Why we predicted ictogenic tricyclic compounds treat epilepsy?

The epilepsy section of our initial report states:

As an example, we predicted five tricyclic antidepressants primarily based on their binding to the GABAᴬ receptor.

This statement derived from an earlier comment that.

The 15 predicted drugs that are known to induce seizures include five are tricyclic antidepressants (TCAs) (amitriptyline, imipramine, nortriptyline, clomipramine, desipramine)

However, our new visualization of the top epilepsy predictions and their targeted genes makes it clear that binding GABAᴬ isn't the cause of these predictions. For convenience, this visualization is reproduced below:

Specifically, I'm referring to amitriptyline, amoxapine, clomipramine, clozapine, cyproheptadine, desipramine, imipramine, loxapine, and nortriptyline, which all share a tricyclic structure and cluster together in the visualization.

Literature survey

Below is a collection of related literature, which I may update as the research continuous. The primary questions is why the 9 cyclic compounds listed above are ictogenic.

From a 2010 article [1]:

The mechanisms through which antidepressants alter neuronal excitability and modify seizure threshold are still largely unknown. Antidepressants act mainly by blocking the re-uptake of monoamines. Both animal and human data have shown that blocking the re-uptake of norepinephrine and/or serotonin has an anticonvulsant effect [2]. The convulsive properties of antidepressants have been suggested to be the result of their possible local anaesthetic or anticholinergic effect [3]. It has been proposed that selective serotonin re-uptake inhibitors (SSRIs) are less likely to cause seizures than cyclic antidepressants [4]. On the other hand, seizures have been associated with SSRIs in previous studies of adverse events as in the case of escitaloprame [5].

From a 2016 article [6]:

Antidepressants may disturb the neuronal balance and control of excitability, leading to seizures. Seizures may occur as a consequence of a misbalance between inhibitory GABAergic and excitatory glutamatergic neurotransmission with increase in glutamatergic activation and, thus, excessive calcium influx, initiating intracellular processes. The underlying mechanisms are not clear [7].

From a 2002 article [8]

Different specific mechanisms may be involved, which are mediated by the γ-aminobutyric acid (GABA) system and other neurotransmitters. Discussion of these mechanisms is beyond the scope of this review and readers may refer to specific reviews [9].

From a 1996 article [3] (referenced in [1] above):

Taken together, the total body of information strongly suggests that the pharmacodynamic action by which antidepressant drugs cause seizures is unrelated to their ability to block norepinephrine or serotonin reuptake. Rather, it seems more likely that these drugs produce convulsions by virtue of their local anesthetic or their antihistaminic/antimuscarinic properties.

Other references: [10]

Cholinergic receptors?

One visually striking pattern is that of the 9 ictogenic tricyclic compounds, 8 target cholinergic receptors. Furthermore, clomipramine also likely exhibits anti-cholinergic effects [1, 2, 3], which would mean all 9 ictogenic tricyclic compounds bind to cholinergic receptors. I have not confirmed this, but I believe these compounds are all antagonists of cholinergic receptors.

There are two anti-ictogenic tricyclic compounds: oxcarbazepine and carbamazepine. Although these compounds likely have anti-cholinergic effects [4, 5, 6], they are unique in their targeting of the sodium channel (according to our visualization).

Interestingly, there's evidence that cholinergic receptor inhibition may a therapeutic mechanism of action for carbamazepine [7]. Quoting from [6]:

The increased sensitivity of these mutant receptors supports the hypothesis that the antiepileptic activity of carbamazepine can, at least to some extent, be attributed to the nAChR inhibition.

And furthermore, the barbiturates — which clustered together and were all anti-ictogenic — also inhibit cholinergic receptors [8]. Pharmacologists believe the primary mechanisms of action for barbituates on epilepsy are GABAᴀ agonism, blocking AMPA/kainate receptors, and inhibiting glutamate release [9]. Potentially, the anti-cholinergic effects of barbiturates are overshadowed by these other mechanisms.

@pouyakhankhanian, do you also find the cholinergic receptors interesting here?