News about neural signature of negative symptoms

patient · May 28, 2017, 8:32am

You did some good research lol, but ive read about it and if im right it only seems to help with anxiety and mood. I have differebt negative symptoms mine are like tired motivation and alogia.

patient · May 28, 2017, 8:34am

Im serious excited about min 101, but were iti 007 and encenicline also this promising or less?

Anon10 · May 28, 2017, 8:48am

Encenicline was going to be the first cognitive med. On top of that it seemed to have a surefire mechanism of action on paper. I was convinced it couldn’t not work.

As for iti-007, the reason to get on it is probably not for its efficacy. It is appealing because it is so safe compared to our current antipsychotics. So no metabolic syndrome and possibly much less tardive especially at lower doses. If Iti works for your psychosis you should stay on it for your own health.

The reason min-101 might work for negative symptoms is that it doesn’t have any direct dopamine blocking. That means, if the sigma 2 and serotonin 2a blocking increase dopamine in key areas then that is not blocked by the dopamine blocking. Minerva are using half an atypical antipsychotic without the half which might be stopping the other half from improving negative symptoms.

patient · May 28, 2017, 8:53am

But if you use lets say haldol will have min effect, because of the full dopamine blocking?

Anon10 · May 28, 2017, 9:33am

Depends on how far apart you take them. Haldol stays in your system quite a while. Chances are taking a strong D2 blocker with min-101 will decrease the effects of the latter on negative symptoms.

Good observation. I thought of this too. Usually if you take two of these types of drugs at the same time one will block some receptors and the other will go to the remaining ones which it then blocks. So it will be like you are on one antipsychotic.

Anon10 · May 28, 2017, 9:39am

It might have less of an effect on the negative and cognitive symptoms. More factors play a role, such as dosages and the nature of the treatee’s individual dysfunction.

It’s being tested as a monotherapy in the trials, meaning nobody knows exactly how it will react if used alongside other atypical or typical aps.

patient · May 28, 2017, 10:02am

So it might get to work for negs, but if it comes to positive symptoms it will be exciting, because there is a chance that it wont work for positive symptoms for some like every ap. If this is true i think that might be the reason why people dropped out of the trial, but its al speculation lol

Anon10 · May 28, 2017, 10:08am

Wow, you are really observant. Thanks for pointing that out, that so many people dropped out. Maybe Minerva are covering that up by drawing attention to the good results for those who remained.

Some people also brought up that the good results might just be from a “drug holiday” where people were taken off their normal antipsychotic. They said that might be the reason negative sx improved in some.

A lot of big gaping holes in the story, thanks for pointing that out, actually I guess @twinkle pointed it out.

patient · May 28, 2017, 10:14am

I didnt observed it by myself but i heard it on this forum, but coudl my theory be right?
And do you believe it that if people stopped with their ap that negs improved? In my case i just went nuts when i quitted.
But i sense you are a bit sceptical with min 101 right so i want to know what your view is on min 101?

Anon10 · May 28, 2017, 10:22am

I started out really skeptical, especially since iti-007 at lower doses didn’t improve negative symptoms much. Since they are similar (along with nuplazid) if one of these three does something for negative sx I would be convinced the others might.

There is also the issue of sub-optimal effectiveness for positive sx. Basically the current atypicals are effective (and a bit better than typicals) because they have a two or three pronged attack. Hitting dopaminergic, serotonergic and possibly adrenergic receptors (and maybe some others I don’t know). If you remove one of the heavy hitters (D2) you might find less people responding less to the new “antipsychotic”.

twinklestars · May 28, 2017, 4:57pm

Minerva says that positive symptoms remained stable - but presumably that would be in the patients who remained in the trial. (Edited to add, it actually says general psychopathology improved over the study period. But it doesn’t say by how much, if it wasn’t statistically significant, that would be why they would want to concentrate on negative symptoms to get it approved.)

I don’t know what the average level of dropouts is in sz trials.

The phase 3 trials will focus on people with predominately negative symptoms.

I think for some people, current meds add to negative symptoms but for others, it’s just the disease.

They are not testing MIN 101 in florid psychosis. Possibly it will be used in polypharmacy. It’s probably not going to act fast, the way Haldol or risperidone would to stop a psychotic episode, but over time, perhaps the brain’s chemistry could stabilize.

twinklestars · May 28, 2017, 5:09pm

Perhaps for people with both strong positive and negative symptoms they will investigate polypharmacy with future drugs like evenamide, naben, F17464, and CBD. I think they did find CBD as effective as amisulpride for positive symptoms without much in the way of side effects.

patient · May 28, 2017, 5:14pm

And are you excited about min 101 or a different drug?
Tnx for answering my questions btw

twinklestars · May 28, 2017, 5:21pm

I’m excited about them all, frankly.

Sadly, some of them will fail, but I do think some will succeed.

patient · May 28, 2017, 5:25pm

Do you have a thought about which med has the highest chance of getting approved?

Andrey · May 28, 2017, 5:43pm

What makes me lean toward a structural abnormality as the cause of the negative symptoms is the fact that they are very stable (at least in my form of illness), they don’t fluctuate in time. Whereas positive symptoms tend to dip and rise more.

twinklestars · May 28, 2017, 6:01pm

While there clearly is a structural difference, you may have had that since birth without overt symptoms. So something has changed, probably chemically. Although there’s no answers now, that could change.

twinklestars · May 28, 2017, 6:05pm

I’m guessing that sodium benzoate and CBD both have excellent chances since there has been a lot of study in addition to the phase 1 and 2 trials.

It’s harder to say with proprietary meds like MIN 101 and evenamide because not as much information is public. I think they have fair or better chances, but ultimately it will come down to the results of the trials.

twinklestars · May 31, 2017, 9:47pm

Maybe I should make a new thread for this, but since we discussed it earlier here the dropout rate on the clinical trial for MIN 101. It seemed very high, but I found this for a study on risperidone, which works, however much it may suck - a 60% dropout rate, with a higher dropout rate among the placebo group, for probably obvious reasons.

ncbi.nlm.nih.gov

Risperidone versus placebo for schizophrenia.

RD Rattehalli, MB Jayaram and M Smith, The Cochrane database of systematic reviews, Jan 2010 20

Risperidone is the first new generation antipsychotic drug made available in the market in its generic form.To examine the clinical effects of oral risperidone for people with schizophrenia and schizophrenia-like psychoses in comparison with placebo.We searched the Cochrane Schizophrenia Group's Register (February 2008), references of all included studies, and contacted industry and authors of included studies for relevant studies and data.Randomised clinical trials comparing oral risperidone with placebo treatments for people with schizophrenia and/or schizophrenia-like psychoses.Two reviewers independently inspected citations and/or abstracts, ordered papers, re-inspected and assessed the quality of results and extracted data. For dichotomous data, we calculated the relative risk (RR), the 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT), on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD).One study (n=599) compared risperidone against placebo but the attrition rate was 60% over a period of six weeks rendering most of the efficacy and global improvement data unusable. The attrition rate was higher for placebo compared with risperidone (n=1363, 10 RCTs, RR 0.70 CI 0.57 to 0.86, NNT 13 CI 9 to 29) and less participants left the trial in the risperidone arm due to lack of efficacy (n=888, 5 RCTs, RR 0.38 CI 0.20 to 0.73, NNT 7 CI 5 to 15). Risperidone was no better than placebo on the CGI global score (n=397, 3 RCTs, RR 0.80 CI 0.55 to 1.15) but significantly more number of participants in risperidone arm had more than 20% reduction in their BPRS/PANSS score (n=856, 7 RCTs, RR 0.43 CI 0.32 to 0.58, NNT 7 CI 6 to 10). Data became considerably more homogeneous (and positive) when the one study independent of industry funding was removed (I(2) 75% to 55%). Despite poor reporting, it is clear that around 24% of all participants receiving either risperidone or placebo developed some form of extrapyramidal effects (n=723, 5 RCTs, RR 1.40 CI 0.93 to 2.10). Three people on risperidone had prolonged QTc (n=198, 1 RCT, RR 7.5 CI 0.4 to 144), more on risperidone gained weight (n=303, 2 RCTs, RR 5.14 CI 1.79 to 14.73, NNH 10 CI 3 to 51) and had a raised prolactin (n=323, 2 RCTs, RR 12.54 CI 5.11 to 30.79, NNH 3 CI 2 to 5). Fewer in the risperidone arm needed an additional psychotropic during the trial period (n=186, 1 RCT, RR 0.62 CI 0.45 to 0.85, NNT 10 CI 7 to 28).Risperidone appears to have a marginal benefit in terms of clinical improvement compared with placebo in the first few weeks of treatment but data are limited, poorly reported and probably biased in favour of risperidone. The margin of improvement chosen by the researchers as their outcome may not be clinically meaningful. Even after so much use of this drug, we feel that further independent trials can be justified.

So, these new meds aren’t the only ones with these problems, even the (now) old standards have them.

twinklestars · May 31, 2017, 10:36pm

A study of 21 studies of APs with an average drop out rate of 57%. @eduvigis

ncbi.nlm.nih.gov

Quetiapine versus other atypical antipsychotics for schizophrenia.

K Komossa, C Rummel-Kluge, F Schmid, H Hunger, S Schwarz, M Srisurapanont, W Kissling and S Leucht, The Cochrane database of systematic reviews, Jan 2010 20

In many countries of the industrialised world second generation ('atypical') antipsychotic drugs have become the first line drug treatment for people with schizophrenia. It is not clear how the effects of the various second generation antipsychotic drugs differ.To evaluate the effects of quetiapine compared with other second generation antipsychotic drugs for people with schizophrenia and schizophrenia-like psychosis.We searched the Cochrane Schizophrenia Group Trials Register (April 2007), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.We included all randomised control trials comparing oral quetiapine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random-effects model.The review currently includes 21 randomised control trials (RCTs) with 4101 participants. These trials provided data on four comparisons - quetiapine versus clozapine, olanzapine, risperidone or ziprasidone.A major limitation to all findings is the high number of participants leaving studies prematurely (57.6%) and the substantial risk of biases in studies. Efficacy data favoured olanzapine and risperidone compared with quetiapine (PANSS total score versus olanzapine:10 RCTs, n=1449, WMD 3.66 CI 1.93 to 5.39; versus risperidone: 9 RCTs, n=1953, WMD 3.09 CI 1.01 to 5.16), but clinical meaning is unclear. There were no clear mental state differences when quetiapine was compared with clozapine or ziprasidone.Compared with olanzapine, quetiapine produced slightly fewer movement disorders (6 RCTs, n=1090, RR use of antiparkinson medication 0.49 CI 0.3 to 0.79, NNH 25 CI 14 to 100) and less weight gain (7 RCTs, n=1173, WMD -2.81 CI -4.38 to -1.24) and glucose elevation, but more QTc prolongation (3 RCTs, n=643, WMD 4.81 CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (6 RCTs, n=1715, RR use of antiparkinson medication 0.5 CI 0.3 to 0.86, NNH 20 CI 10 to 100), less prolactin increase (6 RCTs, n=1731, WMD -35.28 CI -44.36 to -26.19) and some related adverse effects, but more cholesterol increase (5 RCTs, n=1433, WMD 8.61 CI 4.66 to 12.56). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n=522, RR use of antiparkinson medication 0.43 CI 0.2 to 0.93, NNH not estimable) and prolactin increase. On the other hand quetiapine was more sedating and led to more weight gain (2 RCTs, n=754, RR 2.22 CI 1.35 to 3.63, NNH 13 CI 8 to 33) and cholesterol increase than ziprasidone.Best available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks. Comparisons with amisulpride, aripiprazole, sertindole and zotepine do not exist. Most data that has been reported within existing comparisons are of very limited value because of assumptions and biases within them. There is much scope for further research into the effects of this widely used drug.