down the neurotransmitter. This causes a build-up in all monoamine neurotransmitters, not just the ones listed below (except GABA, glutamate, and CRF, which aren’t monoamine neurotransmitters) to varying degrees, both within and on the surface of a neuron. In an oversimplified way (this is an overview after all), MAOIs have end results that are similar to reuptake inhibitors, with the most popular ones on the market acting like high-potency SNRIs.

An antagonist attaches itself (binds) to the receiving neuron’s receptors that soaks up the brain juice involved and reduces transmission of the neurotransmitter and decreases the strength, or volume, of the signal. How well it does so is called its affinity.

What an agonist does is on spectrum of functions1. As far as most crazy meds are concerned it’s just like the name implies, the opposite of an antagonist. It binds to a neuron’s receptor and enhances, or otherwise fine-tunes reception of the signal.

4.  Know Your Neurotransmitters

There are dozens of known neurotransmitters, perhaps hundred yet to be discovered, but the brain juices most crazy meds are thought to do the most work on are:

  • Dopamine (DA)
  • Serotonin (5HT)
  • Norepinephrine/Noradrenaline (NE)
  • Acetylcholine (ACh)
  • Glutamate (Glu)
  • Histamine (H)
  • Gamma-aminobutyric acid (GABA)
  • Corticotropin-releasing factor/hormone (CRF)
  • Melatonin (MT)

As far as antidepressants (ADs) are concerned the first three is where most of the action is. Acetylcholine (ACh) and melatonin (MT) are the targets of some new ADs. CRF has being recently studied as something responsible for why medications of many different classes work and, unfortunately, make you fat as well.

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4.1  Dopamine: Everybody’s Favorite Brain Juice

Dopamine, sweet, sweet, dopamine. While it is best known as the reward & pleasure neurotransmitter, the pleasure title really belongs to others, like the endorphins and oxytocin2. In addition to making us feel good about ourselves, dopamine also makes us feel energetic and helps us to think imaginatively. Anyone who has experienced, or has been around someone experiencing bipolar mania or the positive symptoms of schizophrenia can recognize how too much dopamine can explain things like over-inflated self-worth, not needing to sleep, and delusional behavior to the point of hallucinating.

To my knowledge five different dopamine receptors have been identified (D1 through D5). It’s an overabundance of dopamine, mostly at the D2 and D3 receptors, and particularly in the mesolimbic and mesocortical pathways3, that is suspected to be the likely culprit for many of the positive symptoms of schizophrenia and bipolar mania. The D1 and D4 receptors are involved as well, but as few meds work on those they are less studied. Other sections of the brain, as well as the liver, pancreas, and maybe other organs, use dopamine, and too little dopamine, whether naturally or as a result of taking APs, results in things like Parkinson’s (or the Parkinson’s-like movement disorders caused by APs) and unwanted enlargement of breasts.

4.2  Serotonin: The Answer to Everything

Serotonin, or 5-hydroxytryptamine (5HT)4, carries the signals for so many things in your brain, your gut, your cardiovascular system and elsewhere that it actually makes sense why drugs that affect it have contradictory side effects like constipation and diarrhea, insomnia and excessive drowsiness, or that serotonergic drugs like SSRIs can make depression worse. There are at least 20 5HT receptors in the human brain dealing with practically everything: anxiety, addictive behavior, appetite, cognition, hallucinations, impulsiveness, memory & learning, mood, nausea & vomiting, sleep, sociability, sexuality, and thermoregulation. To further complicate matters, serotonin regulates dopamine, which is one reason why too much serotonin can make you depressed.

4.3  Norepinephrine: I Can’t Decide

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4.4  Histamine: Heavy-Duty Sleep

4.5  Melatonin: Night-Night

This hormone you can buy OTC is used not only for sleep but also as an antidepressant.

4.6  Too Much is Never Enough

5.  Express Yourself

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Common and not-so common uses of Antidepressants | AD Topic Index | Antidepressant Dosage Equivalents

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6.  Bibliography

Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (Essential Psychopharmacology Series) Third edition by Stephen M. Stahl © 2008 Published by Cambridge University Press.
Primer of Drug Action 12th edition by Robert M. Julien Ph.D., Claire D. Advokat, Joseph Comaty © 2011 Published by Worth Publishers.
Serotonin Receptors – From Molecular Biology to Clinical Applications M. PYTLIAK, V. VARGOVÁ, V. MECHÍROVÁ, M. FELŠÖCI PHYSIOLOGICAL RESEARCH 60: 15–25, 2011
”Serotonin Receptors” David E. Nichols and Charles D. Nichols Chemical Reviews, 2008, Vol. 108, 1614–1641
”Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system” Małgorzata Filip, Michael Bader Pharmacological Reports, 2009, Vol. 61, 761–777
1 Technically an antagonist is on the agonist spectrum, in the same slot as malfunctioning receptor, between partial agonist and inverse agonist.

2 You can also get both from sex and opioids, although the quantity and quality of those neurotransmitters from either source, especially the oxytocin, varies greatly from person to person. Which explains a shitload of things. In other people's lives as well I imagine.

3 Be honest with yourself, if I spelled out the exact neuroanatomical structures involved, would you know what the hell I was talking about? If you do, you can look it up. If you don't, just accept that people with an impressive array of letters after their names think the action is in specific, long-ass-named parts of the brain.

4 Yup, the same stuff you can buy in a vitamin store. And it will go to your brain. And it may be enough to fix what you have. Assuming what you buy is what the label claims to be. And you need more everywhere and not less in specific places.

How Antidepressants (ADs) Work by Jerod Poore is copyright © 2014 Jerod Poore

Last modified on Friday, 15 April, 2016 at 20:19:49 by JerodPoorePage Author: Jerod PooreDate created: 11 March 2014

All drug names are the trademarks of someone else. Look on the appropriate PI sheets or ask Google who the owners are. The way pharmaceutical companies buy each other and swap products like Monopoly™ real estate, the ownership of any trademarks may have changed without my noticing.

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1 While there are plenty of books to help you with hypochondria, for some reason there’s not much in the way of websites. Then again, staying off of the Internet is a large part of curing/managing the disorder.

2 Remember kids, Microsloth operating systems are like TOS Star Trek movies with in that every other one sucks way, way more. With TOS Star Trek movies you don’t want to bother watching the odd-numbered ones. With Microsloth OS you don’t want to buy and install the even-numbered ones. Anyone who remembers ME and Vista knows what I mean.

3 Have I mentioned how open source operating systems for commercial applications is one of the dumbest ideas in the history of dumb ideas?* I don’t even need my big-ass rant any more. Heartbleed has made my case for me. And that’s just the one that got all the media attention. The very nature of an open source operating system makes security as much of an illusion as anonymity on teh Intergoogles. Before you flip out too much: the domain Crazymeds is hosted on uses a version of SSL that is not affected by the Heartbleed bug. That’s one of the many reasons why I pay a lot of money and keep this site on Lunarpages.

* Yes, I know I’m using open source browsers. I also test the site using the now-defunct IE and Safari browsers. Their popularity - and superiority - killed IE and Safari, so that’s why I rely on the open source browsers. It’s like brand vs. generic meds. Sometimes the generic is better than the brand.

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