http://www.pharmavoice.com/newsreleases/pierre-fabre-laboratories-announce-promising-results-phase-iia-clinical-trial-f17464-schizophrenia/
“This six-week multinational trial showed positive results in terms of efficacy and F17464 was well tolerated by patients, with no metabolic syndrome. Thus, targeting preferentially the D3 receptor should make a difference compared to other treatments available today. This novel mechanism could help treat acute psychotic episodes with a lower risk of causing motor or metabolic impairments as well as increase the activation of relevant circuits for the treatment of negative symptoms, based on the outcome of preclinical studies.”
I don’t know, but maybe they feel that is the indication that it is most likely to pass trials for. With sicker people, it is easier to see substantial improvement.
Doesn’t always work though, that cognitive drug, TAK 063, they tested on “acute exacerbation of sz” and following the trial the drug disappeared off the pharma company’s website.
Anything that mentions negative symptoms is worth the effort even if it fails, researchers will surely learn stuff from that failure and wisen up for their next endeavor.
They are testing it as an anti psychotic mainly, however they say it may “increase the activation of relevant circuits for the treatment of negative symptoms, based on the outcome of preclinical studies.”
On paper, sounds like cariprazine. Partial agonist activity is supposed to increase d3 signalling in hypoactive circiuts and decrease it in hyperactive ones. I don’t see anything which differentiates this drug from cariprazine, maybe that it has a lower preference for d2. But then no antipsychotic activity and it fails trials.
Actually i just read the blurb, missed important info. Apparently this is a d3 antagonist, something new and never seen b4.
i feel like d3 antagonism shouldn’t be antipsychotic activity bcoz d2 receptors are present in mesolimbic pathway associated with positive sx. I don’t think blocking d3 will produce a response robust enough for approval. Abilify and cariprazine partial agonists at d3 i think. Cariprazine has a higher affinity for it than d2. But d2 blocking is important if not essential. If not why does every aap so far have it?
I found some more info on D3 antagonists in this paper on a failed (or discontinued anyway) schizophrenia drug which targeted D3. It may explain lack of robust enough effects - either not enough receptor occupancy, or a strong genetic component to the response or lack of response.
"The therapeutic efficacy of D3 antagonism in schizophrenia has not yet been confirmed. A minimum receptor occupancy may be required for D3 antagonism to produce antipsychotic effects, as has been shown for the D2 receptor.9, 10 A follow-up study on 50 and 150 mg regimens of ABT-925 revealed <60% receptor occupancy at the D3 receptor,3 which may have limited the clinical efficacy of these doses. Nonetheless, our results coupled with the reported increased D3 receptor binding affinity for dopamine and D3 antagonists resulting from the DRD3 S9G polymorphism,4 suggest that possessing at least one G allele may confer a wider therapeutic window for D3 antagonists. Similarly, subjects with increased dopamine tone resulting from expression of the COMT V158M polymorphism11 may be less likely to respond to D3 receptor antagonists.
Given the size of the data set, we cannot eliminate the possibility that the observed clinical significance of these markers is surrogate for factors which were not analyzed (for example, ethnicity). In addition, the current findings might not apply to patients not represented in the original clinical trial, such as treatment-resistant schizophrenia. Although sample sizes of the S/S and M/M genotype groups were relatively small, and the regimens did not provide sufficient receptor occupancy to assess clinical significance, these results support the notion that pharmacogenetic analyses may reveal sub-populations of schizophrenia patients who could respond favorably to D3 receptor antagonists. However, higher D3 receptor occupancy by a D3 antagonist should be achieved in order to fully understand therapeutic efficacy in schizophrenia and the effects of DRD3 polymorphisms. Thus, further research in this area is warranted."
and perhaps too little?
Perhaps too little dopamine is part of the problem, at least for a subset of schizophrenics?
for example @AmateurUnlicensedQuack and @catsrcool claimed that L tyrosine helped them,
and it supposedly increases the amount of dopamine in the brain.
I took a break from it, but yeah it seemed to help my concentration. I read that since it increases the amount of dopamine in your brain you have to stack it with 5-HTP so you don’t become deficient or something along those lines.
even if it fails, researchers will surely learn stuff from that failure and wisen up for their next endeavor.