What specific interaction between methylphenidate and quetiapine causes toxicity concerns?

Question

A number of reputable sources on drug interactions posit a potential interaction between methylphenidate and quetiapine, described on Medscape as follows:

quetiapine increases toxicity of methylphenidate by pharmacodynamic antagonism

I'm trying to understand the pharmacodynamics of this supposed interaction, and where the elevated toxicity concerns come from. I've been unable to find a direct source for it that describes the exact mechanism of toxicity.

I'm coming at this without a whole lot of background in the topic, but I do understand the basics of binding profiles, dissociation constants, agonists/antagonists, binding affinity, etc., which has at least allowed me to do a bit of preliminary digging. This is what I came up with, based on the reading I've done so far:

Quetiapine's binding profile differs from its primary active metabolite, norquetiapine. Both have a fairly long list of receptors to which they can bind: SERT, NET, 5-HT receptors, α receptors, σ receptors, dopamine receptors, histamine receptors, and muscarinic acetylcholine receptors.

The most frequently theorised hepatotoxicity concern for methylphenidate apparently involves an interaction with β-adrenergic agonists. However, quetiapine does not appear to have any particular binding affinity for β₁ or β₂, and the description above says antagonism rather than agonism.

Methylphenidate mostly affects DAT and NET, along with a couple of 5-HT receptors.

5-HT_1A seems unlikely to be involved, since methylphenidate has a fairly low binding affinity for it, and quetiapine / norquetiapine are agonists.

Quetiapine is an antagonist for 5-HT_2B, but only dexmethylphenidate is known to have any affect on 5-HT_2B, and even then it doesn't appear to have a particularly strong binding affinity.

Quetiapine, unsurprisingly, has a strong effect on SERT. Levomethylphenidate has a mild effect on SERT, but other forms are not known to (both Ki and IC₅₀ exceeding 10000).

This left me with the most likely interaction: methylphenidate is an NDRI, so it fairly strongly blocks the norepinephrine transporter (NET), and norquetiapine also has a strong blocking effect on NET. This seems like a strong candidate for being the source of concern - they're both antagonists on the same receptor. Two drugs blocking the same receptor is usually a recipe for problems.

Reading more of the literature, it seems like α_2A probably also plays a role here. From what I've read it controls norepinephrine production in a negative manner, since it's an autoreceptor. If inhibited, it may increase the amount of norepinephrine in the brain. Quetiapine is an α_2A antagonist, so that's a secondary mechanism by which quetiapine would affect norepinephrine levels. α_2B and α_2C may also be involved here but I couldn't follow the literature well enough to figure that part out.

This is where I start to lose track of things. What I suspect the interaction is referring to is that both drugs increase norepinephrine through one or more mechanisms (e.g. by inhibiting reuptake and/or increasing production) leading to a potential scenario where a person who takes both drugs may end up having far too much norepinephrine. However, it isn't clear to me where the toxicity comes from. The symptoms of excess norepinephrine mimic that of stress, which can lead to increased blood pressure, but it seems odd to refer to that as "[increasing the] toxicity of methylphenidate" - that phrasing implies that some aspect of methylphenidate is already inherently toxic, and that quetiapine somehow specifically amplifies that. I'm struggling to reconcile that with my understanding of the pharmacodynamics. It also seems odd, to me at least, to refer to those symptoms as "toxicity". I guess it's technically correct, in the sense that anything that damages an organism is toxic, but it seems like a stretch.

Can someone provide a clearer explanation of this theorised toxicity? Am I missing something obvious? Is my (admittedly armchair) analysis fairly close, or am I way off?

Medscape reference: quetiapine (Rx) or Methylphenidate. Both have identical statements.

Answer 1

quetiapine increases toxicity of methylphenidate by pharmacodynamic antagonism

Pharmacodynamics refers to the study of drug actions, for example the affinity for different receptors is pharmacodynamics. In contrast, pharmacokinetics is concerned with the fate of a drug: how does it spread/how is it distributed after administration, how is it metabolized.

An antagonist is something that blocks/reduces the effect of a drug/ligand.

By stating "pharmacodynamic antagonism" we can infer that there is not a pharmacokinetic concern. A pharmacokinetic interaction could include, say, drug A impacts the absorption of another drug B: that could lead to lower or higher concentrations of B when co-administered with A rather than alone. It could involve interference with the metabolism of the drug, like by inhibiting or activating liver enzymes, causing more or less of B to be in an active form for longer/short periods of time.

Okay, so how can pharmacodynamic antagonism increase toxicity? That seems to be the primary question here. How can blocking the effect of a drug make it more toxic, without having any pharmacokinetic effects?

First, it seems like this Medscape reported interaction is mostly a theoretical one. I do not see reports of this being a substantial interaction of concern, and Medscape gives it a rather low "monitor closely" guideline.

I believe the concern they are raising is that because quetiapine may reduce the effectiveness of methylphenidate, higher doses of methylphenidate may be necessary to get the same effect. That could increase the potential for hepatotoxicity, particularly in combination with other drugs. I think this warning is meant to advise providers to think about this and consider all the combination of drugs given.

It's difficult to build a database of all possible higher-order combinations of concern, and that's why this sort of information is meant to be interpreted by a physician (particularly a primary care doctor who acts as a central point of care) or pharmacist to decide what level of concern is relevant for each specific individual case.

Answer 2

Think I should first start by mentioning that I am not a physician nor I am trained to make any clinical or diagnostic reasoning. With that in mind, let me try my best to clarify most part of the question.

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regarding a somewhat theoretical point of view, pharmacodynamic interactions

are those in which drugs influence each other’s effects directly source

drug to drug interactions often are classified as synergistic, additive, or antagonistic in nature reference and thus when the effect of one drug is impeded by another, the effects of these drugs are antagonistic

Back to the point,

methylphenidate, in a nutshell, acts by blocking the reuptake of dopamine and noradrenaline which leads to the increasing levels of dopamine and noradrenaline in the synaptic cleft

on the other hand, quetiapine (is almost the opposite) a second generation antipsychotic has antagonist actions on 5-HT2A/D2 receptors (serotonin receptor/dopaminergic receptor) but are also partial agonists at 5-HT1A receptors (another serotonin receptor).

as I've mentioned quetiapine is a second generation antipsychotic (which is still, at present time, synonym for "not so clean drugs", what I mean by that is that they bind to almost everything that is receptor.. ) and thus the other receptors that you have mentioned (H1 and alpha 1 antagonism) are linked to side effects source

as one can see

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.

they like to bind.. (a lot..) and thus the side effects.

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Now, once established some background, lets go to the main part of the question: Why some literature reports toxicity interactions between the two? in fact drugbank.com also reports similar

The risk or severity of adverse effects can be increased when Quetiapine is combined with Methylphenidate. Drug Interactions section

that has to do with the pharmacodynamic properties of both, since one has the opposite mechanism of action of the other (pharmacodynamic antagonism) it is expected to notice some increase of side effects.

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Finally I would like to address, once again, to the fact that I'm not a physician and that therapeutically it has been reported with some relative success the combination of those two drugs

Conclusion: Quetiapine addition to methylphenidate was effective in reducing ADHD and aggression in individuals who did not respond sufficiently (based on CGI-S, RAAPP, and ADHD-RS-I criteria for significant improvement) to OROS methylphenidate alone at a 54-mg/day dose. study