common mechanisms of action / pharmacodynamics
Brain Cooties Aren’t Contagious
Medicated For Your Protection
Table of Contents (hide)
- 1. It’s All About Chemistry, Baby. Maybe.
- 2. Communications Breakdown
- 3. How’s the Reception?
- 4. Know Your Neurotransmitters
- 5. Second-Generation Antipsychotic Agents / Neuroleptics
- 6. Express Yourself
- 7. Bibliography
As with all crazy meds, if you look at the Clinical Pharmacology section of the PI sheet of any antipsychotic (AP) 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.
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. Too much dopamine? Overly sensitive dopamine receptors? 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 many or overly-sensitive dopamine receptors, reducing the amount of dopamine they get is the functional equivalent of correcting how many 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.
With a few exceptions every AP on the planet does the same thing to treat schizophrenia & schizoaffective disorder (especially the positive symptoms), and bipolar mania: it reduces the transmission of neurotransmitters between neurons (is an antagonist) by attaching itself (binding) to the part of the receiving neurons (its receptors) that soaks up dopamine, or whatever brain juice that receptor likes, thus decreasing the strength of the chemical signal in the CNS’ communications network. The biggest exception is lithium. Of all the meds that we’re unsure of how they work, lithium is the one where everyone is flummoxed. Some say it does one or both of controlling a voltage ion channel or affecting glutamate. Kay Redfield Jamison likes the lithium is an anti-inflammatory theory.1
A single neuron can send or receive different flavors of brain juice, and a single AP can be an antagonist - as well as encourage chemical signalling - of multiple neurotransmitters and bind to more than one receptor. All APs block dopamine, almost all of them at the D2 receptor, to some extent. Almost all of this signal blocking happens on the receiving end of the transaction. Sending a neurotransmitter is usually controlled by a synapse, and thus is in the territory of antiepileptic drugs and, probably, lithium. A few receptors are on the presynaptic, or sending side of things, so APs can affect how neurotransmitters are squeezed out of a neuron, but that’s getting into med school homework territory. The functional equivalent is still the same: less brain juice getting to the receiving neurons, and that is what these article and the Communications Interference Hypothesis are all about.
APs that work on bipolar depression, the negative symptoms of schizophrenia & schizoaffective disorder, and as add-ons to (adjunctive therapy) depression have a generally positive effect on one or more neurotransmitters, thus strengthening the signal in the communications network. That happens in one or more of the following ways:
- As an antagonist to more than dopamine receptors, 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.
- As a reuptake inhibitor, to increase the time, and often the amount of brain juice that stays on a neuron.
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. Seroquel (quetiapine) and Geodon / Zeldox (ziprasidone) are two of very few APs that have any kind of reuptake inhibition. Once you’re taking the minimum therapeutic dosage (the lowest amount of the drug that works for most people), or thereabouts, the antagonist action effective wipes out much, if not most of the effect of any reuptake inhibition.
What an agonist does is on spectrum of functions2. 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 chemical signal. For APs working on negative symptoms and depression most of them are agonists at the dopamine D2 or serotonin 5-HT1a receptors. More on what that means below.
We already know what an antagonist does. When it comes to working as an antidepressant most of that involves being a serotonin antagonist. What? Blocking serotonin makes you happy? Isn’t serotonin (5HT) supposed to make you feel as good as, if not better than, dopamine? Actually, 5HT doesn’t make you feel like anything. All it does is carry messages from one neuron to another. 5HT is so efficient at doing its job that your body uses it all over the place to carry instructions, such as your digestive system. Unfortunately efficient systems sometimes have complex parts that are subject to failure, which is why Irritable Bowel Syndrome (IBS) is such a popular condition. Does Paxil make your intestines feel happy? I guess if you have IBS and Paxil keeps you from getting arrested for intentionally damaging a government poop shack, you and your intestines would be fairly cheerful.
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)
- Histamine (H)
- Acetylcholine (ACh)
- Gamma-aminobutyric acid (GABA)
- Corticotropin-releasing factor/hormone (CRF)
- Melatonin (MT)
As far as antipsychotics (AP)s are concerned the first five is where most of the action is, with CRF being recently studied as something responsible for why medications of many different classes work and, unfortunately, make you fat as well.
Medicine Is The Best Medicine
Brain Cooties Aren’t Contagious
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 oxytocin. 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’s at the heart of the “too much dopamine hypothesis” for schizophrenia’s positive symptoms and bipolar mania. The D1 and D4 receptors are involved as well, but as few meds work on those receptors 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.
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, including: 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. As far as APs are concerned, the roles of 5HT receptors :
|5-HT1A||Aggression, Anxiety, Addiction, Appetite, Impulsivity, Memory, Mood, Nausea, Sleep, Sociability, Thermoregulation, Sexual behavior|
|5-HT1B||Aggression, Anxiety, Learning, Addiction, Memory, Mood, Sexual behavior|
There isn’t much out there regarding norepinephrine/noradrenaline (NE/NA) and bipolar disorder or schizophrenia, but there is some research on the contradictory roles of NE and anxiety. Contradictory in that some people with anxiety spectrum disorders are helped by serotonin and norepinephrine reuptake inhibitors (SNRIs), while other people who are trembling like the last autumn leaf have sky-high plasma NE levels. So it’s a coin-toss if an AP that affects NE will make anxiety better or worse. To further confuse matters, Seroquel (quetiapine) and Geodon / Zeldox (ziprasidone), do some minor norepinephrine reuptake inhibition similar to what Strattera (atomoxetine) and reboxetine do, but by the time you get to their average dosages their blocking of NE receptors effectively cancels, then surpasses the effect of the NE boost due to reuptake inhibition. Which means that Seroquel’s and Geodon’s effect on anxiety could start out positively or negatively, then change after you raise the dosage!
Medicine Is The Best Medicine stickers
Fuck Schizophrenia stickers
Mental Illness is NOT Contagious
Fuck Bipolar bumper stickers
While 5HT regulates sleep, the two neurotransmitters that have the most affect on sleep are histamines and melatonin. Antihistamines like diphenhydramine are sold as non-prescription, or over-the-counter (OTC) insomnia medications. Many APs are described as Benadryl (diphenhydramine) on steroids, but that really applies to Seroquel (quetiapine) and Zyprexa (olanzapine), as they are several hundred times more potent in their antihistamine effect than Benadryl5. Powerful antihistamines are also mean powerful weight gain. 6
Acetylcholine (ACh) receptors come in two flavors that you’ll probably recognize. The first is muscarinic, named for the stuff you find in Amanita muscaria mushrooms:
The second is nicotinic. You’re born with nicotinic receptors, so it doesn’t matter if you’ve never smoked a day in your life, they’re still there. Blocking nicotinic (N), but mainly muscarinic and (M) receptors are responsible for the anticholinergic side effects common to APs, as well as tricyclic antidepressants (TCAs) and assorted other crazy meds. The worst offenders are Seroquel, Zyprexa, and Clozaril (clozapine), all of which are also potent antihistamines and 5HT2a antagonists. Add all those up and what do you get? Aside from gaining five pounds as soon as you fill your prescription, it’s also next to impossible to get the Parkinson’s-like movement disorders caused by APs. Additionally, based upon little more than my own experience with eating the wrong mushroom, and the medications proven to be most effective in ending episodes of severe ultradian rapid cycling (shifting several times an hour between being extremely manic, extremely depressed, and mixed states where you’re both) - Zyprexa (olanzapine) and Clozaril (clozapine) - that the M1 and M3 receptors are involved in that particularly hellish aspect of bipolar disorder. As is frequently the case with crazy meds, one person’s suckass side effect is another person’s salvation.
Corticotropin-releasing factor/hormone (CRF) has been recently studied as something responsible for why medications of many different classes work and, unfortunately, make you fat as well.
This hormone you can buy OTC is used not only for sleep but also as an antidepressant.
With the exception of lithium carbonate and Haldol (haloperidol), all first-generation antipsychotic agents (FGAs), also known as standard antipsychotics and typical antipsychotics, were thought to work in the exact same way - binding to D2 dopamine, M1 muscarine, H1 histamine, and maybe even a little alpha-1 noradrenergic receptors to interfere with the reception of those neurotransmitters (D2, M1, H1 and α1 antagonists). The only differences being chemical structure, potency at the various receptors, where in your brain this would happen, and each drug’s pharmacokinetics. Haldol is different in that it doesn’t do much as far as M1 and H1 are concerned, and is a lot more potent in binding to alpha-1, so its side effect profile is somewhat different.
With better technology and more competition for grant money, researchers are looking back at FGAs to see how they work. Turns out they all don’t work the same way after all and some (loxapine, chlorprothixene, e.g.) are like Haldol in that they are a lot more like atypical / second-generation antipsychotics than FGAs.
Second-generation antipsychotic agents (SGAs), AKA atypical APs (AAPs) do a hell of a lot more than most FGAs. They are broad-spectrum antagonists of dopamine, alpha-noradrenergic, and serotonin receptors. Except for Risperdal (risperidone) and Invega (paliperidone) - which is Risperdal’s active metabolite (i.e. predigested Risperdal) in pill form - no two of them work the exact same way, hence the term “atypical”. Although it’s now unclear if Invega does a little more than Risperdal, or maybe they missed something that Risperdal does. Clozaril (clozapine), Zyprexa (olanzapine) and Saphris (asenapine) are fairly close in pharmacodynamics, and they bind to practically every neurotransmitter receptor you’ve got, while Risperdal / Invega don’t do much more than Haldol (haloperidol) does. Since they are now prescribed far more often than FGAs, the term “atypical” to describe them, and “standard” to describe the older APs, is counterintuitive. So FGA and SGA are the preferred terms among researchers. On most consumer-oriented mental health sites the term “atypical antipsychotic” (AAP) is still used far more often.
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2 Technically an antagonist is on the agonist spectrum, in the same slot as malfunctioning receptor, between partial agonist and inverse agonist.
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.
5 Warning: Footnote '#potency' referenced but not defined.
6 potency As I write all over the place, potency is not the same as efficacy. And they way the raw power of a drug is measured, even when they use cloned human brain tissue, doesn't always match how it will act by the time it reaches your brain.
|Last modified on Wednesday, 18 March, 2015 at 13:14:56 by JerodPoore||Page Author: Jerod Poore||Date created: 11 March 2014|
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Almost all of the material on this site is by Jerod Poore and is copyright © 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, and 2015 Jerod Poore. Except, of course, the PI sheets - those are the property of the drug companies who developed the drugs the sheets are about - and any documents that are written by other people which may be posted to this site will remain the property of the original authors. You cannot reproduce this page or any other material on this site outside of the boundaries of fair use copying without the express permission of the copyright holder. That’s usually me, so just ask first. That means if want to print out a few pages to take to your doctor, therapist, counselor, support group, non-understanding family members or something like that - then that’s OK to just do. Go for it! Please. As long as you include this copyright notice and something along the lines of following disclaimer, I’m usually cool with it.
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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.