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Pramipexole (Mirapex) for anhedonia and negative symptoms?


#1

I was wondering if anybody had tried a dopamine agonist like Pramipexole to treat their negative symptoms, especially lack of motivation/pleasure, also called anhedonia. Interestingly, Vraylar’s (cariprazine) main mechanism of action is the potent partial agonism of the dopamine D3 receptors and according to studies, that would explain why this antipsychotic is more effective at treating negative symptoms than any other medication on the market. Abilify also is a D3 partial agonist although much weaker than Vraylar.

Dr. Jan Fawcett has been treating refractory (treatment-resistant) depressed and bipolar patients with pramipexole for several years and has reported his very promising findings in the article below. It mainly focuses on anhedonic patients. Importantly, finding the right dosage seems to be key (some needed much lower dosages, some needed much higher dosages)

Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression
http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2015.15060788
Here’s an excerpt from the article
Dopamine agonists, such as pramipexole—a relatively selective dopamine D3 receptor agonist—are thus potential treatments for depression, especially anhedonic depression. D3 receptors are found in the mesolimbic system, which in turn has been implicated in the motoric and hedonic deficits in depression (9, 10). Parkinson’s disease (22, 23) is associated with dysfunction in the dopamine systems. In fact, among the 45% of Parkinson’s patients who suffer from depression, anhedonia is a prominent symptom (24, 25). Both the depression and the anhedonia are frequently reduced with pramipexole (24–26).

It was once tried in schizophrenia patients and resulted in improvements ranging from 22 to 62% as you can see in the article below.


Negative and cognitives getting worse update
#2

I had some luck with Abilify treating my negative symptoms, but they eventually had to take me off the drug because it got me a little too amp’ed up.


#3

https://www.ncbi.nlm.nih.gov/pubmed/?term=pramipexole+schizophrenia


#4

What about buspirone? (Anxiety drug, mostly)

Pierre Fabre has a D3 drug in development too. (I actually wrote to them about it but they wouldn’t say anything because it’s in development.)

http://www.pharmavoice.com/newsreleases/pierre-fabre-laboratories-announce-promising-results-phase-iia-clinical-trial-f17464-schizophrenia/


#5

Lack of motivation and pleasure seem to be regulated by the mesolimbic dopamine system, not by the mesocortical dopamine system. Buspirone and Pierre Fabre’s new drug increase mesocortical dopamine, not mesolimbic dopamine.

It seems like increasing mesocortical dopamine is beneficial for those suffering from cognitive symptoms mainly (as they stem from prefrontal cortex functioning abnormalities).

In my case, the only three drugs that have increased my motivation and ability to derive pleasure have been amphetamines (vyvanse), coffee, and ritalin (they are not sustainable/long-term solutions though). All three act on the mesolimbic dopamine system, not mesocortical…In fact, all drugs of abuse act on the mesolimbic dopamine system…

My theory is that all those studies that claim to have found improvement in negative symptoms using drugs that increase mesocortical dopamine actually count cognitive deficits as though they were negative symptoms…

http://psychopharmacologyinstitute.com/cns-receptors/5-ht1a-receptors/


#6

Thank you for the very informative reply.

According to wikipedia, buspirone does have a strong D3 effect as well. " Buspirone has also been found to bind with high affinity to the D3 and D4 receptors (Ki = 98 nM and 29 nM, respectively).[39]"

Perhaps this bodes well for MIN101 and ITI007.

Eta I know some people with GAD but not psychotic illness who swear by this drug. They just make it sound like a godsend… I wish I could find a godsend. My anxiety is so bad.


#7

Interesting, although it’s far from being comparable to the D3 binding affinity of Pramipexole which is Ki = 0.5 nM (the lower it is, the stronger it is).

Just for comparison purposes, Vraylar and Abilify’s affinities at D3 receptors are 0.085 and 5.4 respectively. The difference between Pramipexole and Vraylar/Abilify is that prami is a full agonist, not a partial agonist. From my limited understanding of pharmacology, I think that full agonists increase neurotransmitters activity much more significantly than partial agonists.

As far as Min101 and ITI007 are concerned, their mechanisms of action do not indicate that they can increase mesolimbic dopamine activity, although both seem to improve negative symptoms in studies. I suspect that once again criteria for evaluating negative symptoms have been to loose (e.g. failing to differentiate improvements in cognitive deficits and comorbid depressive symptoms from pure negative symptoms). I hope I am wrong.


#8

I was thinking more of their 5HT1A properties, but, as you pointed out, it’s complicated.

Eta sorry, looks like that’s 5HT2A. Sigh. Maybe one of these days they’ll be able to say what to take based on a blood test or brain scan.


#9

Yes it’s complicated although as of today there is enough evidence to associate dysfunctional dopaminergic system to deficits in motivation and pleasure for example…But we still have a long way to go to understanding fully what’s going on in the brain of someone suffering from a mental illness, let alone why it is happening… My pdoc is completely clueless with regards to neuroscience…She prescribes medications yet hardly knows how they truly affect neurotransmission. Most psychiatrists seem to only have had introductory level courses in neuroscience and pharmacology and that’s a shame

Fairly advanced brain scanning techniques exist, but are kept for research purposes only. They are not integrated into psychiatry practice and that’s really a shame too.

On top of that, new medications take decades to reach the consumer market, sigh indeed…


#10

@szsurvivor what med are you on?
you seem to be doing very well cognitively.


#11

I am currently on no medication as all were ineffective for what I suffer from. My cognition was never impaired luckily. I struggle with motivation and pleasure, to the point where I think about ending my existence everyday. If you can still experience pleasure from listening to music, watching movies, eating good food, and socializing with friends and have drive/motivation to accomplish trivial tasks like cleaning dishes, consider yourself lucky nonetheless…


#12

This drug might work on people that have no history of positive symptoms and/or are able to tolerate methylphenidate kind of drugs. For those who had it , taking Pramipexole would be risky in aggravating positives acting as a dopamine agonist of D2/D3. And I’m one of last group, though, nice find. (Might take the risk in the future, first going to trial Memantine and/or Memantine + Galantamine.)


#13

What puzzles me is that Rexulti (brexpiprazole) has significant affinity for the D3 receptor as well (Ki=1.14), higher than Abilify, and I was on it for 8 weeks at the highest recommended dose and did not feel any improvement of my negative symptoms…

My only hope is that Pramipexole’s affinity for D3 receptors, which is even higher than that of Rexulti, will make a difference. Also the fact that Prami is a full agonist rather than a partial agonist might be significant.

I’d try Vraylar, which has the highest D3 affinity of all, but it’s not available yet in Canada


#14

I’ve been suggested to take Brexi + Memantine as the most beneficial combo on both negatives and positives because of Brexi being the first SDAM - Serotonin Dopamine Activity Modulator, however I do not know why this might work better than taking it with a atypical. I’ve also didn’t research Brexi because it’s not (yet) approved in Europe and won’t be until somewhere in 2018/2019.

Anyway, maybe the affinity of Brexi at D3 is higher on a low dose, have you tried that? I’m also waiting for Vraylar, it’s approved in May this year in Europe but it’s still not on the Dutch market.

If you can tolerate methylphenidate and/or other dopamine agonists without aggravating positive symptoms I would say go on and trial Prami.

(I’ve obtained Memantine through a pharmacy in a foreign country but my dad, who got it for me, is being a dick about giving it to me because I’m a regular alcohol drinker :smiley: ass)


#15

And Prami or the results from the study is quite interesting, a change/improvement of 62% is a life-changing number!


#16

Here’s the table from the full article of Pramipexole adjunctive to Haloperidol showing differences in PANSS scores for the 15 patients included in the study… Looking at the Negative Subscale, the scores are interesting indeed. What bothers me though is that the PANSS negative subscale includes things such as Stereotyped Thinking, Lack of spontaneity and flow in conversation, Poor rapport, and Difficulty in abstract thinking which could all potentially be partly explained by positive symptoms or cognitive symptoms and may hardly have anything to do with motivational and hedonic deficits specifically. Patients could have improved in those aspects and it would already have dramatically reduced their PANNS-Neg. scores…They don’t break down individual negative symptoms improvement so it’s always difficult to conclude anything. But again, Prami has successfully been used in treatment resistant depression and parkinson’s with anhedonia so that is still encouraging. One thing to note also is that in the Haloperidol-Pramipexole study they’d increase Pramipexole dosages to as high as 10.25mg/day, whereas in the TR-Depression and Parkinson’s studies they’d only go as high as 5mg/day I believe.

Here’s a link in which the individual PANSS subscales items are explained if anybody’s interested.
http://egret.psychol.cam.ac.uk/medicine/scales/PANSS


Negative and cognitives getting worse update
#17

I was on Wellbutrin which is a dopamine agonist (kind of, it also increases dopamine) but it did literally nothing for me except aggravate my positive symptoms


#18

This new drug is actually a 5HT1A agonist.


#19

@twinklestars

5-HT1A agonist drugs, as well as 5-ht2a antagonist drugs, increase dopamine in the prefrontal cortex, 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)…


#20

For anyone interested in pramipexole, I contacted the famous psychiatrist in the US known to use it for treatment-resistant depressed and bipolar patients suffering predominantly from anhedonia. Here’s his answer, which is encouraging, , followed by my original email:

From Jan Fawcett ( jfawcett@salud.unm.edu)
​"Charles - Pramipexole is reasonably successful (nothing works all the time) look in my article for the response rates and duration of follow-up. I dose it all at night (as explained in my publication) I have followed patients up to 6 years without a relapse. Stimulants added to MAOI medications (Fawcett 1991) don’t seem as likely to develop tolerance, but it is difficult to get patients off of stimulants without a relapse. Re-read my paper and most of your questions will be answered. There are side effects in some cases. Jan Fawcett"

My original e-mail:
"Hi Dr. Fawcett, I suffer from anhedonia very badly and recently found out about pramipexole (I found your articles and youtube conference). However, I was wondering about two things:

  1. How successful does it seem to be? Meaning, does it help only SOME anhedonics, or nearly all? And if so, do the benefits seem to be long-lasting? (or do many patients eventually develop tolerance to pramipexole?)

  2. Do you recommend dosing it 3 times a day, or 1 time a day? (in some article you say one time, in others you say 3 times a day)

Lastly, I know you also prescribe stimulants to anhedonic patients but from what I’ve read there is definitely a risk of developing tolerance to the effects and therefore a need to constantly increase the dose to maintain the benefits. That said, I invite you to look at the scientific and anecdotal reports of people using nmda antagonists like memantine along their opiate and stimulant use to prevent tolerance. Thank you, Charles"

The article he is referring to is the first article of the two that I linked above in my original post. Here’s another article I found which he wrote which you can also look at (it’s the one that caused me to be unsure about the dosing schedule. In it, you see he starts by giving pramipexole T.I.D (thrice daily) and then later ends up giving it HS (at bedtime/once a day) Here’s the link for that article:
https://www.healio.com/psychiatry/journals/psycann/2016-8-46-8/{b63a041d-8eec-4b17-bae0-99b8d1f34913}/dextroamphetamine-and-pramipexole-combination-for-treatment-resistant-unipolar-depression

You can also have a look at the youtube webinar in which he describes in some detail successful cases he’s treated with pramipexole. Here’s the link for that one:
-https://www.youtube.com/watch?v=jHA-Gu0ZtMQ&t=2837s


New Treatments for Negative Schizophrenia Symptoms Stir Debate