Schizophrenia: Mechanism of Action of the Atypical Antipsychotic Agents

Mechanism of Action of the Atypical Antipsychotic Agents

A higher ratio of the serotonin 5-HT_2A receptor to dopamine D₂ receptor blockade is reported to predict atypicality. This, along with other data, formed the basis of the serotonin–dopamine hypothesis that explains the possible mechanism of action under-lying the efficacy of the atypical antipsychotics. However, studies using PET paradigm failed to detect differences in the serotonin

receptor affinities between typical and atypical antipsychotics. Moreover, atypical antipsychotic agents produce high 5-HT_2A receptor occupancy at doses that are not sufficient to produce

antipsychotic effects. This has raised some questions about the importance of 5-HT_2A blockade for a drug to be either atypical or have antipsychotic efficacy. Though the typical antipsychotics,

compared with the atypical ones, show a much higher affinity for the D₂ receptors, both are effective only when their D₂ receptor occupancy exceeds 65%, suggesting that D₂ antagonism is impor-tant in producing antipsychotic effects. Thus, some suggest that the major difference between typical and atypical antipsychotic medications may lie in their affinity for the D₂ receptor. Affinity is the ratio of the rate at which the drug moves off of and on to the receptor. Interestingly, Seeman and colleagues found that 99% of the difference in affinity of the antipsychotic was driven by differences in their K_off at the D₂ receptor. Difference in the K_on did not account for any significant differences in affinity. Thus, PET studies suggest that all antipsychotics (typical as well as atypical) attach to the D₂ receptor with a similar rate constant but differ in how fast they come off the receptor. Thus, Kapur and Seeman (2001) propose that this relationship between fast K_off and low re-ceptor affinity of the antipsychotic drug for dopamine D₂ recep-tor may explain atypicality. Furthermore, in vivo, antipsychotic agents modulate dopaminergic transmission and compete with endogenous dopamine. Thus, drugs with fast K_off (e.g., clozap-ine, quetiapine, etc.) modulate dopamine transmission differently from drugs with a slow K_off (e.g., haloperidol). For example, cloz-apine reaches equilibrium and goes on to and off the receptors significantly faster than haloperidol. When the concentration of endogenous dopamine rises physiologically, drugs like clozapine decrease their D₂ occupancy much faster and accommodate to natural surges of dopamine more readily then haloperidol.

Clinically, a significant difference between the typical and the atypical antipsychotic medications is the extent to which EPS occurs during treatment with therapeutic doses of antipsychotic drugs. PET studies suggest that the threshold for clinical antipsy-chotic response is lower than that of developing EPS and can be sep-arated based on D₂ receptor occupancy. Specifically, D₂ occupancy of 65% or more significantly predicted clinical response, while D₂ occupancy of 78% or above significantly predicted EPS. Similarly, D₂ occupancy of 72% or higher resulted in prolactin elevation (Kapur et al., 1996, 2000). Risperidone and olanzapine achieve strong antipsychotic activity only at doses that occupy 65% or more D₂ receptors, which is similar to haloperidol (Nordstrom and Farde, 1998). On the other hand, although clozapine and quetiapine show less than 60% D₂ occupancy 12 hours after drug administration (Seeman and Tallerico, 1999) these differences partly reflect a fast decline in D₂ occupancy. For example, quetiapine showed 60 and 20% D₂ occupancy 2 and 12 hours after receiving the medication. Similarly, clozapine showed 71% D₂ occupancy 1 to 2 hours after dose administration with a decline to 55% at 12 hours and 26% at 24 hours. It appears that both typical and atypical antipsychotics block sufficient number of D₂ receptors to achieve antipsychotic effect but differ in the kinetics of receptor occupancy.

It has been proposed that 5-HT_2A occupancy exerts an attenuating effect on the D₂ related EPS. Antipsychotic agents, both typical and atypical, give rise to EPS only when they exceed 78 to 80% D₂ occupancy; and when they do so, concomitant 5-HT_2A blockade does not appear to offer protection from these. Since clozapine and quetiapine never exceed this threshold of D₂ occupancy, they do not give rise to EPS. Since olanzapine and risperidone exceed this threshold in a dose-dependent fashion, they give rise to EPS also in a dose-dependent fashion.