New Operational Agents for Psychotic Illnesses?


Moderator: MH
Staff member
Jul 2, 2008
I was thinking that there seem to be just a few chemical mechanisms that have been targeted for psychotic symptoms. We have the typicals (D2 antagonism); we have the atypicals (D2 antagonism and 5-HT2a antagonism); we have the (debated third) class (D2 partials and 5-HT2a antagonists); we have clozapine (D2 partial, 5-HT2a antagonism, D4 activity, and other, non-obvious mechanisms which makes it paramount). There are also other mechanisms interspersed in these substances such as 5-HT1a partial agonism, which is supposed to create an anxiolytic effect, and 5-HT7 antagonism, said to promote concentration.

For some reason, DM-clozapine, the main metabolite of clozpaine, didn't prove effective for psychosis despite its mechanism profile.

How about D2/D3 autoreceptor agonsts? Is this feasible?

Modafinil is supposed to be relatively safe in terms of psychosis-promoting potential. Just a few years ago dubbed the "worlds first smart drug), it largely works in the neocortex. Also, atomoxatine is an NRI, but it also increases dopaminergic activity in the prefrontal cortex. We're talking here about more power of the critical thinking part of the brain to rival that of the brainstem and primitive brain structures in general (thinking the amygdala here mostly). This effectively would make CBT/DBT easier to teach and used to more magnitude when applied.

Since both 5-HT2a agonists and 5-HT2a antagonists both down-regulate this receptor subtype, and given that the negative symptoms of schizophrenia are significantly more associated with prognosis and greater recovery as opposed to positive symptoms, couldn't a psychedelic hallucinogen (5-HT2a partial agonist) work to ultimately improve odds of recovery?

What about salvinorum a? After the main experience, to be clear.

From what literature exists, what about mu/delta agonists on negative symptoms? We know that opioids are anxiolytic, but if this effect remains constant after tolerance development, well I doubt literature on this exists. Guesses/ideas?

There is some evidence that an AP that tightly (relatively) binds to D2, like Haldol, and a stimulant, could work to reduce negative symptoms, and if nothing else, cognitive symptoms (dividing the two for clarity, though some feel that the cognitive symptoms are separate fromt he negative symptoms).

CBD has literature behind it, but as I understand, as an adjunct. DOes anyone know how it works in this manner? FAAH/FAGL inhibitor? CB2 agonism itself can boost the immune system but it's not powerful enough on its own to create this effect. It also has been shown to improve depression singularly, which is not something we hear a lot with extant antipsychotics.

I'd say that in the next decade or so, when weed becomes legal, there will be many, many other phytocannabinoids with such versatile applications.

Getting off topic a bit here, but how does artane work in the brain? People call it potentially abusable. I think it increases D1/D5 neurotransmission, effectively reducing cognitive (and likely negative) sympotms.

I don't understand how benzos and GABAergic mood stabilizers don't work directly against psychotic symptoms, as the Glutamate:GABA ratio is lowered so that there is effectively more GABAergic activitty than glutamatergic action in the brain, too much glutamate being somewhat responsible for manic/psychotic effects. And lets not forget that they are the main excitatory/inhibitory nt's in the CNS.

Not really coming up witha nything else...oh wait: hydergine. Ergoloids, whcih are used mostly for headaches, seem to have some diverse dopaminergic activity. On a different level, microdosing for this population could again, as stated before, empower the thinking part of the brain over the regions that pass along the "fear" message.

Theanine. I forgot. It is both GRAS and is supposed to be really beneficial to the brain of those with schizophrenia. I couldn't get through my second semester of college without it. It's a light GABAergic, but there must be more. hmmm...


Jun 9, 2013
Well SEP-363856, purportedly a 5-ht1a and TAAR agonist, got a breakthrough designation. Interesting to see where TAAR agents will go.

GPR139 is an intriguing target, especially in co-localization with DRD2. (See TAK-041).

Selective muscarinic (e.g. KarXT) and selective mGlu drugs are coming up, though the mGlu2/3 partial one didn't fully meet some expectations. The muscarinic aspects of artane may play a part, but it does have all that DA stuff. I think people who have tried out some muscarinic drugs could see there being some room to work there

PDE selective agents have a habit of looking promising but running into trouble, haha. Like PDE10, PDE9, PDE1.

Nicotinic receptors, all those a7 drugs, gotta have some agent there at least for cognitive symptoms.

Did Biogen pick up that AMPA receptor modulator for cognitive symptoms? I believe it did. I'm still waiting to see about major glucocorticoid and retinoid receptor drugs, though that estrogen receptor drug I think was halted for schizophrenia?

Optimizing some of the known targets can still generate quite valid drugs. We'll see how pimavanserin will do, 5-ht2a inverse agonism.

Lumateperone has interesting postsynaptic d2 antagonism with partial agonism of presynaptic d2, but also has some other targets (5-ht2a, SERT) so could match some of the other AAPs. Relative D2 or D3 agents may be possible but cross-targets can be hard.

D-serine had a couple of good trials there, though I wonder where that DAAO inhibitor went?

Weirdly the second one seemed to be accessible even though the pdf was not. Modafinil still has had mixed results- definite promise in some and then limited in others, and positive switches are still possible.

I think there is some debate between augmentating APs as they are now with say, stimulants like modafinil, and reducing doses / changing to a more partial drug.

Speaking of opioids, dxm-quinidine has popped in as an investigation route, even a deuterated version. If someone told me DXM was going to be used for schizophrenia research, I would have guessed more like a model a la PCP than a treatment option.


Oct 12, 2016
I believe artane is a muscarinic antagonist that is supposed to balance the imbalance of cholinergic-dopaminergic signaling in the areas of the brain involvent in movement.


Bluelight Crew
Jul 21, 2002
Theanine. I forgot. It is both GRAS and is supposed to be really beneficial to the brain of those with schizophrenia. I couldn't get through my second semester of college without it. It's a light GABAergic, but there must be more. hmmm...
It's an NMDA agonist, perhaps underlying its usefulness for the disorder..

I used it with suprising effectiveness to kill a dissociative trip, which prompted me to wonder of its possible utility in the treatment of schizophrenia.