# Future possible treatment



## frenchguy (Mar 20, 2016)

Hi all,

wanted to create a topic for the new possible treatment that could be beneficial to DP

please feel free to add some others if you know about, i'll try to update this post:

(these drugs or mostly tested for depression and not dp, as it is of a broader appeal, but they could have some effect on dp)

for the complete list of all new upcoming drugs in all psychiatric disorder (dating of 2014 but do seem relevant):

http://www.phrma.org/sites/default/files/pdf/2014-mental-health-report.pdf

*ALKS 5461*


Mechanism: Mu receptor partial agonist / kappa receptor antagonist
Status: Phase III clinical trials
Company: Alkermes

ALKS 5461 is among the most promising new antidepressants in development. It is essentially a compound drug comprised of buprenorphine and samidorphan. The buprenorphine elicits an antidepressant effect by acting as a partial agonist at the mu opioid receptor and full antagonist at the kappa receptor. The other component, Samidorphan (ALKS 33) functions as a selective mu receptor antagonist.

This means that when combined, the Samidorphan offsets the euphoria (and abuse potential) of Buprenorphine by blunting the effects at the mu receptor. However, the antagonist effect at the kappa receptor is highly important due to the fact that it inhibits release of peptides called "dynorphins." Dynorphin inhibition allows for the release of glutamate (to facilitate neuroplasticity) and improve dopaminergic signaling throughout the brain.

*Amitifadine* (DOV-21,947 or EB-1010)


Mechanism: SNDRI
Status: Phase III clinical trials
Company: Euthymics Bioscience

Amitifadine is an antidepressant under development by Euthymics Bioscience, a company based in Cambridge, Massachusetts. The drug functions as a "triple reuptake inhibitor" (SNDRI), meaning it prevents the reuptake of serotonin, norepinephrine, and dopamine. It seems to affect serotonin to the greatest extent, followed by norepinephrine, and lastly dopamine.

Specifically, it inhibits reuptake of serotonin approximately 2-fold norepinephrine and 8-fold dopamine. It is known that low serotonin, low norepinephrine, and low dopamine could cause a person's depression. Elevating levels of three neurotransmitters simultaneously is likely to deliver more potent antidepressant effects, faster-acting relief, with less side effects.

That said, there will likely be significant downstream long-term consequences of taking a medication that affects a broad spectrum of neurotransmitters. The drug is likely to be effective for depression and will initially be considered a panacea due to lack of weight gain and sexual dysfunction (as a result of norepinephrine and dopamine increases). However, those who use the drug over a long-term may find that withdrawal is more debilitating than other antidepressants; picture an SSRI (Lexapro) combined with an NDRI(Wellbutrin) and you've got something similar to Amitifadine.

*AV-101* (4-Cl-KYN)


Mechanism: NMDA receptor antagonist
Status: Phase II clinical trials
Company: VistaGen Therapeutics

AV-101 (4-CI-KYN or L-4-chlorokyurenine) is a prodrug under development by VistaGen Therapeutics for major depressive disorder. It is also being investigated for the treatment of various other neurological conditions including: epilepsy, neuropathic pain, and neurodegenerative diseases. As a prodrug, AV-101 is biologically inactive until ingested and enzymatically converted within astrocytes into 7-CL-KYNA (also known as 7-chlorokynurenic acid).

The 7-CL-KYNA functions as a highly potent selective NMDA receptor antagonist and is capable of modulating dopaminergic and GABAergic neurotransmission. In other words, it binds to the NMDA receptors - specifically at the glycine binding site. Like most NMDA receptor antagonists, AV-101 is expected to be rapidly-acting for nearly instantaneous antidepressant effects following administration.

Perhaps most promising is the fact that in animal models, AV-101 acts as a neuroprotective agent against excitotoxicity. Assuming the substance is neuroprotective, well-tolerated, and effective - it may be superior to current-market medications. This could be considered among the most promising NMDA receptor antagonists in development due to its neuroprotective potential, rapid antidepressant effect, and ability to treat a variety of neurological conditions.

*AVP-786*


Mechanism: NMDA/sigma-1 receptor antagonist
Status: Phase II clinical trials
Company: Avanir Pharmaceuticals

AVP-786 is a drug under investigation for the treatment of refractory depression. It was developed by Avanir Pharmaceuticals and is comprised of "deuterium modified dextromethorphan" (d-DXM) and "ultra-low dose quinidine." Dextromethorphan is most commonly known as an antitussive or cough suppressant, hence its inclusion in many formulations of cough syrup.

The DXM component functions as an NMDA receptor antagonist, sigma-1 receptor agonist, and SERT/NET inhibitor. The modification of dextromethorphan with deuterium fortifies chemical bonds, thereby minimizing likelihood of enzymatic cleavage without altering its effect and first pass metabolism. As a result of the low metabolism rate, only a small amount of quinidine is necessary to inhibit enzyme CP450 (cytochrome P450).

The inhibition of CP450 allows for a longer half-life of d-DXM and maintenance of therapeutic blood levels. There is some evidence that DXM could cause drug-induced psychosis, so investigation will require some caution. That said, there is evidence that some DXM may provide neuroprotective effects, possibly a mechanism by which it alleviates depression.

*AZD6423*


Mechanism: NMDA receptor antagonist
Status: Phase I clinical trials
Company: AstraZeneca

AstraZeneca has a new drug in the development pipeline tentatively dubbed "AZD6423." It functions as an NMDA receptor antagonist and would be used specifically for the treatment of suicidal ideation. NMDA receptor antagonists often elicit anesthetic effects, causing dissociation and sometimes psychotomimetic reactions.

It is thought that AZD6423 will rapidly ameliorate suicidal ideation, but it is unknown as to how frequently the drug will require administration among those who are suicidal. While the class of NMDA receptor antagonists may be promising for the alleviation of depression and suicidal thoughts, the implications of their usage will require further investigation. AZD6423 is a long ways from getting FDA approval.

The drug will need to first be considered safe, well-tolerated, with a minimal side effect profile. Should this drug advance to Phase II, and inevitably Phase III clinical trials, more information will emerge regarding the specifics of its effects. Research will likely progress slowly due to the fact that NMDA receptor antagonists may facilitate neurotoxicity - especially over the long-term.

Source: https://clinicaltrials.gov/ct2/show/NCT01926366

*Basimglurant* (RG7090)


Mechanism: mGluR5 antagonist
Status: Phase II clinical trials
Company: Roche

Basimglurant (RG7090) is a drug under investigation by Roche for the treatment of major depression. It was initially investigated as a treatment for the genetic condition known as "Fragile X Syndrome" characterized by abnormal X chromosomes that are susceptible to damage - resulting in significant neurological impairment. Although Roche realized that RG7090 wasn't well-suited for the treatment of "Fragile X Syndrome," the drug is thought to significantly improve mood.

It functions as a selective antagonist of mGluR5 (metabotropic glutamate receptor-5) with high potency and a long half-life. By antagonizing the mGluR5 receptor, the drug inhibits the binding of excitatory neurotransmitter "glutamate" and may promote increased neuroplasticity. Since individuals with depression are thought to exhibit abnormal glutamatergic neurotransmission, Basimglurant may facilitate correction of certain abnormalities.

Preliminary evidence suggests that Basimglurant may promote wakefulness and increases delta waves during deep sleep. While most monoamine levels are mostly unaffected by Basimglurant, the drug appears to increase dopamine levels in the nucleus accumbens. It offers a novel mechanism of action that could treat depression, as well as comorbid conditions such as anxiety.


Source: http://www.ncbi.nlm.nih.gov/pubmed/25665805

*CERC-301*

CERC-301 is a new NDMA receptor modulator in development to be used as an antidepressant adjunct for those with refractory depression. It is also being investigated for the treatment of suicidal ideation - an increasingly problematic domain. Although it is currently in Phase II clinical trials, the FDA granted the drug "Fast Track Designation" as of 2013.

The drug is considered selective in that it elicits an effect on NMDA receptor's 2B subunit. Developers believe that it will have a rapid-onset of action (like other NMDA receptor antagonists) and will be well-tolerated without significant unwanted side effects. This drug may be preferred over other NMDA receptor antagonists in that it is highly selective.

The high selectivity of CERC-301 could minimize psychotomimetic side effects and other adverse reactions. That said, the drug will still need to finish Phase II clinical trials to determine whether it is safe and well-tolerated. It should be suspected that the FDA likes what it sees thus far with CERC-301 (hence the fast-tracking).

*DSP-1053*


Mechanism: SSRI / 5-HT1A partial agonist
Status: Phase I clinical trials
Company: Sunovion

DSP-1053 is a drug under development by Sunovion for the treatment of depression. It will function as an SSRI (Selective Serotonin Reuptake Inhibitor) and 5-HT1A partial agonist. Although many consumers are sick of the incessant suggestions to use an SSRI for the treatment of depression, most approved SSRIs are relatively safe compared to other antidepressants and still have favorable side effect profiles.

What may make DSP-1053 unique compared to other SSRIs is that preclinical evidence suggests that it is faster-acting with less side effects. A study conducted in rats noted that it improved depressive behaviors within 2 weeks of administration, whereas another SSRI took 3 weeks. The fact that DSP-1053 inhibits reuptake of serotonin and acts as a partial agonist at the 5-HT1A receptor may result in improved efficacy for certain individuals.

Although DSP-1053 is being marketed as "novel" - there really isn't anything novel about an SSRI. The drug Viibryd inhibits serotonin reuptake and acts as a partial 5-HT1A agonist; this is relatively similar. Realistically, this drug likely won't offer significant improvements over other serotonergic antidepressants - but it could provide consumers with yet another antidepressant option.

Source: http://www.ncbi.nlm.nih.gov/pubmed/26171224

*JNJ-42847922*


Mechanism: OX2 receptor antagonist
Status: Phase I clinical trials
Company: Janssen Pharmaceuticals / Minerva Neurosciences

JNJ-42847922 is a drug in Phase I clinical trials and was developed by Janssen Pharmaceuticals and Minerva Neurosciences. It function as a selective orexin receptor antagonist, specifically targeting the OX2 receptor. Orexin (also referred to as "hypocretin") is a neuropeptide responsible for regulating arousal, wakefulness, and appetite.

While this drug is primarily thought to help treat insomnia, it is simultaneously being tested for the treatment of depression. Since individuals with depression often struggle to get a good night's sleep, targeting the OX2 receptors with JNJ-42847922 appears to accelerate sleep induction, prolongs sleep duration, and facilitates deep, restorative sleep. Those with depression may find that this drug may improve their sleep to such an extent that mood also improves.

As a result of the selective OX2 receptor antagonist effects, this drug may be more successful among those with depression and comorbid insomnia (or vice-versa). Preliminary evidence from Phase 1b single-dose trials suggests that the drug has a favorable safety and pharmacokinetic profile. It should be noted that there are several other new orexin receptor antagonists undergoing clinical trials as sleeping pills, some of which may also improve mood.

Source: http://www.ncbi.nlm.nih.gov/pubmed/26177655

Source: https://clinicaltrials.gov/ct2/show/NCT02067299

*Ansofaxine HCl* (LY03005)


Mechanism: SNDRI
Status: Phase I clinical trials
Company: Luye America Pharmaceuticals

Anxofaxine (LY03005) is a drug under development by Luye America Pharmaceuticals. It functions as an SNDRI (serotonin-norepinephrine-dopamine reuptake inhibitor), also known as a triple reuptake inhibitor. Inhibiting the reuptake of these three major neurotransmitters is thought to elicit a faster-acting antidepressant effect compared to traditional SSRIs or even dual-uptake inhibitors like SNRIs.

It has long been understood that increasing extracellular levels of serotonin and norepinephrine can improve mood, but most recently dopamine has been investigated as a mood booster. The specific ratios of reuptake for each of the respective neurotransmitters (serotonin, norepinephrine, dopamine) hasn't been released by Luye America. It is likely that the mechanism will target serotonin to the greatest extent, followed by norepinephrine, and then dopamine.

Preclinical evidence suggests that it may have higher overall efficacy and fewer side effects compared to current-market medications. Since norepinephrine and dopamine are being increased, side effects such as: cognitive impairment, sexual dysfunction, and weight gain will be less likely. That said, the long-term consequences and discontinuation effects associated with "triple reuptake inhibition" may be more deleterious than drugs primarily targeting one neurotransmitter (e.g. SSRIs).


Source: http://www.luye.cn/en/uploads//2015-03/27/_1427445007_nwt59.pdf
Source: https://clinicaltrials.gov/ct2/show/NCT02271412

*LY2940094*

Mechanism: NOC-1 antagonist
Status: Phase II clinical trials
Company: Eli Lilly

LY-2940094 is a new antidepressant under development by the pharmaceutical juggernaut Eli Lilly. This drug is designed to function as a NOC-1 antagonist, selectively binding to the nociceptin-1 receptor. Nociceptin is a neuropeptide that acts similar to opioids and is capable of eliciting analgesic effects, but doesn't act on opioid receptors.

There is mounting evidence from animal research to suggest that dysfunction of the nociceptin system can contribute to depression and anxiety. By preventing nociceptin from binding to the NOC-1 receptor, depressive symptoms significantly improve. Some speculate that LY2940094's antagonist effect at the NOC-1 receptor may also indirectly influences neurotransmission of dopamine and GABA to improve mood.

In addition to it being tested as an antidepressant, LY2940094 is being investigated for the treatment of alcohol dependence. Those dealing with alcohol dependence and comorbid depression may find the drug especially effective since it is designed to treat both conditions. Currently, LY2940094 is in Phase II clinical trials and is considered Eli Lilly's most advanced antidepressant in the pipeline.


Source: https://clinicaltrials.gov/ct2/show/NCT01798303

*Mifepristone* (RU-486)

Mechanism: Antiprogestogen / antiglucocorticoid
Status: Phase III clinical trials
Company: Corcept Therapeutics

Mifepristone (or RU-486) is a non-monoaminergic agent under investigation for the treatment of depression with psychotic features. The drug is already FDA approved for the termination of pregnancies, as an emergency contraception, as well as for the treatment of Cushing's syndrome. It is considered a synthetic steroidal antiprogesterone and antiglucocorticosteroid agent.

It binds primarily to the progesterone receptor, but still elicits strong binding affinity at the glucocorticoid receptor. It is also regarded as a modest antiandrogen and does not bind to the estrogen receptor. Researchers believe that the antiglucocorticoid effects may be responsible for improving mood and minimizing likelihood of psychosis via modulation of the HPA (hypothalamic-pituitary-adrenal) axis.

Mifepristone may be a jack-of-all-trades type medication in that it has been investigated as a treatment for an array of other conditions including: HIV, cognitive dysfunction, PTSD, glaucoma, various types of cancer, etc. It appears likely that this hormonal-modulating drug will likely receive FDA approval for depression with psychotic features, serving as a non-monoaminergic treatment option. Assuming it is approved, pharmaceutical companies may attempt to pinpoint the mechanisms responsible for its antidepressant effect and develop a revised version of the drug without the unnecessary, non-targeted effects.


Source: http://www.ncbi.nlm.nih.gov/pubmed/19412444
Source: http://www.ncbi.nlm.nih.gov/pubmed/20149549
Source: http://www.ncbi.nlm.nih.gov/pubmed/16160710
Source: http://www.ncbi.nlm.nih.gov/pubmed/11593077

*MIN-117*

Mechanism: SDRI / 5-HT1A receptor antagonist
Status: Phase II clinical trials
Company: Minerva Neurosciences

MIN-117 is an investigational drug under development by Minerva Neurosciences for the treatment of depression. It functions as a 5-HT1A receptor antagonist, but also acts as a SDRI (serotonin-dopamine reuptake inhibitor). Many currently-approved antidepressants act on the 5-HT1A receptor, making it a popular target for new investigational drugs.

The drug is also listed as inhibiting the serotonin transporter (SERT) and dopamine transporter (DAT); it is likely that it affects serotonin to a significantly greater extent than dopamine. Additionally, the drug acts on 5-HT2A receptors, as well as Alpha-1A and Alpha-1B adrenergic receptors. The drug is currently in Phase II clinical trials and will be further evaluated for safety, pharmacokinetics, and efficacy.

While the exact mechanism of action is unclear, it seems as though MIN-117 will affect a multitude of neurotransmitters and receptors. In terms of its effects, the drug is primarily serotonergic, but can affect dopamine and influence noradrenergic receptors. It is unclear as to whether this drug will offer any major advantages over current-market options.


*NRX-1074*

Mechanism: NMDA receptor partial agonist
Status: Phase II clinical trials
Company: Naurex

NRX-1074 is a drug under development by Naurex for the treatment of depression. It as an NMDA receptor partial agonist, specifically at the glycine site. Although NRX-1074 functions similar to another drug in the Naurex development pipeline called "GLYX-13" - it differs in that it is significantly more potent (several thousand-fold) by weight and will be manufactured for oral and intravenous administration (GLYX-13 is solely intravenous).

I've already written about the novelty of using NRX-1074 for depression, noting that it is fast-acting, well-tolerated, and doesn't trigger psychotomimetic effects (like other drugs affecting NMDA receptors). It is currently in Phase II clinical trials for the treatment of major depression in the injectable format, and Phase I clinical trials in the orally-administered format. Following administration of NRX-1074, depression symptoms generally improve within 24 hours.

The antidepressant effects derived from NRX-1074 appear to be dose-dependent, meaning the higher the dose - the greater the therapeutic relief. In clinical trials, the antidepressant effect attained from a single dose of NRX-1074 was greater than that derived from using SSRIs for several weeks. Many people with severe forms of refractory depression are looking forward to the FDA approval of NRX-1074.


Source: https://www.naurex.com/pipeline/nrx-1074/

*NSI-189*

Mechanism: Neurogenesis

Status: Phase I clinical trials

Company: Neuralstem Inc.

NSI-189 is an investigational drug developed by Neuralstem Inc. for the treatment of depression, and possibly an array of other neurological disorders. NSI-189 has a truly novel mechanism of action in that it stimulates neurogenesis (growth of new brain cells) within the hippocampus of the brain. While other antidepressants are known to stimulate neurogenesis, this drug has been suggested to increase hippocampal volume by up to 20% in mice.

The novelty of hippocampal neurogenesis as a treatment for depression quickly captured the interest of DARPA (Defense Advanced Research Projects Agency) and the National Institute of Health (NIH). As a result, both DARPA and the NIH have funded clinical research of NSI-189 for depression. Many speculate that NSI-189 could spur an entirely new class of neurorestorative drugs that aim to strategically increase brain volume.

Since the hippocampus is involved in mood regulation, memory formation, and spatial navigation, NSI-189 may improve a broad-spectrum of neurological functions. Preliminary research from Phase I trials indicated that the drug was well-tolerated and improved mood at dosages of 40 mg and 80 mg per day. The drug is currently in Phase II clinical trials for depression, but could eventually get tested as a treatment for other neurological conditions.

Source: http://www.neuralstem.com/pharmaceuticals-for-depression/120

Source: https://clinicaltrials.gov/ct2/show/NCT02067793

*Rapastinel* (GLYX-13)

Mechanism: NMDA receptor modulator

Status: Phase II clinical trials (complete)

Company: Naurex

Rapastinel is a drug under development by Naurex as an adjunct treatment for major depression. The drug is classified as a NMDA receptor modulator, acting as a partial agonist at the glycine site of the NMDA receptor. What's unique about using GLYX-13 to treat depression is that it is considered an "amidated tetrapeptide" - and is suggested to rapidly cross the blood-brain barrier.

However, the drug will not be developed in the format of an oral pill; Naurex has stated that Rapastinel will be manufactured as a pre-filled IV (intravenous) syringe formulation that can be administered in under 1 minute. Due to the fast-acting antidepressant potential of GLYX-13, the FDA has granted "Fast Track Designation" to Naurex for its development, thereby expediting clinical trials. Phase III clinical trials for Rapastinel are slated to begin in 2016.

Thus far the drug has been tested on over 500 participants and appears to be well-tolerated, effective, and produces a sustained antidepressant effect - lasting up to 10 weeks with repeated dosing. Since the drug works within 2 hours of administration and the effects of a single injection can last up to 7 days, Rapastinel will be a hot commodity among those with refractory depression should it eventually get FDA approval. Perhaps most promising is the fact that the drug has no psychotomimetic effects, may be neuroprotective, and could enhance aspects of learning and memory.

Source: https://www.naurex.com/pipeline/glyx-13/

Source: https://www.ncbi.nlm.nih.gov/pubmed/23455590

Source: https://www.ncbi.nlm.nih.gov/pubmed/19446371

*Strada* (MSI-195 or Ademetionine)

Mechanism: Methylation

Status: Phase II clinical trials

Company: MSI Methylation Sciences

Strada (MSI-195) is an antidepressant agent under development by MSI Methylation Sciences. It is thought to function by modulating cytokines within the CNS that may influence depression, as well as indirectly altering levels of dopamine. Developers suggest that Strada may also influence membrane fluidity and reduce neuroinflammation.

Since many people with depression also have chronic neuroinflammation, it makes sense that an anti-neuroinflammatory could reverse symptoms. The active ingredient within Strada is Ademetionine is a form of the amino acid methionine, more commonly known as SAMe (S-adenosylmethionine). Individuals with undermethylation as a result of genetic polymorphisms may lack sufficient levels of methionine and end up depressed.

Taking Strada with the active ingredient Ademetionine (a synthetic version of methionine) could ameliorate depressive symptoms. Thus far Strada has advanced to Phase II clinical trials as an adjunct for major depression. MSI Methylation Sciences intends to evaluate Strada as a standalone monotherapy for depression in the future.

Source: http://methylationsciences.com/index.php/clinical-trial/

*Tedatioxetine* (Lu AA24530)

is a drug under development by Lundbeck and Takeda for the treatment of depression. It functions as a triple reuptake inhibitor or "SNDRI," preventing the reuptake of serotonin, norepinephrine, and dopamine. Like other triple reuptake inhibitors, it affects serotonin to the greatest extent, followed by norepinephrine, and to a lesser extent - dopamine.

In addition, it also acts as an antagonist at a variety of receptors including: 5-HT2A, 5-HT2C, 5-HT3, and the Alpha-1A adrenergic receptor. It was in Phase II clinical trials as of 2009 and it remains unclear as to whether its development has been postponed and/or abandoned. Some speculate that the drug Brintellix may have been more favorable than Tedatioxetine, and as a result, it was discontinued.

The drug appeared to be well-tolerated and was slated to become one of the preeminent triple-reuptake inhibitors to hit the market. It is unlikely that Lundbeck and Takeda will continue development of Tedatioxetine after such a long hiatus.

*MI-4*

The latest hope as a psychiatric rescue drug is called MI-4, and news of its promise was reported earlier this week at the 
San Diego meeting of the Federation of American Societies for Experimental Biology (FASEB). Scientists also have 
identified the drug as Ro-25-6981.

In the test tube, MI-4 was found to simultaneously increase the availability in the brain of three neurotransmitters that
play a key role in depression: serotonin, dopamine and norepinephrine. Researchers led by Jeffery N. Talbot of Roseman 
University of Health Science in Henderson, Nev., found that in mice that had been stressed and trained to expect no rescue 
from frightening circumstances -- a depression-like condition called "learned helplessness" -- MI-4 quickly restored more 
hopeful behavior and continued to do so for three weeks -- a lengthy stretch for a mouse.

Compared with a placebo medication, MI-4 made virtual social butterflies of mice who had been brought low by social defeat,
and whose depression manifested as withdrawal. And for a continuous three-week period, it helped fortify those mice against 
the soul-crushing effects of further social defeat.

MI-4 appears to have several advantages over ketamine, which, as a drug that induces a sort of out-of-body high when used at 
higher doses and is, therefore, considered to have abuse potential. Mice taking MI-4 were no more likely to hang out close to
the drug-dispenser than they were to wander around and explore and socialize -- a clear sign that its abuse or addictive 
potential is low.

*PH10*

*URL: *http://www.practiceu...e.com/news/2741

An investigational intranasal spray antidepressant known for now as PH10 shows early promise in addressing two major unmet needs in the treatment of major depressive disorder: faster-acting drugs with novel mechanisms of action.

PH10 showed a large antidepressant effect in a small phase II study after just 1 week, when the first scheduled assessment took place. Future studies will look for an antidepressant effect even sooner, perhaps as early as day 1 of treatment, Dr. Michael R. Liebowitz said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

PH10 is a proprietary pherine. The pherines are a class of intranasally administered psychoactive therapeutic agents that bind locally on nasal chemosensory receptors and trigger responses in the hypothalamus, amygdala, prefrontal cortex, and hippocampus. They have an excellent safety and tolerability profile, are effective in nanogram quantities, and do not circulate systemically in the blood. Instead, they initiate neural impulses that follow defined pathways in order to directly affect brain function, explained Dr. Liebowitz, professor of clinical psychiatry at Columbia University, New York.

He presented an 8-week, phase II, double-blind, single-site pilot randomized trial involving 30 patients with major depressive disorder. None had treatment-resistant depression. The participants were randomized to two self-administered inhalations in each nostril twice daily at a dose of 3.2 mcg/day of PH10 from a metered-dose spray device, or a high-dose group receiving 6.4 mcg/day, or placebo spray.

*RGH-618*

RGH-618 involves a series of compounds that target metabotropic glutamate receptors and are agonists, which represent potential agents for the treatment of anxiety, depression and other central nervous system (CNS) conditions. In March 2012, the Company initiated a Phase I study in healthy volunteers of RGH-618.

*ANAVEX 1-41*

*URL: *http://anavex.com/rn...depression.html

A new compound in the advanced preclinical phase for the treatment of depression and fatigue

Mode of action: ANAVEX 1-41 presents mixed pharmacological activity involving serotoninergic, sigma-1 and sodium channel components suggesting a prototype mechanism of action and representing a new class of anti-depressants.

Results to date: ANAVEX 1-41 exhibited an outstanding profile in the Forced Swim Test (FST) (80 - 100% of anti-immobility at 100 mg/kg, per os) suggesting anti-depressant properties that have not been observed so far with any of the currently available anti-depressants. In addition, ANAVEX 1-41 demonstrated anti-convulsive action (ED50 = 50 - 100 mg/kg per os).

Moving forward: The company has initiated scale-up manufacturing of ANAVEX 1-41, its second lead compound for a range of important CNS diseases. With sufficient quantities of ANAVEX 1-41 in hand we will be in a position to advance the program and begin preclinical studies on large animals in the near term. This is expected to take ANAVEX 1-41 an important step closer to Phase 1 trials in humans.

The required quantities of ANAVEX 1-41 will be manufactured by Syntagon AB under GMP conditions, the quality assurance system required in the production of medicinal products.

*E-2508*

URL: http://www.abstracts...a2-eebfa14cd9f1

Corticotropin-releasing factor (CRF) is known as one of key mediators involved in stress responses, and has been suggested to play a role in stress-related disorder like anxiety and depression. CRF1 receptor antagonist is expected to be an anxiolytic medicine or an anti-depressant with a new mechanism of action. We have discovered E2508, a novel orally active antagonist of CRF1 receptor. E2508 inhibited the [125I]-CRF binding to human CRF1 receptor in a concentration-dependent manner, with a pKi 7.96 ± 0.08 (mean ± SEM), and inhibited CRF-induced cyclic adenosine monophosphate (cAMP) production in a concentration-dependent manner in HEK293 cells expressing the human CRF1 receptor , with a 50% inhibitory concentration (IC50) value of 24.9 nmol/L. These results indicate that E2508 is a potent CRF1 receptor antagonist in vitro. Next we found that orally administered E2508 inhibited the CRF-induced increase of ACTH in a dose-dependent manner in rats, with significance at 30 mg/kg. However, oral administration of E2508 did not affect plasma ACTH concentration at ≤ 100 mg/kg in normal rat. These results indicate that E2508 does not affect the plasma ACTH concentration in normal rats. Finally, the binding of E2508 to 75 various physiologically important cellular targets in vitro were evaluated. No significant binding of E2508 against any receptors was observed at either 1 μmol/L or 10 μmol/L. E2508 is a selective CRF1 receptor antagonist in vitro and in vivo, and is expected to be a new approach for the treatment of stress related disease like anxiety or depression.

*NNI-351*

*URL *http://www.neuronasc...-depression.htm

Neuronascent is developing therapeutics aimed at intervening at the level of reduction in neurogenesis in patients with chronic depression and anxiety. Our lead therapeutic candidate represents an exciting new class of drugs that is not a serotonin or norepinephrine reuptake inhibitor, but one that complements those already on the market for noncompliant and refractive patients. In vivo preclinical proof of concept for this lead therapeutic candidate showed not only antidepressive and anxiolytic activity, but also memory improvement not normally observed with an antidepressant. These behavioral benefits correlated with the long-term induction of new neurons, or neurogenesis, in a critical cognitive region of the brain.

Neuronascent's lead candidate for depression is also the lead candidate for post-traumatic stress disorder, which may be observed along with depression, but is considered a separate disorder. In a mouse model of the disorder, NNI-351 reversed the deficits and improved anxiety to better than normal mice.

*Our lead candidate for depression and post-traumatic stress disorder, NNI-351, is in the preclinical phase of development, where we are initiating IND-enabling studies.*

*sTMS*

Penn Medicine is currently one of the first research sites in the country that is testing the effectiveness of another non-invasive, medication-free treatment called synchronized transcranial magnetic stimulation (sTMS). This is a new brain stimulation treatment that may also help alleviate symptoms of depression. The sTMS system uses low energy, synchronized transcranial magnetic stimulation synchronized to an individual's natural brain rhythms as opposed to the stronger, high-frequency pulses utilized with traditional rTMS. Penn is one of only 16 sites in the country testing this new technology.

"sTMS is an exciting new development in psychiatry since it offers the potential for an additional non-pharmacological treatment for the disabling symptoms of depression," says Mahendra Bhati, MD, assistant professor of Clinical Psychiatry, who, along with Michael Thase, MD, professor of Psychiatry and chief, Division of Mood and Anxiety Disorders Treatment & Research Program, is researching the new treatment at Penn. "Many patients can't tolerate medications and TMScan be an effective treatment for these patients. sTMS is unique when compared to all other treatments in psychiatry since sTMS uses physiological markers of brain activity to tailor treatment. This offers the hope of individualized and potentially more effective treatment for the disabling and difficult to treat symptoms of depression."

So how exactly does it work? Research has shown that the neuronal activity in the brains of people with depression shows abnormal brain rhythms in areas associated with depressive symptoms. sTMS therapy is based on the theory that the brain rhythms can be "tuned" to a normal resting rhythm using low energy magnetic fields synchronized to an individual's brain activity. It is believed that this will restore normal brain rhythms leading to a reduction of depression symptoms and improved mood. Unlike conventional rTMS or medications, this type of magnetic stimulation is tailored to a patient's individual brain physiology.

More research is needed to determine the safety and efficacy of sTMS and the system is not yet FDA approved. Data from preliminary studies have shown that sTMS can improve depressive symptoms in a significant number of patients. The ongoing study at Penn and other sites seeks to confirm the findings from earlier studies and obtain FDA approval for sTMS when treating depression.

"They also have plans to make the device portable so it can be used at home where you can plug into the wall and listen to a built-in mp3 player. It's painless, relaxing, and a physiologically tailored treatment for depression," says Dr. Bhati. "If it works, it may be a treatment patients can administer to themselves in the convenience of their own home, unlike rTMS which requires five times a week visits to a doctor's office."

Researchers are hopeful that this kind of personalized approach to depression treatment will offer patients a greater variety of options to treat depression. Learn more about this trial and other depression research at Penn.

D Cycloserine

26 adult out-patients with Recurrent Major Depressive Disorder, currently resistant to treatment (defined as 20 plus score on the 21-item Hamilton Depression Rating Scale, despite two or more adequate antidepressant medication trials) and been treated for at least 4 wk with a stable clinically determined dose of antidepressant medication, were randomised using a double-blind, placebo controlled parallel group design to receive increasing dose of DCS or placebo.The mean duration of the current episode was 13-14 months.

Results

DCS treatment led to significant improvement in depressive symptoms as measured by HAMD.Seven of 13 (54%) patients assigned to DCS qualified as responders (i.e. 50% HAMD total score reduction) vs. two of 13 (15%) assigned to placebo. Five of 13 (38 %) patients assigned to DCS were also considered remitters (i.e. HAMD total score below 7) vs. two of 13 (15%) assigned to placebo, although this difference was not statistically significant. More patients ( 3 against one in placebo group) withdrew from experimental arm siting discomfort as reason.

Limitations: Small study. Remission rates were not statistically significant.

Conclusion: This study provides proof of concept evidence that antagonistic activity at the NMDAR-associated glycine site can induce antidepressant effects and reduce MDD severity. 54 % of DCS-treated subjects achieved treatment response. This is to be considered against the usually reported 60-65% response rate to the first antidepressant agent in depression. Authors also measured serum glycine levels and comment that treatment targeting NMDAR glycine site may be particularly appropriate in those with high glycine levels.

*7,8-Dihydroxyflavone*

*Living a traumatic experience favours the persistence of fear associated with an aversive stimulus, known as fear conditioning and which, in mice, can be eased with a single dosis of 7,8-Dihydroxyflavone, a type of flavonoid which boosts the ability to acquire new emotional habits. These findings were published in the American Journal of Psychiatry in a study carried out by researchers at Emory University, USA, and UAB, who consider that the drug could be used in the effective treatment of post-traumatic stress, panic and phobia disorders in persons.*

References

"Effect of 7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, on Emotional Learning". Raul Andero, Scott A. Heldt, Keqiang Ye, Xia Liu, Antonio Armario, Kerry J. Ressler. Am J Psychiatry, December 1, 2010, doi: 10.1176/appi.ajp.2010.10030326.

Mice previously exposed to traumatic situations demonstrate a stronger ability to react to fear conditioning - acquired by associating a sonorous stimulus with an aversive stimulus - and lack the ability to inhibit this fear. This phenomenon is similar to that of people who suffer from Post-Traumatic Stress Disorder (PTSD), an anxiety disorder which appears after being exposed to highly traumatic situations, such as a violent attack, a natural disaster or physical abuse.

In the study researchers verified that the 7,8-Dihydroxyflavone dosis injected into mice who had undergone a traumatic experience made them eliminate fear conditioning quicker. The boost in this new behaviour is the result of 7,8-Dihydroxyflavone activating the TrkB receptors in the brain, probably those found in the amygdala, which are essential for emotional learning and memory.

7.8-Dihydroxyflavone is a type of flavonoid. These chemical compounds are present in our diets in elements such as red wine, citrus, cereals, tea and chocolate (at least 70% cocoa), etc. Chronic administration of foods rich in flavonoids in lab animals has demonstrated neuroprotective effects in long-living rodents, but the activation of TrkB receptors produced by these foods is surely low compared to the effects of 7,8-Dihydroxyflavone.

TrkB receptors in the brain are activated in mammals with the BDNF protein. There are different pathologies, such as depression or anxiety disorders, in which this protein shows alterations in its expression. Unfortunately, administration of the BDNF protein as a drug is limited given that a large part of the amount injected does not permeate the blood-brain barrier and cannot access the brain. Very recent studies have demonstrated that 7,8-Dihydroxyflavone is the first drug to imitate BDNF actions and enter the brain with much more efficacy than the same protein, thus revealing therapeutic actions in animal models suffering from Alzheimer's, strokes, Parkinson's and/or depression.

The results obtained in this study postulate that 7,8-Dihydroxyflavone as a drug could be useful as a treatment of disorders based on fear, such as PTSD, panic attacks and phobias. Researchers consider it convenient to study its effects combined with psychotherapy, administrating the drug in fear elimination therapy sessions for anxiety disorders or even shortly after a person experiences a traumatic situation.

Led by Dr Kerry Ressler of Emory University, Atlanta, the study was developed with the participation of Dr Antonio Armario, researcher at the Institute of Neuroscience of the UAB and professor of the Department of Cell Biology, Physiology and Immunology, and Dr Raul Andero, researcher at the Emory University. The article published in the American Journal of Psychiatry is part of Dr Andero's doctoral thesis.

*RG1578/RG7090*

Link to PDF: http://www.researchg...antidepressants

This review focuses on the metabotropic glutamate (mGlu) receptors and their potential for drug targets for the treatment of depression. In particular, accumulating evidence has indicated the potential importance and usefulness of agents acting on mGlu2/3 and mGlu5 receptors. Preclinical and clinical evidence of mGlu2/3 receptor ligands and mGlu5 receptor antagonists are described. Moreover, their potential in clinic will be discussed in the context of neuronal mechanisms of ketamine, an agent recently demonstrated a robust effect for patients with treatment-resistant depression. This article is part of a Special Issue entitled 'mGluR'.

*CERC-501 *

*CERC-501* (originally known as *LY-2456302*) is a potent, selective, short-acting (non-"inactivating") antagonist of the κ-opioid receptor (KOR) (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; ~30-fold selectivity for the KOR) that was originally developed by Eli Lilly.[1][2][3] In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code name of CERC-501).[4]

CERC-501 is under development for the treatment of major depressive disorder and substance use disordersincluding alcoholism, nicotine addiction, and illicit drug dependence.[5] As of 2016, it has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[6][7] In animal models of depression, CERC-501 has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[7] A phase II study of CERC-501 in heavy smokers will be commenced in early 2016 and results of the study are expected before the end of 2016.[8]

In December 2015, the results of a human pharmacokinetic study of CERC-501 were released.[5][8] CERC-501 was shown to reproducibly penetrate the blood-brain-barrier, and positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that CERC-501 is being explored at in clinical trials.[5][8]Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[8] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[8] No serious side effects were observed, and all side effects seen were mild to moderate and not considered to be due to CERC-501.[8]

CERC-501 has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), indicating that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[9]


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## TDX (Jul 12, 2014)

ALKS-5461 might have an anti-depersonalisative effect, because it's a kappa-opioid-antagonist. Unfortunately it failed in 2 of 3 phase III studies for depression.

If the NMDA-modulators might have that too is unknown. We have to wait for Rapastinel to find out. Same for the other substances.

The triple reuptake inhibitors won't make things better. Just combine an SNRI with Bupropion and you have a "triple reuptake inhibitor". MAOIs also affect these 3 neurotransmitters.


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## frenchguy (Mar 20, 2016)

as far as *ALKS* research: "The third and final core Phase III study is currently ongoing, with results expected sometime in 2016. As of March 2016, results of FORWARD-5 trial are reportedly expected by Q4 2016. Also, failures of endpoint efficacy goals in FORWARD 3 & 4 Phase III clinical trials; were analyzed and found to be unreliable based on an usually strong placebo effect. In addition, near-efficacious results were received using higher dosages only, indicating that ALKS-5641 will only be effective in higher than initially expected doses. No clinically relevant side effects were reported with the higher dosage trials. "

also *Basimglurant* seems interesting: "the drug inhibits the binding of excitatory neurotransmitter "glutamate" and may promote increased neuroplasticity"

also *Mifepristone :*Researchers believe that the antiglucocorticoid effects may be responsible for improving mood and minimizing likelihood of psychosis via modulation of the HPA (hypothalamic-pituitary-adrenal) axis.

*NSI-189* did help some people with dp too


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## TDX (Jul 12, 2014)

*Basimglurant* and *NSI-189* may be interesting, too.

But who knows if all these NMDA- and glycine-antagonists might help. But maybe we'll know in 1-2 years, when Rapastinel might become available.


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## frenchguy (Mar 20, 2016)

i don't really understand much about the NMDA receptor, but don't you mean glycine agoniste for raspatinel : "acting as a partial agonist at the glycine site of the NMDA receptor" as i know that NMDA antagonist like DMX causes depersonalization-like high.

also i don't understand why they could use both NMDA antagonist and agonist to treat depression?


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## frenchguy (Mar 20, 2016)

update:

*PH10*

*URL: *http://www.practiceu...e.com/news/2741

An investigational intranasal spray antidepressant known for now as PH10 shows early promise in addressing two major unmet needs in the treatment of major depressive disorder: faster-acting drugs with novel mechanisms of action.

PH10 showed a large antidepressant effect in a small phase II study after just 1 week, when the first scheduled assessment took place. Future studies will look for an antidepressant effect even sooner, perhaps as early as day 1 of treatment, Dr. Michael R. Liebowitz said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

PH10 is a proprietary pherine. The pherines are a class of intranasally administered psychoactive therapeutic agents that bind locally on nasal chemosensory receptors and trigger responses in the hypothalamus, amygdala, prefrontal cortex, and hippocampus. They have an excellent safety and tolerability profile, are effective in nanogram quantities, and do not circulate systemically in the blood. Instead, they initiate neural impulses that follow defined pathways in order to directly affect brain function, explained Dr. Liebowitz, professor of clinical psychiatry at Columbia University, New York.

He presented an 8-week, phase II, double-blind, single-site pilot randomized trial involving 30 patients with major depressive disorder. None had treatment-resistant depression. The participants were randomized to two self-administered inhalations in each nostril twice daily at a dose of 3.2 mcg/day of PH10 from a metered-dose spray device, or a high-dose group receiving 6.4 mcg/day, or placebo spray.

*RGH-618*

RGH-618 involves a series of compounds that target metabotropic glutamate receptors and are agonists, which represent potential agents for the treatment of anxiety, depression and other central nervous system (CNS) conditions. In March 2012, the Company initiated a Phase I study in healthy volunteers of RGH-618.

*ANAVEX 1-41*

*URL: *http://anavex.com/rn...depression.html

A new compound in the advanced preclinical phase for the treatment of depression and fatigue

Mode of action: ANAVEX 1-41 presents mixed pharmacological activity involving serotoninergic, sigma-1 and sodium channel components suggesting a prototype mechanism of action and representing a new class of anti-depressants.

Results to date: ANAVEX 1-41 exhibited an outstanding profile in the Forced Swim Test (FST) (80 - 100% of anti-immobility at 100 mg/kg, per os) suggesting anti-depressant properties that have not been observed so far with any of the currently available anti-depressants. In addition, ANAVEX 1-41 demonstrated anti-convulsive action (ED50 = 50 - 100 mg/kg per os).

Moving forward: The company has initiated scale-up manufacturing of ANAVEX 1-41, its second lead compound for a range of important CNS diseases. With sufficient quantities of ANAVEX 1-41 in hand we will be in a position to advance the program and begin preclinical studies on large animals in the near term. This is expected to take ANAVEX 1-41 an important step closer to Phase 1 trials in humans.

The required quantities of ANAVEX 1-41 will be manufactured by Syntagon AB under GMP conditions, the quality assurance system required in the production of medicinal products.

*E-2508*

URL: http://www.abstracts...a2-eebfa14cd9f1

Corticotropin-releasing factor (CRF) is known as one of key mediators involved in stress responses, and has been suggested to play a role in stress-related disorder like anxiety and depression. CRF1 receptor antagonist is expected to be an anxiolytic medicine or an anti-depressant with a new mechanism of action. We have discovered E2508, a novel orally active antagonist of CRF1 receptor. E2508 inhibited the [125I]-CRF binding to human CRF1 receptor in a concentration-dependent manner, with a pKi 7.96 ± 0.08 (mean ± SEM), and inhibited CRF-induced cyclic adenosine monophosphate (cAMP) production in a concentration-dependent manner in HEK293 cells expressing the human CRF1 receptor , with a 50% inhibitory concentration (IC50) value of 24.9 nmol/L. These results indicate that E2508 is a potent CRF1 receptor antagonist in vitro. Next we found that orally administered E2508 inhibited the CRF-induced increase of ACTH in a dose-dependent manner in rats, with significance at 30 mg/kg. However, oral administration of E2508 did not affect plasma ACTH concentration at ≤ 100 mg/kg in normal rat. These results indicate that E2508 does not affect the plasma ACTH concentration in normal rats. Finally, the binding of E2508 to 75 various physiologically important cellular targets in vitro were evaluated. No significant binding of E2508 against any receptors was observed at either 1 μmol/L or 10 μmol/L. E2508 is a selective CRF1 receptor antagonist in vitro and in vivo, and is expected to be a new approach for the treatment of stress related disease like anxiety or depression.

*NNI-351*

*URL *http://www.neuronasc...-depression.htm

Neuronascent is developing therapeutics aimed at intervening at the level of reduction in neurogenesis in patients with chronic depression and anxiety. Our lead therapeutic candidate represents an exciting new class of drugs that is not a serotonin or norepinephrine reuptake inhibitor, but one that complements those already on the market for noncompliant and refractive patients. In vivo preclinical proof of concept for this lead therapeutic candidate showed not only antidepressive and anxiolytic activity, but also memory improvement not normally observed with an antidepressant. These behavioral benefits correlated with the long-term induction of new neurons, or neurogenesis, in a critical cognitive region of the brain.

Neuronascent's lead candidate for depression is also the lead candidate for post-traumatic stress disorder, which may be observed along with depression, but is considered a separate disorder. In a mouse model of the disorder, NNI-351 reversed the deficits and improved anxiety to better than normal mice.

*Our lead candidate for depression and post-traumatic stress disorder, NNI-351, is in the preclinical phase of development, where we are initiating IND-enabling studies.*

*sTMS*

Penn Medicine is currently one of the first research sites in the country that is testing the effectiveness of another non-invasive, medication-free treatment called synchronized transcranial magnetic stimulation (sTMS). This is a new brain stimulation treatment that may also help alleviate symptoms of depression. The sTMS system uses low energy, synchronized transcranial magnetic stimulation synchronized to an individual's natural brain rhythms as opposed to the stronger, high-frequency pulses utilized with traditional rTMS. Penn is one of only 16 sites in the country testing this new technology.

"sTMS is an exciting new development in psychiatry since it offers the potential for an additional non-pharmacological treatment for the disabling symptoms of depression," says Mahendra Bhati, MD, assistant professor of Clinical Psychiatry, who, along with Michael Thase, MD, professor of Psychiatry and chief, Division of Mood and Anxiety Disorders Treatment & Research Program, is researching the new treatment at Penn. "Many patients can't tolerate medications and TMScan be an effective treatment for these patients. sTMS is unique when compared to all other treatments in psychiatry since sTMS uses physiological markers of brain activity to tailor treatment. This offers the hope of individualized and potentially more effective treatment for the disabling and difficult to treat symptoms of depression."

So how exactly does it work? Research has shown that the neuronal activity in the brains of people with depression shows abnormal brain rhythms in areas associated with depressive symptoms. sTMS therapy is based on the theory that the brain rhythms can be "tuned" to a normal resting rhythm using low energy magnetic fields synchronized to an individual's brain activity. It is believed that this will restore normal brain rhythms leading to a reduction of depression symptoms and improved mood. Unlike conventional rTMS or medications, this type of magnetic stimulation is tailored to a patient's individual brain physiology.

More research is needed to determine the safety and efficacy of sTMS and the system is not yet FDA approved. Data from preliminary studies have shown that sTMS can improve depressive symptoms in a significant number of patients. The ongoing study at Penn and other sites seeks to confirm the findings from earlier studies and obtain FDA approval for sTMS when treating depression.

"They also have plans to make the device portable so it can be used at home where you can plug into the wall and listen to a built-in mp3 player. It's painless, relaxing, and a physiologically tailored treatment for depression," says Dr. Bhati. "If it works, it may be a treatment patients can administer to themselves in the convenience of their own home, unlike rTMS which requires five times a week visits to a doctor's office."

Researchers are hopeful that this kind of personalized approach to depression treatment will offer patients a greater variety of options to treat depression. Learn more about this trial and other depression research at Penn.

D Cycloserine

26 adult out-patients with Recurrent Major Depressive Disorder, currently resistant to treatment (defined as 20 plus score on the 21-item Hamilton Depression Rating Scale, despite two or more adequate antidepressant medication trials) and been treated for at least 4 wk with a stable clinically determined dose of antidepressant medication, were randomised using a double-blind, placebo controlled parallel group design to receive increasing dose of DCS or placebo.The mean duration of the current episode was 13-14 months.

Results

DCS treatment led to significant improvement in depressive symptoms as measured by HAMD.Seven of 13 (54%) patients assigned to DCS qualified as responders (i.e. 50% HAMD total score reduction) vs. two of 13 (15%) assigned to placebo. Five of 13 (38 %) patients assigned to DCS were also considered remitters (i.e. HAMD total score below 7) vs. two of 13 (15%) assigned to placebo, although this difference was not statistically significant. More patients ( 3 against one in placebo group) withdrew from experimental arm siting discomfort as reason.

Limitations: Small study. Remission rates were not statistically significant.

Conclusion: This study provides proof of concept evidence that antagonistic activity at the NMDAR-associated glycine site can induce antidepressant effects and reduce MDD severity. 54 % of DCS-treated subjects achieved treatment response. This is to be considered against the usually reported 60-65% response rate to the first antidepressant agent in depression. Authors also measured serum glycine levels and comment that treatment targeting NMDAR glycine site may be particularly appropriate in those with high glycine levels.

*7,8-Dihydroxyflavone*

*Living a traumatic experience favours the persistence of fear associated with an aversive stimulus, known as fear conditioning and which, in mice, can be eased with a single dosis of 7,8-Dihydroxyflavone, a type of flavonoid which boosts the ability to acquire new emotional habits. These findings were published in the American Journal of Psychiatry in a study carried out by researchers at Emory University, USA, and UAB, who consider that the drug could be used in the effective treatment of post-traumatic stress, panic and phobia disorders in persons.*

References

"Effect of 7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, on Emotional Learning". Raul Andero, Scott A. Heldt, Keqiang Ye, Xia Liu, Antonio Armario, Kerry J. Ressler. Am J Psychiatry, December 1, 2010, doi: 10.1176/appi.ajp.2010.10030326.

Mice previously exposed to traumatic situations demonstrate a stronger ability to react to fear conditioning - acquired by associating a sonorous stimulus with an aversive stimulus - and lack the ability to inhibit this fear. This phenomenon is similar to that of people who suffer from Post-Traumatic Stress Disorder (PTSD), an anxiety disorder which appears after being exposed to highly traumatic situations, such as a violent attack, a natural disaster or physical abuse.

In the study researchers verified that the 7,8-Dihydroxyflavone dosis injected into mice who had undergone a traumatic experience made them eliminate fear conditioning quicker. The boost in this new behaviour is the result of 7,8-Dihydroxyflavone activating the TrkB receptors in the brain, probably those found in the amygdala, which are essential for emotional learning and memory.

7.8-Dihydroxyflavone is a type of flavonoid. These chemical compounds are present in our diets in elements such as red wine, citrus, cereals, tea and chocolate (at least 70% cocoa), etc. Chronic administration of foods rich in flavonoids in lab animals has demonstrated neuroprotective effects in long-living rodents, but the activation of TrkB receptors produced by these foods is surely low compared to the effects of 7,8-Dihydroxyflavone.

TrkB receptors in the brain are activated in mammals with the BDNF protein. There are different pathologies, such as depression or anxiety disorders, in which this protein shows alterations in its expression. Unfortunately, administration of the BDNF protein as a drug is limited given that a large part of the amount injected does not permeate the blood-brain barrier and cannot access the brain. Very recent studies have demonstrated that 7,8-Dihydroxyflavone is the first drug to imitate BDNF actions and enter the brain with much more efficacy than the same protein, thus revealing therapeutic actions in animal models suffering from Alzheimer's, strokes, Parkinson's and/or depression.

The results obtained in this study postulate that 7,8-Dihydroxyflavone as a drug could be useful as a treatment of disorders based on fear, such as PTSD, panic attacks and phobias. Researchers consider it convenient to study its effects combined with psychotherapy, administrating the drug in fear elimination therapy sessions for anxiety disorders or even shortly after a person experiences a traumatic situation.

Led by Dr Kerry Ressler of Emory University, Atlanta, the study was developed with the participation of Dr Antonio Armario, researcher at the Institute of Neuroscience of the UAB and professor of the Department of Cell Biology, Physiology and Immunology, and Dr Raul Andero, researcher at the Emory University. The article published in the American Journal of Psychiatry is part of Dr Andero's doctoral thesis.

*RG1578/RG7090*

Link to PDF: http://www.researchg...antidepressants

This review focuses on the metabotropic glutamate (mGlu) receptors and their potential for drug targets for the treatment of depression. In particular, accumulating evidence has indicated the potential importance and usefulness of agents acting on mGlu2/3 and mGlu5 receptors. Preclinical and clinical evidence of mGlu2/3 receptor ligands and mGlu5 receptor antagonists are described. Moreover, their potential in clinic will be discussed in the context of neuronal mechanisms of ketamine, an agent recently demonstrated a robust effect for patients with treatment-resistant depression. This article is part of a Special Issue entitled 'mGluR'.

the list starts to be long! but honestly there are some that do look interesting for dp, although there are some i didn't post cause they don't seem that interesting for dp.


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## frenchguy (Mar 20, 2016)

PH-10 seems interesting because it trigger responses in the hypothalamus, amygdala, prefrontal cortex, and hippocampus

*ANAVEX 1-41 *looks interisting since it' represent a new class of anti-depressant and also have anti-convulsive property

*E-2508 * looks also interesting it's also a new class of anti-depressant and is involved in stress response in general

*NNI-351 * is also a new type of drugs targets neurogenesis and seems to be effective for anxiety and PTSD

*sTMS* well seems like a more effective rTMS

*7,8-Dihydroxyflavone * looks promising too, supposed to treat disease based on fear and 7 by activating the TrkB receptors in the brain, probably those found in the amygdala, which are essential for emotional learning and memory. could possibly help with inhibition of the amygdala seen in dp

*RG1578/RG7090* looks interesting because of his action on glutamate.


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## TDX (Jul 12, 2014)

According to Simeons book they tried Cycloserine on some patients without success.


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## frenchguy (Mar 20, 2016)

ok thx for sharing your knowledge, although it doesn't seem like the most interesting of the list imo


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## Max XR (Apr 9, 2016)

Why is CERC-501 not on the list? By the pharmacology and notable effects, it seems like a really good treatment for DP and it's in phase 3... however, it's not looking so good to make it to the market.


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## frenchguy (Mar 20, 2016)

yeah add him

*CERC-501 *

*CERC-501* (originally known as *LY-2456302*) is a potent, selective, short-acting (non-"inactivating") antagonist of the κ-opioid receptor (KOR) (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; ~30-fold selectivity for the KOR) that was originally developed by Eli Lilly.[1][2][3] In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code name of CERC-501).[4]

CERC-501 is under development for the treatment of major depressive disorder and substance use disordersincluding alcoholism, nicotine addiction, and illicit drug dependence.[5] As of 2016, it has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[6][7] In animal models of depression, CERC-501 has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[7] A phase II study of CERC-501 in heavy smokers will be commenced in early 2016 and results of the study are expected before the end of 2016.[8]

In December 2015, the results of a human pharmacokinetic study of CERC-501 were released.[5][8] CERC-501 was shown to reproducibly penetrate the blood-brain-barrier, and positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that CERC-501 is being explored at in clinical trials.[5][8]Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[8] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[8] No serious side effects were observed, and all side effects seen were mild to moderate and not considered to be due to CERC-501.[8]

CERC-501 has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), indicating that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[9]


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