Author: Flavio Guzman, MD

Psychiatrist
Pharmacology Department
University of Mendoza
Argentina

Quetiapine is a second-generation antipsychotic that has affinity for D2, 5-HT2A, H1, alpha 1 and 5-
HT1A receptors. Its precise mechanism of action is unknown, but according to the dopamine
theory of schizophrenia, antipsychotic effects might be related to the drug’s ability to reduce
dopaminergic neurotransmission in the mesolimbic pathway.

Quetiapine mechanism of action might involve rapid dissociation from D2 receptors.

PET studies show that there is a relationship between D2 receptor occupancy and antipsychotic
effects [1]. D2 receptor occupancy in the ranges of 60 % to 75% is associated with antipsychotic
efficacy. Interestingly, quetiapine has been shown to occupy approximately 30% of D2 receptors
at therapeutic doses [2].

To explain the apparent discrepancy, Kapur proposed the “kiss and run” hypothesis. In a series of
studies they found that in contrast to other antipsychotics, quetiapine had a more rapid “run-off”,
or rapid dissociation, from D2 receptors [2].

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This section is an illustrated representation of the most relevant pharmacodynamic properties of
quetiapine.

Putative mechanism of action of quetiapine involves 5-HT2A/D2 antagonism and 5-HT1A partial agonism.
H1 and alpha 1 antagonism are linked to side effects.

Quetiapine has antagonist actions at 5-HT2A receptors, one of the key properties of second-
generation antipsychotics is that they have a high 5-HT2A/D2 ratio. Quetiapine has higher affinity
for 5-HT2A receptors than for D2 receptors [3].

Quetiapine, aripiprazole, asenapine and ziprasidone are partial agonists at 5-HT1A receptors. Affinity
for this receptor is one of the proposed mechanisms of action of quetiapine’s antidepressant
effects [4].

Alpha 1 antagonism can cause orthostatic hypotension, this potential side effect can be prevented
by slow dose titration.

Quetiapine is a strong antagonist at H1 receptors. H1 antagonism is linked to sedative effects and

weight gain [2].

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This table shows Ki values for quetiapine at different neurotransmitter receptors. Ki is inversely
proportional to affinity. This means that high Ki numbers suggest low affinity at a given receptor,
while low Ki numbers are associated with high affinity.

Receptor type Ki value (nM)

D2 380

5HT1A 390

5HT2A 640

5HT2C 1840

D1 990

D4 2020

M1 37

Alpha 1 A 22

Alpha 2 A 2900

H1 6.9

Binding potency of quetiapine at different receptors. Modified from [5]

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1. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2)
occupancy, clinical response, and side effects: a double-blind PET study of first-episode
schizophrenia. The American journal of psychiatry 2000;157:514-20.
2. Schatzberg, AF, Nemeroff, C . The American Psychiatric Publishing Textbook of
Psychopharmacology. 4th ed.American Psychiatric Publishing, 2009.
3. Tasman, A; Lieberman, J; Key, J; Maj, M. Psychiatry. 3rd ed. John Wiley & Sons, 2008
4. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL. N-
desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist,
as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology :
official publication of the American College of Neuropsychopharmacology 2008;33:2303-12.
5. Brunton LB, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. 12th ed. New York: McGraw-Hill; 2010.