Olanzapine as an antidote in serotonin toxicity

Abstract

We thank Chiew and Isbister for their review of serotonin toxicity (ST) and while we can think of no authors who have done more to improve our general understanding of ST, we respectfully disagree with the pessimistic view on the current role of specific serotonin antidotes in their latest instalment.¹ We believe parenteral olanzapine to be a highly effective serotonin antagonist with symptom-alleviating effects that cannot always be achieved by supportive measures alone, as advocated by the authors. We base this belief on our clinical experience from a few dozen cases where the effects of olanzapine, particularly in severe ST, have been nothing short of remarkable.^{2, 3} We are aware that nothing principally distinguishes this claim of efficacy for olanzapine from claims of efficacy for cyproheptadine and chlorpromazine that others have made; claims for which we share the scepticism expressed by Chiew and Isbister. However, we think that there is a strong “pharmacological case” to be made in favour of olanzapine that is overlooked in their review. We understand their thread of reasoning to flow from the data they present in tab. 2 on page 6, and we will call this reasoning “tab. 2 logic” (relevant parts of tab. 2, alongside other data points pertinent to our case can be found in the adjoining Table 1).^{1, 4, 5, 7-9} In tab. 2 of Chiew and Isbister, 5-HT_2A affinities are given as 170 for risperidone, 71 for chlorpromazine and 25 for olanzapine, forming a series of descending numbers that might give the casual reader the impression of serotonin blocking abilities rapidly approaching zero. That this is not so becomes evident when the affinity values are converted to the equilibrium dissociation constants (K_d) from which they were derived (using an equation provided by the authors). These K_d values are all in the low nanomolar range (a standard intramuscular injection of olanzapine yields plasma levels more than an order of magnitude over its K_d at 5-HT_2A).⁶ The authors do not claim that the potencies in tab. 2 are in fact approaching zero; nevertheless, a “tab. 2 logic” is established, anchored on the assumption that antidotes can be ranked based on K_d. We believe this to be incorrect. The limitations of the K_d value in this context can be illustrated by comparing the 5-HT_2A receptor blocking effects to the dopamine D₂ receptor blocking effects of olanzapine in PET-studies. According to recent studies, olanzapine has the same K_d value (6.8 nmol/L) at both receptors.^{9, 10} However, PET-signals are dramatically different in patients with therapeutic plasma levels of the drug: the radioligand blocking effect on the 5-HT_2A receptor is near 100% in most patients, while D₂ binding rarely exceeds 75%.^{4, 7} Thus, neuroleptic function in vivo is determined by dynamic binding properties that are not reflected by the K_d.^{9, 10} Likewise, while olanzapine and chlorpromazine have similar K_d values at 5-HT_2A, this similarity is not reflected in the radioligand blocking effect of the respective drug in PET-studies where patients with therapeutic chlorpromazine plasma levels rarely show 5-HT_2A receptor occupancy exceeding 50%.^{4, 7, 8} It is likely that different dissociation rates in olanzapine and chlorpromazine at the 5-HT_2A and D₂ receptors explain the strikingly different patterns of receptor occupancy seen in the PET-studies.^{4, 9} Olanzapine dissociates at a much faster rate from D₂ than from 5-HT_2A, with a dissociation t_1/2 of 40 s from the former, compared to 1 min and 12 s from the latter receptor.^{9, 10} Chlorpromazine has a 5-HT_2A dissociation t_1/2 of only 12 s.⁹ A drug with a short dissociation half-life will be more sensitive to ligand competition compared to a drug that binds to the receptor more persistently. This difference in competitive resistance will lead to increasing differences in receptor blocking ability as ligand concentrations increase.⁴ Severe ST, which can lead to ligand-surges up to 1000-fold over basal concentrations, will be a “stress test” that chlorpromazine- struggling to bind even 50% of 5-HT_2A receptors in the unstressed state- is unlikely to pass even in theory, and that it does not pass in animal studies.¹ Olanzapine, which binds over 90% of 5-HT_2A receptors at subtherapeutic plasma levels in the unstressed state, should have better prospects.⁴ Unlike chlorpromazine, olanzapine has never been “stress-tested” in any animal study, but we believe our clinical experiences are encouraging. It would be unfortunate if the “tab. 2 logic” of Chiew and Isbister were to dissuade researchers from the further investigations needed to clarify the matter. Our experience suggest olanzapine could be particularly useful as an adjunct to supportive measures in cases of severe ST; where antagonists with oral formulation (cyproheptadine) or fast dissociation kinetics (chlorpromazine) are distinctly unsuitable, and to which, in our opinion, olanzapine should not be compared in the way done by Chiew and Isbister.^{1, 9}