Thomas A. M. Kramer, MD

Disclosures

Introduction

We are now being told that just as we became accustomed to a whole new generation of antipsychotic medications, they will soon be replaced by an even newer generation. Just as we got used to the idea that antipsychotic medications needed to block both dopamine and serotonin receptors, specifically the D-2 receptor and the 5HT-2A receptor, and these (somewhat begrudgingly) became the standard of care, we are now told that soon they will be passé. This is not going to be easy for the psychopharmacology world. After all, these drugs are so much better than their predecessors. As a teacher of psychopharmacology, I have always insisted that residents shy away from the term "atypical antipsychotic" because these are the drugs that should be used typically, as the rule, not the exception. I always encouraged the use of the term "new-generation antipsychotic" to describe serotonergic/dopaminergic blockers to treat psychosis. These new-generation antipsychotics appear to be safer (as far as causing tardive dyskinesia), better tolerated, and have greater effectiveness in that the patients appear to not only have diminished symptoms, but also seem to be more functional. To supplant these drugs, the next generation must be truly extraordinary by comparison.

And indeed, as described, they are. These medications, referred to as dopamine system stabilizers and exemplified by the prototype drug aripiprazole, sound magical. They are described as binding to dopamine receptors, particularly D-2 receptors, in such a way that they are neither agonists nor antagonists, but instead magically affect the receptor in just the right way to make the patient better. This sounds too good to be true.

The problem with understanding this concept is how we are taught, for the most part, about receptors and psychopharmacology. If we are told that a drug is active at a certain receptor, our next question is whether it is an agonist or antagonist. That is, either the drug binds to the receptor but doesn't activate it, which makes it an antagonist, or it binds to the receptor and activates it as if it were the actual neurotransmitter the receptor was designed for, which makes it an agonist. In most discussions of psychopharmacology, this is presented as an all-or-nothing, on-or-off, binary situation. If the drug binds to the receptor, there is only 1 of 2 things it can do and it does either one with some absolute quality. We deal with the issue of different affinities for the receptor with dosing. Thus, a drug with a high affinity for the D-2 receptor, like haloperidol, can be used in relatively low dose because it has a very high affinity for the dopamine receptor, while chlorpromazine has a relatively low affinity for the D-2 receptor and, as such, requires considerably higher numbers of milligrams to get the same effect.

This, however, is not the way psychopharmacology, or pharmacology in general for that matter, works. There are many compounds that bind to receptors and have both antagonistic and agonistic properties. An example of this is pentazocine (Talwin). Pentazocine is an opiate-based painkiller that can function both as an agonist and an antagonist at opiate receptors. It can be quite effective in pain control; we can also see some patients become dependent on it and abuse it. However, severe heroin or morphine addicts will often tell healthcare professionals that they have an allergy to pentazocine. They know that this means they will never receive the drug. They hate the drug because it interferes (as an antagonist) with the effect of the drug to which they are addicted. Thus, for some people, the drug works as an agonist, and for others, it works as an antagonist. How can this be?

The answer to this dilemma lies in a rethinking of how we understand and discuss drugs and their effect at the receptor. When a drug binds to a receptor, the effect will be different from the effect of the neurotransmitter for which the receptor was designed. It may be less intense, it may be more intense, but to say that it is either going to have an effect or no effect makes things too simple. All things that bind to a receptor can have a full spectrum of effect, starting from having absolutely no effect but blocking anything else from binding to the receptor, to having a mild effect, to having a more intense effect than the actual intended neurotransmitter. One thing that is fairly universal is that when drug is bound to the receptor, nothing else can bind to it for the period of time the drug is there. As such, one of the ways to understand receptor affinity is to consider how long the drug sticks around. This may be the best way to understand what these magical new drugs called dopamine system stabilizers do. They bind to dopamine receptors. Once they are there, they prevent dopamine from binding to the receptor for as long as they are bound. They have a mild effect similar to dopamine in the receptor, but less intense. Since we assume that the state of being psychotic has something to do with an overactivity in the dopamine system, if you put in a drug that gets in the way of dopamine but still does some of the good stuff that dopamine does, you will effectively "stabilize" the system. Thus, these drugs are agonist/antagonists and they work, in large part, by getting in the way transiently of dopamine binding. In doing so, they behave like a milder form of dopamine.

One way to understand the virtue of this activity is to think about chairs at a party. If everyone sits down in a chair and stays there (the analogy to something with very high affinity that binds to the receptor and doesn't leave), the party will not get too wild, but nobody will stand up, and the party is sort of dead. This may be a good example of what happens with dopamine antagonists such as haloperidol. If, however, you have people who sit down in chairs but then stand up and are constantly sitting down and standing up, getting out of the chair and getting into the chair, you probably have a pretty good party. Guests are only sitting down for part of the time and then allowing other people to sit down so that everybody there has a chance to sit in the chairs. This kind of movement not only makes for a good party; it is illustrative of probably the best way for dopamine receptors to be occupied (ie, transiently so that they are bound part of the time but also allow some opportunity for dopamine to bind occasionally). In other words, you want movement in and out of the seats so that no one sits too long and everyone has a chance for a seat. This is probably the stabilizing effect.

Generally, the new concept of antipsychotic medication is that transient occupancy of the D-2 receptor is probably responsible for the increased benefit of newer antipsychotic medications. What are currently called atypical antipsychotics do this in part by blocking some D-2 receptors and also blocking serotonin receptors that have a downstream effect of pushing more dopamine into the system. This, in effect, competes with the dopamine blockade of the original drug. What dopamine system stabilizers may do is make this feedback loop effect simpler, more direct, and more effective: fundamental ways to improve the clinical pharmacology of any disorder.

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