# ALKS 5461



## Jackk11 (May 9, 2018)

Tomorrow the FDA will decide on whether or not to approve ALKS 5461. It is not likely that it does get approved however if it does this is huge for DP sufferers. Considering Yuri Nullers highly successful Naloxone study, it is likely that KOR antagonism could be the answer to MANY of our problems. Everybody keep your fingers crossed. God bless.


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## Aridity (Jun 12, 2011)

Could you further elaborate as to why exactly this medication would be a great for us?


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## Jackk11 (May 9, 2018)

Aridity said:


> Could you further elaborate as to why exactly this medication would be a great for us?


 it has been speculated that antagonism of the Kappa Opiod Receptor could be very effective in the treatment of DP however this is nearly impossible to selectively antogonize because you would need extremely high doses of naltrexone or nalmefene. A study in 2000 backed up this claim when Yuri Nuller administered Naloxone intravenously to his patients and yielded something like a 60% response rate. This rate could be even higher with ALKS 5461, the first market KOR antagonist.


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## Aridity (Jun 12, 2011)

that's great to bad Yuri is dead.


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## Jackk11 (May 9, 2018)

Yes it’s a shame however I know of a fellow DP sufferer who is going to write ALKERMES (the drug manufacturer of ALKS 5461) to do a studies on DP with ALKS 5461 if it is not approved for depression.


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## Broken (Jan 1, 2017)

I imagine it will get rejected. I do think the reason that THC causes the symptoms of DP (or did with me when I was high) is because it acts on the kappa opioid system:

https://www.researchgate.net/publication/320744792_Antagonism_of_the_kappa_opioid_receptor_attenuates_THC-induced_place_aversions_in_adult_male_Sprague-Dawley_rats

A study on rats showed THC affects were affected by a kappa opioid antagonist. It's believed that CBD has opposing effects to THC and I have found this to be true in my experience. CBD has helped me relax and sleep better, and fingers crossed long term it may help my DP symptoms


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## Jackk11 (May 9, 2018)

Broken said:


> I imagine it will get rejected. I do think the reason that THC causes the symptoms of DP (or did with me when I was high) is because it acts on the kappa opioid system:
> 
> https://www.researchgate.net/publication/320744792_Antagonism_of_the_kappa_opioid_receptor_attenuates_THC-induced_place_aversions_in_adult_male_Sprague-Dawley_rats
> 
> A study on rats showed THC affects were affected by a kappa opioid antagonist. It's believed that CBD has opposing effects to THC and I have found this to be true in my experience. CBD has helped me relax and sleep better, and fingers crossed long term it may help my DP symptoms


 I believe it will get rejected as well. But this leaves them open to the suggestion that they could do studies for depersonalization. I imagine that there investors won't be very happy so Alkermes may want to take their drug in a different direction.


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## Aridity (Jun 12, 2011)

I HOPE IT GETS FUCKING APPROVED


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## Jackk11 (May 9, 2018)

Aridity said:


> I HOPE IT GETS FUCKING APPROVED


I agree. This means that we can get it covered by insurance providers. It's a long shot but we will see.


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## Jackk11 (May 9, 2018)

Well I dont know if anyone kept up with the news but it was not approved. They are still pushing forward with studies on depression though and they are conducting studies in many locations throughout the USA. I contacted the people in charge of the study requesting to be a part of the ongoing clinical trial so I might be able to get my hands on the drug.


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## Jackk11 (May 9, 2018)

https://www.clinicaltrials.gov/ct2/show/study/NCT03188185?term=ALKS-5461&recrs=ab&rank=1&show_locs=Y#locn if you live in the us and want to give it a shot here you go.


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## Messirocks (May 29, 2019)

Did you improve


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## seanob (Jun 29, 2019)

I used naloxone and it didnt help me. I still have one injector left.


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## teal (Oct 9, 2019)

Jackk11 said:


> I contacted the people in charge of the study requesting to be a part of the ongoing clinical trial so I might be able to get my hands on the drug.


Did they write back? We should let them know a pilot study on DPDR is warranted. Just some twenty patients would go a long way.


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## 35467 (Dec 31, 2010)

Why is this thread even a debate? There have been several with heroin addiction and depersonalisation disorder who has been on suboxone/buprenophine with a very low respons as 20 -30% reduction in symptoms. It has a high antagonistic effect on the kappa opioid receptor . It is the kappa opioid system that can shot drown for emotions and the reward system to stress, anxiety and addiction other parts of the opioid system cannot do that so they are excluded. Drugs like naltrexone, nalmefeme and naloxone have either a very short half-life or a very low affinity for the kappa-opioid receptor. The trails done with these drugs where small, not repeated and 20-15.years old. They have never been replicated in larger trails but many on this forum has tried them with no to limited effect effect. Those who have tried drugs like suboxone has had a limited effect. Here is one that had a 20-30% reduction in symptoms with suboxone;

"I wouldn't do it if I were you. I have been on it long term. It's a serious drug. It's what they give heroin addicts to help during the withdrawal process. Most people don't stay on it long term. If you do stay on it long term and want to quit at some point a Suboxone withdrawal is 4x worse than an actual heroin withdrawal. I think it's insanely reckless that people on here are recommending Suboxone/Subutex for depersonalization treatment. These are people who in large have probably not tried it themselves and if so are just being guinea pigs. I highly doubt Suboxone is going to cure or help anyone with DP. If you want to try it that's your call, but if it doesn't help I wouldn't stay on it long term. "

https://www.dpselfhelp.com/forum/index.php?/topic/54131-suboxone/?hl=suboxone

But, depersonalisation is a disorder of cognitive regulation of emotions with many brainstructures involved. This emotional regulation emotions starts at the prefrontal cortex and one structure can use dynorphin in the inhibition of anxiety, stress and addiction is the medial prefrontal cortex and it has been found to be active with other structures in the prefrontal cortex in functional brain studies of depersonalisation. So, emotional inhibition is also done by other structures in the prefrontal cortex that will not be affected by a opioid antagonist. But, these debates are kept alive by ignorants . You can inhibit that response in the medial prefrontal cortex with rTMS and some trails have done it in with people with cocaine addition. But, the right ventrolateral prefrontal cortex that is active in emotional regulation might not be a supressor by itself but likely to mobilised other structures in the prefrontal cortex to regulate emotions. To use rTMS at the right VLPFC will inhibit the instruction to regulate emotions given to other areas in the prefrontal cortex including the medial prefrontal cortex. A selective kappa antagonist if it existed would not cure depersonalisation disorder. It would likely give a reduction in symptoms of 20-30%

The role of the ventrolateral prefrontal cortex but also the angular gyrus in cognitive regulation of emotions can be read here.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801480/


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## teal (Oct 9, 2019)

Mayer-Gross said:


> Why is this thread even a debate? There have been several with heroin addiction and depersonalisation disorder who has been on suboxone/buprenophine with a very low respons as 20 -30% reduction in symptoms.


If there were a study on DPDR showing a 20-30 % reduction in symptom severity following ALKS 5461 treatment, then that would be valuable, if not as a treatment then as a clue to which mechanisms are at play.

It would also be valuable to repeat the Russian study on Naloxone, seeing how many would benefit and to what extent. If it'd have no effect on all, that would also be a clue. At the time of writing the British Medical Journal writes the following about treatment of DPDR
"A study of lamotrigine as an adjunct therapy reported dose related benefits, as did studies using opiate antagonists"

https://www.bmj.com/content/356/bmj.j745.full


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## 35467 (Dec 31, 2010)

Totally irrelevent. The right VLPFC cortex that is active in depersonalisation works as a switch to other regions in the prefrontal cortex. We know that from basic research of different areas in the prefrontal cortex and functional studies of depersonalisation disorder. To inhibit the right VLPFC with rTMS will stop all inhibitions of emotions by the all areas of prefrontal cortex, including those areas that works though the opioid system. To inhibit the right VLPFC reduces depersonalisation with 45% on average -especially emotional numbing -but not dissociation.

The study with lamotrigine only mentions a reduction of 30% in 56% of those who tried. On this forum i would say that the response rate in lower among those who have tried.


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## teal (Oct 9, 2019)

Mayer-Gross said:


> The study with lamotrigine only mentions a reduction of 30% in 56% of those who tried.


And this was as an adjunct to an antidepressive, I suppose. Which doesn't say much about lamotrigine monotherapy.



Mayer-Gross said:


> To inhibit the right VLPFC with rTMS will stop all inhibitions of emotions by the all areas of prefrontal cortex, including those areas that works though the opioid system. To inhibit the right VLPFC reduces depersonalisation with 45% on average -especially emotional numbing -but not dissociation.


I take it it's this study you're referring to. "20 sessions of rTMS treatment to right VLPFC significantly reduced scores on the CDS by on average 44%" It does look promising. Even though it's based on only seven patients.


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## 35467 (Dec 31, 2010)

There was a trail with lamotrigine as mono-therapy prior to that without any response.https://www.ncbi.nlm.nih.gov/pubmed/12680746

Yes, the sample size is small. They didn't have any funding for a larger trial. Since 2016 there has been no funding for research at the depersonalisation research unit. Staff is highly reduced.

But, we have functional studies of depersonalisation disorder and we have basic research into models on how the brain regulates emotions. So, we have an idea of the role of the right VLPFC is. We also know that numbing and dissociation might involve two related networks and that is the reason that people can get numbing reduced but not dissociation or dissociation reduced but not numbing.

Here is one who had rTMS done a the right VLPFC after mapping with a MRI-neuronavigation was used;

"So today, my VLPFC was targeted at 1HZ per second I believe? Point is, it fucking worked. Probably a 20-30% reduction in numbness. I particularly noticed when I was driving I looked at the clouds-and they looked like they used to. Really. I have tried tons of meds, and none of them has ever produced an effect remotely close to what I'm experiencing now. There really is something to this, and I'll definetly be continuing with more sessions. More to follow!"

https://www.dpselfhelp.com/forum/index.php?/topic/54723-starting-tms-next-thursday-over-tpj-and-vlpfc/?hl=vlpfc


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## 35467 (Dec 31, 2010)

The role of the right VLPFC in emotional regulation,- basic research.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742320/


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## teal (Oct 9, 2019)

Mayer-Gross said:


> Since 2016 there has been no funding for research at the depersonalisation research unit. Staff is highly reduced.


For heaven's sake!

Here we have a forum of 20.000 members. On Reddit there are 17.000 people following the subreddit for DPDR. According to population-based surveys the prevalence of DPDR is about 1-2 %. There ought to be clamor for research spending. But rather they've reduced the staff and cut the funding at the only research unit for DPDR. Hurray.

I've always thought the ME/CFS community have been utterly unsuccessful at getting enough attention and thereby funding for studies, but I guess with regards to DPDR it's another story entirely.










Basic research is good. I like basic research. But at the same time, I've seen time and time again that what's true in a model hasn't been successfully translated into effective treatment. It's very (!) good though that case studies and small studies support their findings.

Anyways. So here we have professional medical doctors, with a will to help a huge patient group, but who's had their spending cut. And we have private rTMS clinics, opting to give ineffective treatment, making money in the process.

If the people behind the private rTMS clinics aren't totally unscrupulous, then it would benefit all of us if they were matched with the researchers, getting them on the right path to offer better treatment for us all.


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## 35467 (Dec 31, 2010)

There is the first patient interest group for depersonalisation disorder in UK. They are just started but they have been in contact with politicians to get funding for research and more understanding of the disorder, so people can get the right diagnosis sooner.

https://www.unrealuk.org/aboutus


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## teal (Oct 9, 2019)

So, I've done some research and see that the costs of neuronavigation systems, including software, equipment and operative instruments ranges anywhere from $250,000 to just under $1 million.

For the sake of the example, let's say they charged regular prices, plus a premium of $2,500 for every treatment with neuronavigated rTMS. Then they'd need 100 patients to recover the costs if they went for the cheapest equipment, and 400 patients if they went for the most expensive.

We, as a people, have sent men to the Moon; we should be able to convince a clinic that this is the path to go. If everything fails, and fails miserably, they'd still have the machine to sell second hand. Or conversely, they could buy second hand equipment in the first place, cutting the costs and risks further.

Source for the claim for the costs for neuronavigation equipment.


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## 35467 (Dec 31, 2010)

Well your research is totally wrong. Neuronavigation is used in brain surgery and in rTMS. The cost your are giving is for brain surgery with operation equipment that can be calibrated for operation. Will you open our brains too with a russian doctor and someone who has replied to your mail in Lagos?

The cost of neuronavigation for rTMS is; . "We note that the cost of our set-up is much lower than many commercial systems in the market (<$5000 vs $50,000). Our results also showed that the tracking performance of the system was on a par with other high-end commercial systems"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738908/

Your assumption are also wrong. The reason there is not neuronavigation is because you do not need it for most disorders like depression or OCD. Localisation with the use of neuronavigation will also increase the cost for the patient with 500-700 euros- that is a cost 95% of patients can avoid because they don't need for location. rTMS is also relatively new on the private european market. From around 2017

You need neuronavigation for disorders that are very atypical for the normal rTMS clinic right now and are regarded as "off-label" because of the small trails done. You also need someone who are highly skilled into the publications into the disorder and understanding the basic research into cognitive regulation of emotions.

Such a person is not likely to find in a rTMS clinic but in a university as a researcher.


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## freezeup (Oct 1, 2016)

T



Mayer-Gross said:


> Totally irrelevent. The right VLPFC cortex that is active in depersonalisation works as a switch to other regions in the prefrontal cortex. We know that from basic research of different areas in the prefrontal cortex and functional studies of depersonalisation disorder. To inhibit the right VLPFC with rTMS will stop all inhibitions of emotions by the all areas of prefrontal cortex, including those areas that works though the opioid system. To inhibit the right VLPFC reduces depersonalisation with 45% on average -especially emotional numbing -but not dissociation.
> 
> The study with lamotrigine only mentions a reduction of 30% in 56% of those who tried. On this forum i would say that the response rate in lower among those who have tried.


Its a solution that could possibly work. I'm not sure why you're so against people trying lamictal, and in every other thread saying it wont work for them. Its worked for me after having chronic DP/DR for 9 years. Glutamate is a highy understated neurotransmitter that I feel for people with drug induced DP/DR is to blame. Hyper-vigilance,dissociation,OCD and depression are all correlated with glutamate dysfunction. Lamotrigine inhibits glutamate thus bringing back a balance to the brain.

Besides, any of this is just us bullshitting with hypotheticals. None of us have any idea why this is going on. The only real treatment is to try everything remotely viable and hope that it works.


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## 35467 (Dec 31, 2010)

freezeup said:


> T
> 
> I'm not sure why you're so against people trying lamictal, and in every other thread saying it wont work for them. Its worked for me after having chronic DP/DR for 9 years.


I have never spoken against the use of lamotrigine. I have just stated that only 50% have a response to it and the average reduction in symptoms it is around 30% in the response group. That is not to speak against it. I have tried up a dose of 500.mg without effect and never claimed that it wouldn't worked for others.


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## teal (Oct 9, 2019)

Mayer-Gross said:


> The cost of neuronavigation for rTMS is; . "We note that the cost of our set-up is much lower than many commercial systems in the market (<$5000 vs $50,000). Our results also showed that the tracking performance of the system was on a par with other high-end commercial systems"
> 
> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738908/


Alrighty then. That's good news. So even at the high-end it's affordable.



Mayer-Gross said:


> Localisation with the use of neuronavigation will also increase the cost for the patient with 500-700 euros- that is a cost 95% of patients can avoid because they don't need for location. rTMS is also relatively new on the private european market. From around 2017
> 
> You need neuronavigation for disorders that are very atypical for the normal rTMS clinic right now and are regarded as "off-label" because of the small trails done.


From your writings I knew the stuff about OCD and depression where you don't need neuronavigation for rTMS and so forth. The gist of my message was that it's achievable for someone to make an investment pay off. If someone got neuronavigated rTMS for DPDR in Europe, they'd be close to having a monopoly, and if they'd charge a premium, I wouldn't mind.

Doctor Kelley, with her private practice in Arizona, is able to offer her patients effective rTMS, according to the thread you linked to. If it's feasible for her ... I see Smart TMS has clinics in London, Birmingham, Manchester, Bristol and Havant. And they're soon opening a new clinic in Holborn. So it looks like their business is going well, well indeed. They write that «Studies show that DPD could affect one person in every 50 in the UK», so they know there are patients out there. They should have one clinic which specializes in DPDR, one of their five clinics in England. If each clinic has a high level of autonomy, one could get in touch with each of the five in sequence, explaining the high potential for neuronavigated rTMS, the feasibility of it, and that patients from Europe would flock there if everything went dandy.

What we need is at least one clinic willing to invest, and at least one researcher willing to give guidance, or become some sort of commercial partner.



Mayer-Gross said:


> Localisation with the use of neuronavigation will also increase the cost for the patient with 500-700 euros- that is a cost 95% of patients can avoid because they don't need for location.


700 euros for extra time spent is cheap. They don't have to spend extra time on all conditions, it's just to not use the neuronavigation machine when they've got a patient with say OCD or depression. That's no problem.



Mayer-Gross said:


> Will you open our brains too with a russian doctor


Yes. Yes, I would!

The number I dug up was slapdash, quick and dirty. I googled and pasted in a flash. But yeah, I would trust a Russian research institution to do neuronavigated rTMS-if the people there seemed skilled, trustworthy and wanting to learn more about DPDR. But Nigerian? Nope!


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## 35467 (Dec 31, 2010)

Teal

I have written to a clinic that has neuronavigation and among their founders are university researchers who have done several trials with rTMS with publications .They treat 13.conditions with rTMS. A professor has replied me that they are looking into the disorder and they are likely waiting for the publication of the french trail. I wish you good luck with your very interesting ideas .Have a nice trip to Russia.


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## teal (Oct 9, 2019)

Mayer-Gross said:


> Have a nice trip to Russia.


'Yes, yes I would' was an ironic answer to your snarky comment. You drew a picture of some doc Nick Riviera crossed with Bernie Madoff. It gave me a laugh, but it isn't necessarily what you'd find at a foreign research clinic, nor is Russia at the top of the priority list. The Russian clinic was chosen at random from a long PubMed list of researchers with access to neuronavigation and rTMS, because you wrote it was all but impossible to get treatment, even if you had a million bucks at your disposal.

What it takes is the will of an existing clinic to invest some fifty grand, plus the assistance of researchers. It's not a chimera. It's not impossible. My approach is to get everything on the table, and then adjust or dismiss options afterwards, instead of dismissing everything first. Sure, sure. I've seen private clinics where the docs wear Rolexes and offer experimental, ineffective and overpriced treatment.

I think the mentioned DPDR foundation could play a key role in working with the British rTMS clinics, lobbying for neuronavigation and cooperation with experienced researchers. Impossible is nothing.


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