New Treatments for Negative Schizophrenia Symptoms Stir Debate

Lu is for treatment resistance sz right…

Yes, although depending on the side effect profile and real world effectiveness it might be used in more people.

It’s supposed to be much safer than clozapine.

Based on the statements below that I’ve copy pasted from the article, we shouldn’t put too much hope on min-101… Although, when I emailed Minerva they told me that min-101 had improved anhedonia, a key negative symptom, in the clinical trials…But it is true that pharmacologically, it has nothing new to offer, and I don’t see how it would improve deficiencies of dopamine in the region responsible for feelings of reward/motivation

"However, Dr Lieberman isn’t impressed. “Sometimes, when results seem to be construable as positive, a compound gets advanced. And that’s the case with this one from Minerva,” he said.
“It’s ultimately not going to produce any scientific or clinical value based on the compound’s pharmacology. There’s no clear rationale for why it would be therapeutic for negative symptoms. And there’s nothing from the preclinical and clinical data that gives me even a modicum of hope.”

"To show real efficacy for a potential therapeutic treatment, secondary negative symptoms from psychosis need to be separated from primary negative symptoms. “And the study that was done by Minerva didn’t demonstrate that in a conclusive way,” said Dr Lieberman.

“Overall, I’d say we’re still at ground zero, or square one. It’s not that all hope is dashed, but it is caveat emptor. This is a worthy goal to pursue, but we have not yet found the key to unlock the pathology.”

If MIN-101 improves anhedonia, it’s better than nothing. I don’t think a med that don’t act on glutamate will work for negative symptoms for me. Memantine is doing a great work and I believe that they should focus their research on glutamate modulation.

Which article is that from? If the one posted above (I don’t have a login for that site) that is from 2011. So there is more data available now than there was then.

MIN 101 acts on 5HT2a and sigma 2, and alpha 1 adrenergic receptors, without any direct action on dopamine. If it modulates dopamine indirectly, that could be an explanation of the effect.

It’s from the article posted by SzAdmin:
which was published in august 2017, not 2011

It’s got to be an indirect effect on dopamine, and not dopamine in the prefrontal cortex, but dopamine in the ventral striatum, the area that is hypoactive (underactive) in anhedonic people. Otherwise, my worry would be that that the improvements that they claim to have seen on anhedonia scores, would come from people who would complain of not being able to experience pleasure (anhedonia) because of depressive thoughts, cognitive problems, or psychotic reasons. In my case, I have none of those, and I am still not able to experience pleasure. I have pure negative symptoms and those are the ones that we need treatment for. Basically, since min-101’s main mechanisms of action do not appear to directly affect dopamine transmission, but yet they claim to improve negative symptoms, like anhedonia, I believe that there’s a great chance that they have poorly done the evaluation of negative symptoms and included people with non-pure negative symptoms. And I believe that there’s a slim chance that there’s a miraculous unknown indirect mechanism of action that actually treats hardcore persistent anhedonia. Min-101 supposedly treats positive symptoms also, and positive symptoms are thought to originate from an overactive dopaminergic system. And for that reason I just don’t see how it could treat both positive and negative symptoms at the same time. Abilify, Rexulti, and Vraylar are dopaminergic partial agonists which means that they will theoretically increase underactive dopaminergic systems, and decrease overactive systems, depending on the case, but min-101 is not a partial agonist and therefore should not have that kind of versatility as far as I know…

Anyways, the fact that doctor Lieberman doesn’t see how it could work either has me worried.

Unfortunately I don’t have a login for that site, so I don’t really feel that I can respond adequately, except to say that as far as I know, they have not identified a clear origin of negative symtoms. In the world of antidepressants, for instance, they are not all SSRIs, and it is also not clear that a lack of serotonin is the problem (partial evidence for this is that antidepressants typically take 6 weeks to work, but receptor occupancy occurs quickly.) I know it’s not the same thing, I just say this to show that in some psychiatric illness, like depression, there is more than one way to have an effect, and even with the various methods of action of antidepressants, we don’t really understand why some work for some people and others don’t.

If they have identified a clear origin of anhedonia and I missed it, could you please link to the study?

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Just thought I would add that the folks at Minerva have decided in their phase 3 to use the Marder scale for negative symptoms, so I tried to see how that measurement works, but I didn’t get much.

I did find this paper, it’s long, but you can skip down to anhedonia.

It seems to suggest that improving motivation and episodic memory might improve anhedonia.

As far as how Minerva says it works: “MIN-101 is meant to block a specific subtype of serotonin receptor called 5-HT2A. When 5-HT2A is blocked, certain symptoms of schizophrenia, such as hallucinations, delusions, agitation and thought and movement disorders, as well as the side effects associated with antipsychotic treatments, can be minimized. Additionally, blocking 5-HT2A promotes slow wave sleep, a sleep stage often disrupted in patients with schizophrenia.
Importantly, MIN-101 is also meant to block a specific subtype of sigma receptor called sigma2, which is involved in movement control, psychotic symptom control and learning and memory. Blocking sigma2 also modulates other neurotransmitters in the brain, in particular dopamine, which is important as individuals with schizophrenia often have elevated levels of dopamine in their brains. Blocking sigma2 also increases calcium levels in neurons in the brain, which can improve memory. Recent literature has also indicated that a sub-type of progesterone protein complex might also be a putative binding site for sigma2 receptors and might explain the effects on cognition of MIN-101.”

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Thank you for sharing this article.

Yes I agree that in general when it comes to mental illnesses nothing is simple. I agree that the lack of serotonin theory intuitively doesn’t make sense since SSRIs increase it from the very first dose yet it takes weeks for the antidepressant effects to kick in. However, this is not the case with the “antidepressant” effects of dopaminergic substances like ritalin, amphetamines, and even coffee. The effects, which are on motivation and pleasure, are felt immediately and there’s a clear rationale as to why this is the case. Those substances all increase mesolimbic dopamine (ventral striatum dopamine) and this is in fact exactly what makes those substances potentially addictive: the mesolimbic dopaminergic system is the main reward pathway of the brain. Scientists have known this for a long time now. Speaking from experience with those 3 substances, and also having read many testimonials of anhedonic people using those substances to find temporary relief, it is safe to intuitively conclude that there’s a dopaminergic dysfunction in that specific region of the brain, the pleasure and motivation region, in anhedonic people. As far as I know they haven’t yet found the reason behind the dysfunction itself in people who suffer from depression and schizophrenia, they are only able to observe the hypodopaminergic state. Here are 2 other relevant articles on anhedonia in schizophrenia, and anhedonia in general:

This one talks about ventral striatal underactivity in apathy (of schizophrenia), which they define as avolition/anhedonia/asociality, and which they differentiate from blunted affect and alogia at the neurobiological level.

The one below is one of the most comprehensive articles that I have found on anhedonia. An interesting point that they mention is the fact that endogenous opioids, which are also highly present in the ventral striatum, are also involved in the hedonic/pleasurable experience. Just like in the article that you shared, they highlight the fact that in the recent literature, scientists have started to divide the anhedonia into 2 categories, motivational anhedonia (lack of anticipation of reward), and consummatory anhedonia (lack of “in-the-moment” pleasure). Motivational anhedonia would be linked to dopamine, and consummatory anhedonia would be linked to endogenous opioids according to the latest research.

Furthermore, I participated in a research project involving an fMRI scan of my brain and I am waiting for the results, which I will share with you all once I have them. During the fMRI, they had me do a “game” in which I could win real money, which should have technically activated the reward system of my brain. In the article that you shared they say that schizophrenics with anhedonia only suffer from motivational anhedonia, and not consummatory anhedonia. Well I’m schizophrenic and CLEARLY suffer from both…They also talk about schizophrenics suffering from anhedonia possibly because of cognitive functioning (impaired episodic memory interfering with subject’s ability to recall previous pleasant experiences)…well that’s clearly not my case either…I think it’s gonna be great to see my results from the scan to clarify all this once and for all.


Very interesting about lovingkindness meditation.

Thanks for those great articles, have you tried the amino acid they mentioned?

“A significant reduction of anhedonia in patients receiving ALC at 1 and 3 g/day was found. In conclusion, the results of this study indicate the efficacy and safety of ALC in the treatment of anhedonia, melancholia, and negative symptoms in anhedonic alcoholics after 10 days of intravenous therapy. Accordingly, ALC may be considered as a new potentially useful drug for the treatment of anhedonia.”

I suspect that Minerva knows thru SPECT or PET studies in what areas of the brain dopamine is modulated by their drug - but they haven’t published anything, so far as I’m aware.

I guess another one to watch will be F17464, since that is supposed to indirectly control dopamine release in VTA neurons, and “increase the mesocortical pathway” whatever that means.

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I tried loving kindness meditation and it’s a very pleasurable thing to do. I was in a state of complete bliss for a while after each 10 minute session. Did a month of 10 minutes per day and was doing things like really enjoying the feel of the bed sheets lying in bed after waking up etc, hadn’t been doing that previously. It definitely gives a pleasure and energy increase generally.

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People say lack of dopamine in mesocortical tract causes sz…right sis…!!! And…

Sep856 is another drug to watch on…!!!which is both benificial to positive and negative symptoms…!!!

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Line breaks?


I haven’t tried ALC (also known as ALCAR)…I might try it eventually. In the article it was initially given intravenously, which might be a more powerful way to use it than orally, and it was for anhedonia induced by alcohol withdrawal, which might be different from anhedonia caused by depression or schizophrenia

As for F17464 here’s a copy of my comment on the pramipexole post regarding drugs that increase mesocortical dopamine (prefrontal cortex dopamine):

“5-HT1A agonist drugs, as well as 5-ht2a antagonist drugs, increase dopamine in the prefrontal cortex (mesocortical pathway), not in the reward center of the brain (which is also known as the mesolimbic dopamine pathway)… The original theory that negative symptoms originate from a mesocortical (prefrontal cortex) dopamine deficiency doesn’t hold true for those that suffer specifically from anhedonia. My belief is that they loosely counted people suffering from cognitive deficits (which are thought to stem from prefrontal cortex dysfunctions) as people suffering from negative symptoms (i.e. they put cognitive deficits and negative symptoms in the same basket) when they first came up with the mesocortical dopamine deficiency theory of negative symptoms… Take Abilify, Seroquel, Olanzapine, and I think pretty much all of the atypical antipsychotics for example, they are both 5-ht1a agonist and 5-ht2a antagonists and clearly they do nothing for the majority of people with anhedonia and negative symptoms unrelated to any sort of cognitive dysfunction…Although on paper, and for marketing purposes, it looks good to say that atypical antipsychotics correct the chemical imbalance (mesocortical dopamine deficiency) and therefore improve negative symptoms… When I first met my pdoc she told me right off the bat that they didn’t have any effective medication for negative symptoms and the solution was to do exercise and behavioural activation, yet if you look on the website of abilify and all atypical antipsychotics they will claim that they all work for negative symptoms (by increasing mesocortical dopamine)…”

I invite anybody suffering from anhedonia to have a look at the pramipexole post. It’s one of the most promising treatment that I have found so far for anhedonia… (Pramipexole (Mirapex) for anhedonia and negative symptoms?)


Pramipexole (Mirapex) for anhedonia and negative symptoms
Is it new anti deprassant…

No it’s an “old” medication used for parkinson’s disease @far_cry0

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Does it work for anhedonia…

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Yes possibly! I did not try it myself yet

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Keep us posted. It increases dopamine, hence its use in Parkinson’s … but I suppose it depends on the individual.

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