Antipsychotics: In Search of the Holy Grail

Jeffrey A. Lieberman, MD


January 20, 2011

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Hello. This is Dr. Jeffrey Lieberman of Columbia University, speaking to you today for Medscape. I'm going to speak today about antipsychotic drugs and particularly about the mechanism of action of antipsychotic drugs.

Since the introduction of chlorpromazine in the 1950s, approximately 30 antipsychotic drugs have been developed and are used clinically worldwide, but the reality is that we can think about what mediates their therapeutic effects in a very simple way. Despite the abundance of theories and the proliferation of medications that have affinities for neuroreceptors beyond the dopamine system and the D2 (dopamine) receptor -- serotonin system, norepinephrine system, cholinergic system, histaminergic system -- definitive, irrefutable evidence that you can basically take to the bank (maybe that's a bad metaphor in these economic times -- you can bet the house on) is the action of drugs through dopamine, and more specifically through the D2 receptor. Definitive efficacy of a compound that does not have a modicum of activity to bind to the D2 receptor and to mitigate, attenuate, and antagonize the effects of the endogenous neurotransmitter dopamine has never been demonstrated.

If you accept this admittedly reductionistic point of view in the pharmacology of the therapeutic efficacy of antipsychotic drugs, then you need to consider: How do various antipsychotic drugs differ in terms of their actions on the D2 receptor?

I'd like to spend the rest of my time trying to draw these distinctions. The way antipsychotic drugs ostensibly alleviate psychosis is that they are absorbed, circulate, enter the cerebrovasculature, migrate into the extravascular space, and bind to proteins for which they have affinities, including the D2 receptor on synaptic membranes. They bind and inhibit the stimulation of the effects of dopamine.

The first-generation, conventional antipsychotic medications, such as chlorpromazine, haloperidol, fluphenazine, and trifluoperazine, bind with very high affinity and stay on the receptor, blocking the effects of dopamine for a very long time -- long past the usual dosing interval (once or twice daily) of these drugs. In doing so, they really shut down the postsynaptic cell and neural pathway because psychosis involves an overstimulation of the dopamine system. This is a therapeutic effect.

The second-generation medications, typified by clozapine and then extending through risperidone, olanzapine, quetiapine, ziprasidone, paliperidone, asenapine, iloperidone, and lurasidone, have affinity for the D2 receptor -- but at a much lower level than the first-generation antipsychotic drugs. The second-generation drugs also have affinity for other neurotransmitter receptors, particularly the 5-HT2A receptor, but also for other serotonin receptors, adrenergic receptors, and so on.

The second-generation drugs, which have lower affinity for the D2 receptor, bind to the receptor in the same way that first-generation drugs do, but they stick to the receptor less tightly and for a shorter period of time. They come loose from the receptor and allow for its stimulation by dopamine sooner than would be the case with the earlier drugs, so there is an intermittent attenuation or antagonism of dopaminergic stimulation of the D2 receptor. This is still therapeutic because we know that these drugs work. The activities of these drugs on the other neurotransmitter receptors do not seem to be relevant to the therapeutic effects, but certainly may be relevant to the side effects that these drugs produce, particularly the weight and metabolic side effects.

This third group of antipsychotic drugs is typified by aripiprazole, a partial D2 agonist that binds to the D2 receptor with very high affinity. It sticks to the receptor a long time, but has the ability to stimulate the receptor at a low level, at about 30% of the rate of stimulation of dopamine (hence, the term "partial agonist"). This drug shuts down the cell from overstimulation by dopamine, but it also stimulates it to some degree so that it's not completely inactivated; this also has therapeutic effects because we know that this drug works.

Pharmacodynamically speaking, we have 3 slightly different mechanisms by which these drugs work, all through acting on dopamine and the D2 receptor, which produces their therapeutic effects. Which is superior from a clinical standpoint or a pharmacologic standpoint? We're not really sure, but the pharmacodynamic distinctions of these 3 different groups of medications are variations on a theme. This is simply skinning a cat in 3 slightly different ways, but they're all acting through dopamine at the D2 receptor. The holy grail that the research laboratories and the pharmaceutical community has been searching for is a non-dopamine-acting compound that has antipsychotic effects. We have had a number of tantalizing possibilities, but none has really proven the concept definitively and grabbed the brass ring in terms of a novel mechanism for a nondopamine antipsychotic drug. I hope that very soon we'll be able to see such a compound, but today what we have is a bunch of medications, all of which work in slightly different ways, but acting through a common molecular mechanism on the D2 receptor.

I hope this has been helpful to you in understanding the distinctions between these various medications and how they differ and how they're similar to each other. For today, this is Dr. Jeffrey Lieberman of Columbia University thanking you on behalf of Medscape.


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