[Epistemic status: Very speculative; I don’t fully understand a lot of the studies involved]

Clozapine is an antipsychotic drug sometimes used to treat schizophrenia. Like most antipsychotics, it works by blocking dopamine receptors in the brain. Conventional wisdom among psychiatrists goes that most antipsychotics are about equally good – except for clozapine, which is better.

It’s fun to listen to psychiatrists, usually pretty quick to admit how crappy a lot of the drugs they prescribe are, wax rhapsodic about clozapine. From Joober & Boksa:

Consensus of opinion is rare in psychiatry. Even in the field of clinical trials, where experimentation is tightly controlled and regulatory bodies scrutinize the proof, controversies are frequent and difficult to resolve. One issue for which there is a widespread consensus is the unique place that clozapine occupies in the treatment of severe mental illnesses, particularly refractory schizophrenia. This molecule is distinct because of its effectiveness, numerous and sometimes mysterious pharmacologic characteristics, serious side effects and under use… Every clinician who has prescribed clozapine can recount a few experiences of seeing patients emerge from their chaotic psychotic experience. This is one of the most rewarding experiences that a psychiatrist can have in his or her professional life, and it is among the most important strikes we have made against one of the most devastating diseases affecting mankind.

Psychiatrists wish they could give clozapine to everyone who needs an antipsychotic. They can’t, because its increased efficacy goes side-by-side with greater side effects. The best known are agranulocytosis, metabolic syndrome, seizures, myocarditis, and eosinophilia, and the list just goes on from there.

This has led a lot of people to wonder: why is clozapine so uniquely great? And can we get a version which is just as good without the side effects?

Recently there’s been increased interest in the glutamate system (especially NMDA receptors) in schizophrenia, and in glutamatergic compounds as possible treatments. Various teams have taken schizophrenic patients already on antipsychotics and added NMDA modulators, especially d-serine, glycine, and sarcosine. Meta-analyses have been guardedly positive (Tiihonen & Walbeck) or explicitly positive (Singh & Singh, Tsai & Lin). There’s a widespread hope that the next generation of antipsychotics will be glutamatergic drugs which are able to attack more symptoms than the dopaminergics we have today.

But what if that next generation were already here?

Both of the recent meta-analyses of glutamatergic augmentation of antipsychotics noted the same exception. From Singh & Singh:

When added to clozapine, none of the drugs demonstrated therapeutic potential

And from Tsai & Lin:

Patients receiving risperidone or olanzapine, but not clozapine, improved.

Why should this be? A couple of recent studies have converged on an exciting possibility: clozapine is a combination antipsychotic + NMDAergic. That is, NMDA glycine site agonists don’t add anything to clozapine because clozapine is already agonizing the glycine site.

This is the suggestion of Schwieler et al, based on their electrophysiology studies in rats. They find that clozapine causes a characteristic change in the firing rates of certain rat neurons, a change which is reversed by the glycine site antagonist kynurenic acid. They conclude (I don’t know enough to confirm) that:

The enhanced response of [ventral tegmental area] [dopaminergic] neurons to clozapine seen following lowered [kynurenic acid] is what should be expected from a partial NMDA/glycine-site agonist.

Javitt et al also work with rats, and find that clozapine “inhibited transport of both glycine and MeAIB, but not other amino acids, at concentrations associated with preferential clinical response”. Other antipsychotics do nothing of the sort. A lot of their biochemistry is a little too in-the-weeds for me, but I think what they’re saying is that clozapine increases natural extracellular glycine levels, and so really is a direct analogue of medicinal glycine administration. They conclude:

This study suggests first that System A transporters, or a subset thereof, may play a critical role in regulation of synaptic glycine levels and by extension of NMDA receptor regulation, and second that System A antagonism may contribute to the differential clinical efficacy of clozapine compared with other typical or atypical antipsychotics.

Jardemark et al find that clozapine facilitates NMDAergic neurotransmission through something called protein kinase C. My head is starting to hurt trying to keep track of all of these different chemicals, and in particular I’m not sure whether all of these people are positing different and incompatible mechanisms or if they can be unified into one big biochemical pathway. But it sure looks like a lot of people have found some kind of interesting NMDAergic effect.

This doesn’t really prove anything. For one thing, a bunch of drugs coincidentally have NMDAergic effects that have nothing to do with their mechanism of action – eg the antibiotic cycloserine treats tuberculosis and happens to be a pretty good NMDA agonist on the side. For another thing, what if all antipsychotics have NMDAergic effects? Blocking dopamine is probably going to do something or other upstream. Right now evidence seems pretty mixed on this, with one study suggesting they do (1) and a couple suggesting they don’t (1, 2, 3).

If this really was the source of clozapine’s special powers, it would be a really important big breakthrough. All through residency, I kept hearing “nobody really knows why clozapine is so great” or “it probably has something to do with its weak D2 binding affinity or something”. If we knew it was just because clozapine was an antipsychotic plus glycine, we could just give people an antipsychotic plus glycine, and avoid the agranulocytosis, metabolic syndrome, seizures, myocarditis, eosinophilia, etc.

This theory isn’t ready for prime time yet; it’s still not really proven that the NMDA agonists work for schizophrenia at all. And it probably never will be – it’s hard to patent these chemicals, meaning that it would take extreme creativity to jump the bureaucratic hurdles necessary to get them into the pharmacopoeia. Until that happens, using these chemicals will remain experimental, and replacing clozapine with them downright irresponsible.

Still, it’ll be hard to watch treatment-refractory schizophrenia patients get their agranulocytosis, metabolic syndrome, seizures, myocarditis, eosinophilia, etc without wondering whether another way is possible.