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-HT1A 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-HT2B, but only dexmethylphenidate is known to have any affect on 5-HT2B, 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 α2A 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 α2A antagonist, so that's a secondary mechanism by which quetiapine would affect norepinephrine levels. α2B and α2C 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?