Atypical Antipsychotics: Mechanism of Action
Authors: Seeman Philip 
Published: July 2017

Background: Al though the prin ci pal brain tar get that all an tipsy chotic drugs at tach to is the do pamine D2 re cep tor, tra di tional or typi cal an tipsy chot ics, by at tach ing to it, in duce ex tra py r a mi dal signs and symp toms (EPS). They also, by bind ing to the D2 re cep tor, ele vate se rum pro lac tin. Atypi cal a ntipsy chot ics given in dos ages within the clini cally ef fec tive range do not bring about these adverse clini cal ef fects. To un der stand how these drugs work, it is im por tant to ex am ine the atypical an tipsychot ics' mecha nism of ac tion and how it dif fers from that of the more typi cal drugs. Method: This re view analy zes the af fini ties, the oc cu pan cies, and the dis so cia tion time- course of vari ous an tipsy chot ics at do pa mine D2 re cep tors and at se ro tonin (5-HT) re cep tors, both in the test tube and in live pa tients. Results: Of the 31 an tipsy chot ics ex am ined, the older tra di tional an tipsy chot ics such as tri fluperazine, pi mozide, chlor pro maz ine, fluphe nazine, ha loperi dol, and flupen thixol bind more tightly than dopamine it self to the do pa mine D2 re cep tor, with dis so cia tion con stants that are lower than that for do pa mine. The newer, atypi cal an tipsy chot ics such as queti apine, re moxi pride, clo zapine, ol a nzap ine, sert in dole, zi pra si done, and amisul pride all bind more loosely than do pa mine to the do pamine D 2 re cep tor and have dis so cia tion con stants higher than that for do pa mine. These tight and loose bind ing data agree with the rates of an tipsy chotic dis so cia tion from the human- cloned D2 recep tor. For in stance, ra dio ac tive ha loperi dol, chlor pro maz ine, and ra clo pride all dis s o ci ate very slowly over a 30- minute time span, while ra dio ac tive queti apine, clo zap ine, re moxi pride, and amisul pride dis so ci ate rap idly, in less than 60 sec onds. These data also match clini cal brain-imaging find ings that show ha loperi dol re main ing con stantly bound to D2 in hu mans un der go ing 2 posi tron emis sion to mo gra phy (PET) scans 24 hours apart. Con versely, the oc cu pa tion of D2 by clo zap ine or queti apine has mostly dis ap peared af ter 24 hours. Conclusion: Atypi cals clini cally help pa tients by tran siently oc cu py ing D2 re cep tors and then rap idly dis so ci at ing to al low nor mal do pa mine neu ro trans mis sion. This keeps pro lac tin lev els nor mal, spares cog ni tion, and ob vi ates EPS. One the ory of atypi cal ity is that the newer drugs block 5-HT2A re ceptors at the same time as they block do pa mine re cep tors and that, some how, this serotonin- dopam i n e bal ance con fers atypi cal ity. This, how ever, is not borne out by the re sults. While 5-HT2A re cep tors are read ily blocked at low dos ages of most atypi cal an tipsy chotic drugs (with the im por tant ex ceptions of re moxi pride and amisul pride, nei ther of which is avail able for use in Can ada) the do s ages at which this hap pens are be low those needed to al le vi ate psy cho sis. In fact, the an tipsy chotic thresh old oc cu pancy of D 2 for an tipsy chotic ac tion re mains at about 65% for both typi cal and atypi cal an tipsychotic drugs, re gard less of whether 5-HT2A re cep tors are blocked or not. At the same time, the a ntipsy chotic thresh old oc cu pancy of D2 for elic it ing EPS re mains at about 80% for both typi cal and atypi cal an tipsy chot ics, re gard less of the oc cu pancy of 5-HT2A re cep tors. Relevance: The “fast- off-D 2” the ory, on the other hand, pre dicts which an tipsy chotic com pounds will or will not pro duce EPS and hy per pro lac ti ne mia and which com pounds pres ent a rela tiv ely low risk for tar dive dyski ne sia. This the ory also ex plains why L- dopa psy cho sis re sponds t o low atypi cal an tipsy chotic dos ages, and it sug gests vari ous in di vidu al ized treat ment strategies.