How does Olanzapine work (Question for pharmacists, or other healthcare profesionals)?

Question

I understand that Olanzapine is an antagonist at both dopamine D2 and 5-HT2 receptors (among others). Now, I can see why Olanzapine may reduce the positive symptoms of schizophrenia and related disorders as it acts to block dopamine at the receptor site, but I can't work out why introducing a 5-HT2 antagonist (as olanzapine is) would reduce the negative symptoms. Surely this would decrease serotonin transmission in the brain and increase the negative.

I note that aripiprazole is a 5-HT2 agonist and I can understand why it would reduce negative symptoms.

If someone could please explain Olanzapines mode of action, I'd be most grateful.

Thanks.

Anonymous · Accepted Answer

This is the best that I can come up with:

Aripiprazole is actually a 5-HT1a agonist as well as a 5-HT2a antagonist. Stimulation of HT1a results in central nervous system (CNS) depression and can alleviate symptoms of both anxiety and depression (the psychological/biological aspect of both anxiety and depression are similar). Stimulation of HT2a does the opposite it is a sort of CNS stimulant...this receptor is the main target of hallucinogenic drugs like LSD.  

So if we antagonise (block) HT2a receptors with olanzapine, we can allow more serotonin to stimulate HT1a receptors. There may be other pathways in which this works, but this is certainly one of them. 

Also keep in mind that these drugs only slightly modulate these systems, Zyprexa and Abilify do not activate or block all of their respective targets...only a relatively small percentage of receptors are affected at therapeutic doses. So, with these drugs we just give the body's system a nudge in the direction we want. 

Also, we still really only have a very small amount of knowledge of how the body works.

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How does Olanzapine work (Question for pharmacists, or other healthcare profesionals)?

1 Answer