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20 New Antidepressants In The Pipeline (2015): Drugs In Clinical Trials

For individuals in the United States between the age of 15 and 44, major depression is the leading cause of disability.  Major depression is often a heritable condition, caused by maladaptive genes getting transferred across generations.  That said, not everyone diagnosed with major depressive disorder inherited the condition from ancestors or should be blaming their genes.

A large percentage of individuals with major depression end up depressed as a result of epigenetic changes stemming from exogenous, environmental influences and experiences.  Examples of exogenous factors that could cause depression include: post-traumatic stress, environmental toxins (e.g. air pollution), bullying, substance abuse, inadequate nutrition, poor sleep hygiene, losing a job, death of a loved one, relationship problems, high work-stress, traumatic brain injuries, and more.  Due to the array of possible factors that could prompt a depressive episode, it’s often difficult to treat.

While doctors are equipped to treat depression with an arsenal of medications, these may not be the best option if your depression is caused by exogenous factors like chronic mold exposure.  In this case, the medications would merely mask the underlying problem.  However, for individuals that cannot think of (or correct) any exogenous causes of depression, pharmacological treatments may be their only hope.

New Antidepressants In The Pipeline (2015): Drugs In Clinical Trials

Below is a list of new antidepressants in development as of 2015.  Understand that not all of these drugs will survive clinical trials and get FDA approval.  However, certain drugs on the list exhibit novel mechanisms of action that could improve upon older antidepressant treatments.

  1. 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.

Animal research has shown that antagonism of the kappa receptor can significantly improve mood and anxiety.  Think of ALKS 5461 like using Suboxone for depression without the opioid-induced euphoria and addiction potential.  Currently ALKS 5461 is in Phase III clinical trials, has been “fast tracked” by the FDA, and is slated for a 2017 release.  If any drug has potential to provide potent, fast-acting relief to individuals with refractory depression – this is it.

  1. 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.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25599313
  1. 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.

  • Source: http://www.vistagen.com/?page_id=11
  1. 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.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17848867
  • Source: https://clinicaltrials.gov/ct2/show/NCT02153502
  1. 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
  1. 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
  1. Botox (onabotulinumtoxinA)

  • Mechanism: Facial nerve inhibitor
  • Status: Phase II clinical trials
  • Company: Allergan

Allergan, a company based in Irvine, California, is investigating the usage of botulinum toxin type A (OnabotulinumtoxinA) or Botox  as an antidepressant.  I’ve already written about using Botox injections for the treatment of depression; they would target the corrugator and procerus muscles within the face.  Facial expression is thought to contribute to depressive states via nerve signaling within the face – particularly from the corrugator and procerus muscles.

Facial injections with Botox inhibits nerve activity in corrugator and procerus muscles.  Preliminary evidence from trials indicates that Botox is an effective treatment for depression compared to a placebo (saline injection).  In addition, just one treatment session with Botox can yield a sustained antidepressant effect – eliminating the need for recurrent injections.

Assuming Botox injections are considered efficacious and advance through clinical trials, many may opt for one-time injections over pharmacological interventions.  It should also be considered that Botox injections may have significant cosmetic appeal to aging adults.  Furthermore, many with refractory depression may utilize Botox injections as an antidepressant augmentation strategy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24345483
  1. CERC-301

  • Mechanism: NR2B antagonist
  • Status: Phase II clinical trials
  • Company: Cerecor

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).

  • Source: http://www.cerecor.com/pipeline/cerc-301.php
  1. 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
  1. Esketamine (Intranasal Ketamine)

  • Mechanism: NMDA receptor antagonist
  • Status: Phase II clinical trials
  • Company: Janssen Pharmaceuticals

Esketamine (or Ketanest S) is being touted as a safe ketamine nasal spray for depression.  It incorporates the “S(+)”-enantiomer of the drug ketamine (as opposed to the R-enantiomer).  Upon administration of Esketamine, it functions as a non-competitive NMDA receptor antagonist, and to a lesser extent, inhibits the reuptake of dopamine.

NMDA receptor antagonism is known to rapidly ameliorate depressive symptoms and suicidal ideation.  Despite the rapid-acting antidepressant effects, it is important to consider the potential long-term effects of chronic ketamine usage.  There is reason to believe that Esketamine could cause neurotoxicity when administered consistently over an extended term.

That said, the FDA realizes that many people with depression have failed to derive symptomatic relief from currently available treatments.  As a result, they’ve granted “Fast Track Designation” to Janssen for the development of Esketamine.  The novel mechanism of action (nasal spray) coupled with NMDA antagonism make Esketamine a unique, potent, and (potentially dangerous) antidepressant.

  1. 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
  1. 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
  1. 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
  1. 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
  1. 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.

  1. 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/
  1. 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
  1. 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
  1. 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/
  1. Tedatioxetine (Lu AA24530)

  • Mechanism: SNDRI
  • Status: Phase II clinical trials
  • Company: Lundbeck / Takeda

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.

Depression as a chemical imbalance? It’s a bit more complex.

Depression is marketed by pharmaceutical companies as being a “chemical imbalance,” caused by lack of certain neurotransmitters (e.g. low serotonin).  While a chemical imbalance may be a symptom of depression, it’s an impossibility for it to be the root cause; the chemicals don’t make themselves.  Assuming your depression is caused by endogenous factors, the most likely causes include: brain damage, maladaptive genes, or lack of certain genes.

Maladaptive genes can create changes in the levels of neurotransmitters and alter densities of receptors within the brain.  Lacking certain genes may also cause you to feel depressed due to the fact that your brain doesn’t have the encoders necessary to produce proteins that would improve neurotransmission.  For this reason, futuristic techniques such as: RNAi for depression, gene therapy for depression, and even nanotechnology for depression – are being investigated.

Still, we are a long ways out from being able to correct brain damage with nanobots, silence genes with RNAi, and introduce new genes with gene therapy.  In the meantime, considering a pharmacological option is often a viable treatment strategy.  Assuming you’ve tried: natural cures for depression, have attempted to overcome depression with logic, and tested high tech treatments for depression – medication isn’t a bad idea.

Current Difficulties with Antidepressant Treatment

It is estimated that nearly 2 of 3 people with depression that use a medication achieve symptomatic relief.  However, 1 of 3 people with depression simply don’t derive benefit or find that antidepressants increase their depression.  To make matters worse, many of the responders find that over time, their antidepressant stops working and other options fail to alleviate symptoms.

While antidepressants aren’t known for “tolerance” like an illicit street drug, a person’s neurophysiology eventually adapts to it – often over a period of months and/or years.  Once this adaptation has ensued, the drug will stop working.  This will leave the person to either: stop the drug and face the wrath of withdrawal (causing an array of unforeseen symptoms and worsening of depression), increase the dosage (for more relief plus more side effects), and/or play antidepressant roulette – taking a gamble on another medication.

Other problems associated with pharmacologic treatments include: antidepressant side effects (e.g. weight gain) and the fact that antidepressants take awhile to work (usually 4 to 6 weeks).  It is hoped that newer antidepressants will continue to improve upon past-treatments.  Improvements could be made in terms of: side effect profiles, long-term efficacy (and tolerance), pharmacological mechanisms, speed of onset, and universal efficacy.

Which pipeline antidepressants may be superior to currently available treatments?

While many pharmaceutical companies are attempting to develop new antidepressants, some are more creative in their development than others.  Many companies like to play it safe by targeting the same, proven monoamines such as serotonin, norepinephrine, and dopamine.  As a result, we have several “SNDRIs” also known as triple reuptake inhibitors in the pipeline.

The SNDRI class doesn’t seem to offer much novelty other than the combination of serotonergic, noradrenergic, and dopaminergic action within one pill; this can already be accomplished by combining an SSRI with Wellbutrin.  There are several pipeline antidepressants that may be superior to current-market medications in terms of: onset of action, duration of effect, modality of administration, and ability to attenuate suicidal ideation.

A new class of antidepressants known as the NMDA receptor modulators may be substantially better than current treatments.  Many of these drugs have been engineered to contain neuroprotective properties, minimal side effects, and effectively treat depression within 24 hours of administration.  Moreover, the antidepressant effect of certain NMDA receptor modulators (NRX-1074 and GLYX-13) is more significant and longer lasting after one dose, than SSRIs after weeks of administration.

Other modulators of NMDA receptors like AVP-786, AV-101, and CERC-301 have shown similar fast-acting effects in early trials.  It’s just a matter of time before a boatload of selective NMDA receptor antagonists (or modulators) get FDA approval.  While they may be effective for depression, consequences associated with long-term consistent usage will remain unknown.

An example of a promising non-monoaminergic drug in the pipeline is Mifepristone (RU-486), which is capable of treating depression and psychosis by modulating activity within the HPA axis of the brain; it is already in Phase III clinical trials.  The drug “LY2940094” being developed by Eli Lilly could pave the way for a new class of antidepressants that act as NOC antagonists (targeting nociceptin receptors).  ALKS-5461 under development by Alkermes is also promising in that it may be the first approved antidepressant to target opioid receptors.

That said, perhaps the most exciting drug of all is NSI-189, which functions by increasing hippocampal brain volume.  NSI-189 is being developed by NeuralStem Inc. – a company focused on using small molecules to help the brain repair itself, primarily through neurogenesis.

Which new antidepressants are you most excited about?

There are many novel drugs in the pipeline for the treatment of depression.  Since depression is estimated to cost the United States billions of dollars per year (in health care costs, lack of workplace productivity, etc.) – it remains evident that novel treatments are warranted.  Many people simply aren’t responding well to the currently available treatments.

Assuming you’ve looked at some antidepressants in the development pipeline, which are you most looking forward to trying?  Do you think that any specific mechanisms of action such as NMDA modulation may be favorable over others such as opioidergic, nociceptin antagonists, or triple reuptake inhibitors?  If there was one antidepressant in the pipeline that you could try right now, what would it be?

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{ 7 comments… add one }
  • Jim October 3, 2015, 9:55 pm

    This is a GREAT article. This gives us some hope for a useful pipeline – rather than more me-too’s, knock-offs and Triple Reuptake Inhibitors. The fact that we have NMDA and opioid (and other) truly novel medications coming (pending approval, obviously) is heartening. THANK YOU.

  • Anna Buse November 16, 2015, 7:41 am

    ALKS-5461 sounds very promising to me…something that leaves your serotonin receptors alone at last!

  • Juan March 30, 2016, 12:39 am

    Very good article. I would like to know more about the long term safety of MIFEPRISTONE. Thanks.

  • Jerry March 31, 2016, 5:39 am

    Why not approve tianeptine/Stablon in the US?

    • Drew August 1, 2016, 3:30 am

      It works too well. Same reason they’re banning Kratom all over the place, they want them to help you get better, just not to the point where you don’t occasionally switch meds and quit going to a psychiatrist every month.

  • casey June 11, 2016, 6:25 am

    Hope… They can’t come quickly enough. I did a research study on Ketamine at NIMH in 2013, and the DOCs said they new meds would be available in approximately 5 years. Lots of people suffering. This is a fascinating and hope inspiring article. Thanks!

  • Drew August 1, 2016, 3:27 am

    Selective opioids are the real future of antidepressant and anxiety medications. The problem is that “euphoria” and “abuse potential” are considered to negative side effects, when in reality this is exactly what a person who actually has a mental illness (many on antidepressants don’t) needs. We have the ability now to develop selective opioids that don’t have any of the deadly side effects, they’ll just be euphoric and addictive.

    Most are already addicted to the meds they take, the meds they take just suck at what they’re supposed to do. I encourage people to look into the French antidepressant Tianeptine (which can be bought online in the U.S.) and Tramadol for depression. Weaker opioids that have SNRI like qualities as well which put Prozac to shame.

    Kratom is a just as good if not better option than those two, but may not be legal for much longer specifically because it’s so effective for so many different things without many of the side effects. If you’re desperate for relief from anxiety or depression and have come to the conclusion that you will probably have to take something for the rest of your life, Buprenorphine is the king of current selective opioids and is the most effective substance available in my mind.

    It’s easy enough to get (look up suboxone doctor on google, claim opioid addiction, boom) and is especially effective for dissociative disorders like Depersonalization disorder. Just two cents from a recovered addict who hasn’t ran into many drugs or medications that I haven’t used or studied in depth about.

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