30+ New Antidepressants (2018): Drugs In Clinical Trials

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Research suggests that upwards of 16 million American adults (6.7% of the adult population) are afflicted with major depressive disorder (MDD), a neuropsychiatric condition characterized by overwhelming sadness, behavioral changes, sleep disturbances, and cognitive deficits. As of current, depression is the leading cause of disability in the United States among individuals between the ages of 15 and 44. Moreover, it is known that approximately 1 in 33 children and 1 in 8 adolescents exhibit clinical depression.

First-line treatments for depression generally include a combination of antidepressant medication and cognitive behavioral therapy (CBT). Healthy lifestyle changes such as: eating a nutrient-dense diet, stress reduction, adhering to a sleep schedule, exercising each day, and staying socially active – are also known to help some individuals with depression. Unfortunately, of all individuals with major depressive disorder, only around 50% receive treatment.

Although approximately 70% of individuals who receive antidepressant medication derive substantial therapeutic benefit, the remaining 30% are partial or non-responders. Partial or non-responders to antidepressant medication tend to have poor quality of life, suicidal ideation, and long-term functional impairment. For this reason, there’s a major need to develop new antidepressants in 2018 to help the ~30% of individuals who don’t respond well to current-market medications.

30+ New Antidepressants (2018): Drugs In Clinical Trials

Included below is a list of new antidepressants in development as of Q1 (first-quarter) 2018. In the process of writing this article, I reflected upon an older article highlighting antidepressants that were being developed in 2015. As I expected, many of the drugs in clinical trials throughout 2015 – are still in clinical trials as of 2018. That said, some prospective antidepressants are making good progress through clinical trials and/or are on the verge of hitting the market this year (e.g. ALKS 5461). Additionally, it’s good to see more drugs in the development pipeline during 2018 than there were in 2015.

ALKS-5461

Mechanism: Mu receptor partial agonist + kappa receptor antagonist

Status: Pending FDA approval

Developer: Alkermes

ALKS 5461 is a medication that contains a fixed-dose combination of buprenorphine and samidorphan. I’ve written about the therapeutic potential of ALKS 5461 for depression over the past several years and figured that its unique mechanism of action would facilitate a robust antidepressant effect. Due to its safety and notable efficacy in early clinical trials, the drug was fast-tracked through development.

How does it work? “ALKS 5461” is a combination of 2 distinct substances: buprenorphine and samidorphan. The buprenorphine facilitates mood enhancement via partial agonism of the mu-opioid receptor (MOR) and full agonism of the kappa opioid receptor (KOR). Buprenorphine, the active ingredient in Suboxone and other opioid-replacement therapies, has been effectively utilized on an off-label basis for years to treat refractory cases of depression. (Read: “Suboxone for depression.”)

That said, buprenorphine as a standalone agent is considered to be among the most addictive drugs in the world. For this reason, ALKS 5461 also consists of samidorphan which acts as a selective antagonist of the mu-opioid receptor. Essentially, samidorphan counteracts any euphoric or pleasurable intoxication derived from buprenorphine that might make it addictive, leaving users with mostly antagonism of the kappa receptor to block the release of “dynorphins” which can improve mood and decrease anxiety. Although ALKS 5461 was initially on pace for a 2017 release, it seems as though it should hit the market sometime in 2018 or 2019.

Source: http://www.alkermes.com/research-and-development/pipeline

Apimostinel

Mechanism: NMDA receptor partial agonist

Status: Phase II (IV) & Phase I (Oral) clinical trials

Developer: Allergan

Apimostinel, also referred to as NRX-1074, is a drug that was originally developed by Naurex for the treatment of depression – but is now undergoing co-investigation by Naurex and Allergan (who acquired Naurex). The drug functions as a selective partial agonist upon NMDA receptors, specifically at allosteric sites of the glycine binding site. While Apimostinel exhibits a similar mechanism of action GLYX-13 (another drug undergoing development by Naurex), it differs from GLYX-13 in that it is markedly more potent by weight.

A comparative analysis reveals that, by weight, Apimostinel is over several thousand times the potency of GLYX-13. I’ve previously discussed the potential benefits of utilizing NRX-1074 for depression, mentioning that it is rapid-acting, devoid of psychotomimetic effects, and seemingly well-tolerated. Preliminary evidence indicates that depressive symptoms may dissipate in as quickly as 24 hours after Apimostinel ingestion.

Moreover, the mood enhancing effect of Apimostinel seems to be dose-dependent whereby higher doses exert more prominent antidepressant effects. Worth noting is that, in early trials, a single dose of Apimostinel provided greater relief from depressive symptoms than administration of SSRIs for weeks. Currently there’s an intravenous format of the drug in Phase II clinical trials and an oral format in Phase I.

Source: https://www.allergan.com/research-and-development/allergan-pipeline

AV-101

Mechanism: NMDA receptor antagonist

Status: Phase II clinical trials

Developer: VistaGen Therapeutics

AV-101 (4-CI-KYN or L-4-chlorokyurenine) is a prodrug developed by VistaGen Therapeutics as an adjunct treatment for major depressive disorder. Because it’s a prodrug, AV-101 remains completely inactive until ingested and metabolized into the chemical 7-CL-KYNA (also referred to as 7-chlorokynurenic acid). After its biotransformation into 7-CL-KYNA, it antagonizes NMDA receptors, particularly across sites of glycine binding.

The potent NMDA antagonism exerted by 7-CL-KYNA modulates the neurotransmission of dopamine and GABA (gamma-aminobutyric acid). It is suspected that the neurochemical effects exerted by 7-CL-KYNA yield a nearly-instantaneous antidepressant effect. In other words, this drug may enhance mood within minutes of its administration – rather than after weeks of treatment (as is common with current-market medications).

Perhaps worth noting is that research of AV-101 in animal models indicates that it functions as a neuroprotective agent, counteracting excitotoxicity (damage from excessive excitatory neurotransmitters). Furthermore, AV-101 is under investigation as a possible treatment for other medical conditions such as epilepsy and neuropathic pain. Currently, AV-101 is in Phase II of clinical trials.

Source: https://www.vistagen.com/pipeline/av-101

AXS-05

Mechanism: NDRI, nAChR antagonist + SNRI, Sigma-1 agonist, NMDA antagonist

Status: Phase III clinical trials

Developer: Axsome Therapeutics

AXS-05 is a drug in development by Axsome Therapeutics specifically for treatment-resistant depression, or depression that hasn’t responded to 2 or more conventional treatments. AXS-05 contains a fixed-dose combination of bupropion (i.e. Wellbutrin) and dextromethorphan (DXM). Following ingestion of AXS-05, the bupropion component inhibits CYP2D6 (cytochrome P450 2D6) enzymes in the liver to prolong the metabolism of dextromethorphan and ultimately increase its bioavailability.

Normally, dextromethorphan is subject to rapid metabolism in humans such that it’s difficult to attain potentially-therapeutic dextromethorphan levels in the bloodstream. Because bupropion interferes with otherwise rapid dextromethorphan metabolism, dextromethorphan concentrations increase to potentially-therapeutic levels. This makes it easier for dextromethorphan to exert potent effects within the brain as a nonselective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, sigma-1 receptor agonist, and NMDA receptor agonist.

Additionally, the bupropion component is already understood to be efficacious in the treatment of major depressive disorder as a norepinephrine reuptake inhibitor, weak dopamine reuptake inhibitor, and nAChR antagonist. The widespread effects of AXS-05 across a myriad of neurotransmitter systems may prove effective for those with treatment-resistant depression. AXS-05 is currently in phase III of clinical trials for both treatment-resistant depression and agitation in Alzheimer’s disease.

Source: http://axsome.com/axs-05/about-axs-05/

BLI-1005

Mechanism: NET inhibitor

Status: Phase II clinical trials

Developer: BioLite

BLI-1005 is a botanical extract typically utilized as a sedative in Traditional Chinese Medicine (TCM) that is undergoing development in Taiwan by the company BioLite for the treatment of major depressive disorder. The extract functions as NET (norepinephrine transporter) inhibitor whereby it blocks the reuptake of norepinephrine via the norepinephrine transporter. This increases noradrenergic signaling and indirectly increases dopamine concentrations in certain regions of the brain.

According to BioLite’s website, BLI-1005 is covered by patents in 8 countries: U.S., U.K., Japan, Germany, France, Italy, Switzerland, and Taiwan. In animal studies, BLI-1005 has shown efficacy in treating depression via norepinephrine reuptake inhibition. BioLite suspects that BLI-1005 may help treat cases of major depressive disorder in which serotonergic medications (e.g. SSRIs) are ineffective.

In Phase I of clinical trials, BLI-1005 was discovered to be safe in humans at doses up to 3800 mg. BLI-1005 has apparently been in Phase II clinical trials since 2015 and results are unclear. Though a subset of individuals may find NRIs useful as antidepressants (e.g. Strattera for depression), most NRIs have never made it to market for the treatment of depression in the United States.

Source: http://www.biolite.com.tw/en/new-drug/bli1005.html

Botox® (OnabotulinumtoxinA)

Mechanism: Facial nerve inhibitor

Status: Phase II clinical trials

Developer: Allergan

OnabotulinumtoxinA, commonly known as “Botox,” has been subject to ongoing investigation as a potential treatment for depression. In the past, I reflected upon the therapeutic potential of administering Botox injections for depression. Unlike conventional orally-administered antidepressant medications, Botox (OnabotulinumtoxinA) would be administered via injections at various sites across the face.

More specifically, Botox (OnabotulinumtoxinA) injections would target the corrugator and procerus muscles of the face. By targeting the corrugator and procerus facial muscles, facial nerve signaling would shift and facial expression would change from pre-Botox homeostasis. The combination of altered facial nerve signaling and corresponding facial expression changes are thought to facilitate an antidepressant effect.

Available evidence suggests that Botox injections enhance mood, whereas saline (placebo) injections do not. What’s more, it seems as though just a single Botox treatment may induce a long-lasting antidepressant effect, possibly minimizing the need for ongoing injections. As of 2018, Allergan’s Botox injections remain in phase II of clinical trials.

Source: https://www.allergan.com/research-and-development/allergan-pipeline

BTRX-246040

Mechanism: NOC receptor antagonist

Status: Phase II clinical trials

Developer: BlackThorn Therapeutics

BTRX-246040, formerly known as LY-2940094, is a potent and selective nociceptin (NOC) receptor antagonist being investigated for the treatment of major depressive disorder. The drug was initially investigated by Eli Lilly but now seems to be associated with BlackThorn Therapeutics under a new chemical title. A proof-of-concept study published in 2016 reported that LY-2940094 (40 mg) was safe, well-tolerated, and effective for the treatment of depression in humans – over an 8-week duration.

Its preliminary efficacy as an antidepressant was evidenced by significant changes in GRID-Hamilton Depression Rating Scale-17 total scores from baseline through 8 weeks. Additionally, it was noted that LY-2940094 alters processing of emotional stimuli within the first week of treatment – as evidenced by increased recognition of positive relative to negative facial expressions on emotional test battery. Data from preliminary investigation of LY-2940094 are among first to showcase the therapeutic potential of NOP receptor antagonism in treating depression.

There’s some debate as to whether BTRX-246040 will continue to be developed for major depressive disorder – or instead undergo investigation as a treatment for other neurological disorders. Nevertheless, BTRX-246040 exhibits a unique mechanism of action compared to most antidepressants in development. Antagonizing the NOC receptor seems to increase monoamine concentrations in several brain regions, enhance neurogenesis, and modulate activation of the hypothalamic pituitary adrenal (HPA) axis.

Source: http://www.blackthornrx.com/#pipeline

Source: https://www.ncbi.nlm.nih.gov/pubmed/26585287

CERC-301

Mechanism: NMDA receptor (NR2B-selective) antagonist

Status: Phase II clinical trials

Developer: Cerecor

CERC-301 is a drug that the FDA granted “Fast Track Designation” in 2013 as a potential adjunct treatment for depression and suicidal ideation. Pharmacodynamic research indicates that CERC-301 functions as a highly-selective antagonist upon NR2B subunits of NMDA receptors. Its selective affinity for the NR2B subunits of NMDA receptors is thought to minimize likelihood of psychotomimetic effects (e.g. drug-induced psychosis) that commonly occur with other, less selective NMDA receptor antagonists.

The developer of CERC-301, Cerecor, suggests that CERC-301 will exert rapid antidepressant activity such that relief from depressive symptoms may occur within minutes or hours of its administration – rather than days or weeks. Preliminary data from CERC-301 trials indicate that the drug is well-tolerated and safe. Many believe that CERC-301 is the most promising NMDA antagonist in development for the treatment of depression. However, despite its FDA fast-tracking, the drug has marinated in phase II of clinical trials since 2015.

Source: http://www.cerecor.com/pipeline/cerc-301.php

CERC-501

Mechanism: KOR antagonist

Status: Phase III

Developer: Janssen

CERC-501 is a drug that was first engineered by Eli Lilly under the name LY-2456302. However, in February 2015, Eli Lilly sold LY-2456302 to Cerecor Inc. who renamed the investigational drug CERC-501. In 2016, CERC-501 reached phase II clinical trials as an antidepressant augmentation strategy among persons with treatment-resistant depression.

As of August 2017, Cerecor sold the rights of CERC-501 to Janssen Pharmaceuticals who is continuing its development as an adjunct treatment for depression and intervention for substance abuse disorders. Pharmacodynamic assessments reveal that CERC-501 functions as a selective, short-acting KOR (kappa opioid receptor) antagonist. Research indicates that activation of kappa opioid receptors (KORs) can trigger dysphoria, hallucinations, and psychotomimetic effects – as well as reinforce neurochemical systems implicated in reward deficiency syndrome, chronic stress, and major depression.

Antagonism of the kappa opioid receptor (KOR) with CERC-501 may facilitate an antidepressant effect by counteracting preexisting kappa opioid receptor activation. Animal model data indicate that kappa opioid receptor antagonism reverses learned helplessness. What’s more, the combined administration of CERC-501 and other antidepressants (e.g. SSRIs) yields synergistic mood enhancement (or greater enhancement than would be attained with either agent as a standalone). Side effects of CERC-501 have been reported as mild-to-moderate, but not serious – throughout phase III of clinical trials.

Source: https://clinicaltrials.gov/ct2/show/NCT01913535

Liafensine (DB104)

Mechanism: SNDRI

Status: Phase II

Developer: Denovo Biopharma

Liafensine (DB104), formerly known as BMS-820836, is an SNDRI (serotonin-norepinephrine-dopamine reuptake inhibitor) or triple reuptake inhibitor, that was first developed by AMRI and licensed to Bristol-Myers Squibb for the treatment of major depressive disorder. Through phase II of clinical trials, the drug exhibited efficacy akin to that of escitalopram (i.e. Lexapro) and duloxetine (i.e. Cymbalta). However, Bristol-Myers Squibb terminated its development largely because its efficacy was not markedly superior to that of Lexapro and Cymbalta.

While lack of superiority over Lexapro and Cymbalta wouldn’t usually be considered a setback in antidepressant drug development, Liafensine is suspected to cause a greater number of side effects and exhibits abuse potential. Its efficacy relative to side effect profile and abuse potential was likely the reason that Liafensine development was halted by Bristol-Myers Squibb. That said, Liafensine’s licensing rights were acquired by Denovo Biopharma in 2017 and phase II clinical trials of the triple reuptake inhibitor have continued.

Source: https://www.denovobiopharma.com/index8.html

DSP-1200

Mechanism: Alpha-2A, D2, 5-HT2A antagonist

Status: Phase I

Developer: Sunovion Pharmaceuticals

DSP-1200 is a drug developed by Sunovion Pharmaceuticals for the treatment of treatment-resistant depression. The drug functions as an antagonist at several neurotransmitter receptor sites, including: Alpha-2A adrenergic receptors; D2 dopamine receptors; and 5-HT2A serotonin receptors. Given DSP-1200’s mechanism of action, it surprises me that it wouldn’t first undergo investigation as a treatment for schizophrenia – before treatment-resistant depression.

Perhaps there’s a bigger market for treatment-resistant depression than schizophrenia? In any regard, it blocks Alpha-2 receptors which is a mechanism of action exerted by tetracyclic antidepressants mianserin and mirtazapine. Blockade of Alpha-2A receptors modulates downstream norepinephrine, dopamine, and serotonin levels – plus may affect insulin secretion and blood sugar.

The antagonism of D2 receptors is understood to decrease dopaminergic activity, which isn’t something that’s necessarily helpful in depression. D2 receptor antagonism reduces dopaminergic signaling which tends to alleviate positive symptoms of schizophrenia such as delusions and hallucinations (e.g. hearing voices). Lastly, 5-HT2A receptor antagonism may interact with pyramidal neurons and/or alter prefrontal-subcortical pathways to alleviate depressive symptoms among patients with treatment-resistant depression.

As of current, DSP-1200 is in Phase I of clinical trials. After reflecting upon its mechanism of action, DSP-1200 seems to be nothing more than an antipsychotic masquerading as an antidepressant; nothing to be excited about.

Source: http://www.sunovion.us/research-and-development/pipeline.html

Esketamine

Mechanism: NMDA receptor antagonist

Status: Phase III (completed) clinical trials

Developer: Johnson and Johnson

Esketamine (also known as “Ketanest S”) is being investigated as a form of ketamine nasal spray for depression. Esketamine consists of the S(+)-enantiomer of the chemical ketamine (but not the R-enantiomer), hence its [appropriate] name Es (derived from “S”) + ketamine. When administered intranasally, Esketamine acts predominantly as a non-competitive NMDA receptor antagonist – with additional modest effect as a dopamine reuptake inhibitor (DRI).

Antagonism of NMDA receptors is understood to promptly alleviate symptoms of major depressive disorder, as well as suicidal ideation. While the intranasal ketamine spray may prove efficacious as an antidepressant with rapid-onset of action, there are some long-term risks associated with this treatment, including: neurotoxicity, dissociation, and psychotomimetic side effects (e.g. symptoms of psychosis). Though its therapeutic potential is significant as an antidepressant, it could cause serious short-term and/or long-term adverse effects.

For this reason, Esketamine is being marketed specifically for individuals with treatment-resistant depression, or persons who’ve tried multiple antidepressant medications with inadequate symptomatic relief. It seems as though Esketamine has completed phase III of clinical trials. Johnson and Johnson are expected to file an application for FDA approval by the end of 2018.

Source: http://www.investor.jnj.com/_document/jnj-pipeline-q4-2017?id=00000161-28af-dbe1-a9e9-2bff4e700000

FKB01MD

Mechanism: Serotonin receptor modulator + serotonin uptake inhibitor

Status: Phase II

Developer: Fabre-Kramer Pharmaceuticals

FKB01MD is an antidepressant being developed by Fabre-Kramer Pharmaceuticals. According to the developer, FKB01MD exerts a potent and rapid antidepressant action whereby it downregulates concentrations of 5-HT2 receptors overnight. It exhibits 5 distinct mechanisms of action, some of which include: 5-HT reuptake inhibition; 5-HT2 receptor agonism; 5-HT1A receptor agonism; and 5-HT1D autoreceptor modulation.

Preliminary data suggest that FKB01MD effectively reverses muricidal behavior (propensity to kill mice) among rats where it is more efficacious than fluoxetine (i.e. Prozac) or desipramine. What’s more, it seems as though FKB01MD facilitates a superior antidepressant effect compared to SSRIs among animal models in the Porsolt Forced-Swim test. Developers believe that the myriad of serotonergic effects exerted by FKB01MD will yield more robust and faster-acting antidepressant responses in humans than conventional serotonergic medications (e.g. SSRIs).

Additionally, developers state that FKB01MD exhibits similar: 5-HT reuptake inhibition to tricyclic antidepressants; 5-HT2 receptor antagonism to trazodone; and 5-HT1A receptor interactions to azapirones (e.g. buspirone). As of current, FKB01MD is in phase II of clinical trials. Preclinical data from trials indicate that doses of 10-30 mg (b.i.d.) are well-tolerated with mild side effects of lightheadedness and nausea.

Source: http://www.fabrekramer.com/?page_id=66

Ganaxolone

Mechanism: GABAA receptor modulator

Status: Phase II

Developer: Marinus Pharmaceuticals

Ganaxolone is a drug being developed by Marinus Pharmaceuticals for the treatment of postpartum depression, as well as several other conditions such as: epilepsy and Fragile X syndrome. Pharmacodynamic assessments indicate that Ganaxolone functions as a selective positive allosteric modulator of the GABAA receptor. When administered to animals, Ganaxolone yields antiepileptic and anxiolytic effects whereby it respectively protects against seizures and reduces anxiety-like behavior.

Its action as a positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors aids in the normalization of over-excited neurons and excitotoxicity. Like other GABAA receptor modulators, Ganaxolone binds to allosteric sites of the GABAA receptor which triggers opening of the chloride ion channel to hyperpolarize the neuron. Hyperpolarization of the neuron yields an inhibitory effect upon neurotransmission whereby likelihood of action potentials is reduced.

Compared to other agents that modulate the GABAA receptor, Ganaxolone may be unique in its ability to act upon extrasynaptic receptor sites. Currently, Ganaxolone is in phase II of clinical trials. The most common side effects associated with Ganaxolone reported thus far include: sleepiness, dizziness, and fatigue – (most of which should be expected with GABAA receptor modulation).

Source: http://www.marinuspharma.com/ganaxolone/

Lumateperone (ITI-007)

Mechanism: Serotonin receptor antagonist

Status: Phase II

Developer: Intra-Cellular Therapies

Lumateperone is a drug being investigated by Intra-Cellular Therapies as a potential treatment for multiple neuropsychiatric conditions, including major depressive disorder. Clinical trials of Lumateperone for the treatment of major depressive disorder are currently in phase II. However, trials of Lumateperone for schizophrenia are nearly complete – with two phase III trials already conducted.

Analyses of Lumateperone’s pharmacodynamics reveal that it would likely prove most efficacious as an antipsychotic for the treatment of schizophrenia. Specifically, Lumateperone functions as a 5-HT2A receptor antagonist; D2 presynaptic receptor partial agonist; D2 postsynaptic receptor antagonist; and SERT inhibitor. In addition, it seems as though Lumateperone interacts with D1 receptors; alpha-1A receptors; and alpha-1B receptors.

Compared to other antipsychotics, Lumateperone is unique in that its respective affinities for 5-HT2A and D2 receptors differ by approximately 60-fold; this exceeds all current-market antipsychotics. Moreover, Lumateperone appears to counteract psychotic symptoms and markedly improve negative symptoms such as social deficits and depression among individuals with schizophrenia. Its ability to alleviate negative symptoms of schizophrenia better than risperidone might make it a useful agent in the treatment of major depressive disorder.

Source: http://www.intracellulartherapies.com/products-and-technology/lumateperone/

JNJ-39393406

Mechanism: Alpha-7 nAChR modulator

Status: Phase II

Developer: Janssen

JNJ-39393406 is an experimental medication being developed by Janssen, a subsidiary of Johnson & Johnson, for the treatment of major depressive disorder – as well as smoking cessation. Compared to most current-market antidepressants, JNJ-39393406 is unique in that it functions solely as a selective positive allosteric modulator (PAM) of the alpha-7 nicotinic acetylcholine receptor. Pharmacodynamic research indicates that the medication does not interact with alpha-4-beta-2 or alpha-3-beta-4 nicotinic acetylcholine receptors – or the 5-HT3 receptors.

What’s more, it appears as though the medication does not interact with a comprehensive panel of 62 receptors and enzymes. Administration of JNJ-39393406 appears to reduce the threshold for activation of the alpha-7 nAChRs by 10-fold to 20-fold – depending on the dose, and increases the maximum agonist response of alpha-7 nAChRs between 17-fold and 20-fold. In other words, JNJ-39393406 makes it easier for the alpha-7 nAChRs to activate and enables activation to exceed normative biologic levels.

As of February 2018, JNJ-39393406 is in phase II clinical trials for the treatment of major depressive disorder and nicotine withdrawal. JNJ-39393406 was formerly investigated as an intervention for Alzheimer’s disease and schizophrenia, however, its evaluation for these conditions was abandoned. Given the fact that JNJ-39393406 functions differently than most antidepressant medications and exhibits a highly-targeted mechanism of action – it’s a development worth monitoring.

Source: https://ncats.nih.gov/files/JNJ-39393406.pdf

Source: https://www.ncbi.nlm.nih.gov/pubmed/18583432

JNJ-54175446

Mechanism: Purinergic P2X7 receptor antagonist

Status: Phase I

Developer: Janssen

JNJ-54175446 is another experimental medication being developed by Janssen, a division of Johnson & Johnson, for the treatment of major depressive disorder. Because it’s in early phase I of clinical trials, most details about the safety and therapeutic efficacy of JNJ-54175446 in humans remain unknown. Nonetheless, pharmacodynamic data suggest that JNJ-54175446 functions as an antagonist of purine receptors, specifically P2X7 receptors.

According to scientific reports, the first time a P2X7 antagonist was investigated for the treatment of neuropsychiatric disorders was in 2007. In other words, researchers have only been testing P2X7 antagonists in animal models for approximately 10 years. The preclinical testing of P2X7 antagonists reveals that, in animal models of depression, P2X7 antagonists reduce scores of depression – as well as a host of other neurological conditions including: autism spectrum disorders, bipolar disorder, and neurodegenerative disorders (e.g. Alzheimer’s disease).

Furthermore, in mouse models of depression, knocking out the P2X7 receptor yields antidepressant-like effects – compared to controls. That said, while antagonism of the P2X7 receptor is typically associated with antidepressant effects, not all P2X7 antagonists seem to treat depression in mice. Considering its unique mechanism of action, it will be interesting to learn the effects of JNJ-54175446 in humans.

Source: https://clinicaltrials.gov/ct2/show/NCT02902601

Source: https://www.ncbi.nlm.nih.gov/pubmed/24928329

Ansofaxine (LY03005)

Mechanism: SNDRI

Status: Phase I

Developer: Luye Pharma Group

Ansofaxine hydrochloride (LY03005) is a triple reuptake inhibitor (serotonin-norepinephrine-dopamine) being developed by Luye Pharma Group for the treatment of moderate-to-severe depression. Pharmacodynamic evaluation of Ansofaxine indicates that it functions as an SNDRI and is a prodrug to desvenlafaxine. Yet, when compared to desvenlafaxine (i.e. Pristiq), Ansofaxine exerts a notable dopaminergic effect while simultaneously modulating serotonin and norepinephrine.

Based on preliminary data, one might actually classify Ansofaxine as a DSNRI (dopamine-serotonin-norepinephrine reuptake inhibitor) – considering it seems to exhibit greatest reuptake inhibition of dopamine, followed by serotonin and norepinephrine, respectively. It seems as though Ansofaxine is currently in phase I of clinical trials. According to the developer’s website, Ansofaxine was created in the form of extended-release tablets.

Thus far, Ansofaxine has been evaluated in 2 human trials with 72 and 48 participants, respectively. From available phase I trial data, it seems as though Ansofaxine is well-tolerated and safe at doses ranging from 40 mg to 160 mg. Luye Pharma Group believes that this development will have fewer side effects and a faster onset of action compared to currently-available antidepressants.

Source: http://www.luye.cn/lvye_en/newsshow.php?id=138

MIN-117

Mechanism: SDRI

Status: Phase II

Developer: Minerva Neurosciences

MIN-117 is a serotonin-dopamine modulator being developed by Minerva Neurosciences for the treatment of major depression. Its mechanism of action targets a combination of receptors and transporters, including: alpha-1A receptors; alpha-1B receptors; 5-HT2A receptors; SERT (serotonin transporter); and DAT (dopamine transporters). Specifically, MIN-117 has been shown to act as a 5-HT1A and 5-HT2A antagonist; serotonin and dopamine reuptake inhibitor; and modulator of alpha-1A and alpha-1B adrenergic receptors.

Minerva Neurosciences suggests that MIN-117 is intended to address unmanaged symptoms in persons with major depressive disorder plus comorbid anxiety or anxious symptoms. Developers speculate that MIN-117 will be faster-acting, safer, and better tolerated than most current-market antidepressant medications. Currently MIN-117 is in phase II of clinical trials as an intervention for depression.

Although MIN-117 heavily targets the serotonin system, it also bolsters dopamine concentrations – which may prove beneficial for a subset of individuals with depression attributable to low dopamine signaling. Though I’m skeptical of the suggestion that MIN-117 will be safer and better tolerated than available medications, it’s reasonable to suspect that the dopamine component might make it faster-acting.

Source: http://www.minervaneurosciences.com/innovation-pipeline/min-117/

Seltorexant (MIN-202)

Mechanism: Orexin-2 antagonist

Status: Phase II (complete)

Developer: Minerva Neurosciences & Janssen

Seltorexant, also referred to as MIN-202 (Minerva) and JNJ-42847922 or JNJ-922 (Janssen), is an investigational small-molecule, selective orexin receptor antagonist being developed by Minerva Neurosciences and Janssen. Clinical trials are evaluating Seltorexant for the treatment of major depressive disorder, as well as insomnia – two neuropsychiatric conditions that are often comorbid. According to developers, Seltorexant blocks activation of neurons in the brain that promote wakefulness, specifically via binding to orexin 2 (Orx-2) receptors.

It is known that, within the brain, orexin systems are implicated in maintenance of sleep/wake cycles, as well as metabolism. Seltorexant aims to selectively antagonize (block) orexin 2 receptors which will decrease orexin signaling needed to maintain vigilance and wakefulness. As a result, this may counteract insomnia, as well as enhance sleep by making it deeper and/or more restorative.

Because orexin systems can influence secretion of stress hormones via the HPA (hypothalamic pituitary adrenal) axis, and the HPA axis is frequently overactive in persons with depression, it is believed that Seltorexant could also alleviate depressive symptoms. In depressed persons with high cortisol and/or preexisting sleep disturbances, Seltorexant may be of substantial benefit.

Source: http://www.minervaneurosciences.com/innovation-pipeline/min-202/

Source: https://www.ncbi.nlm.nih.gov/pubmed/27909987

NSI-189

Mechanism: Neurogenesis inducer

Status: Phase III (?)

Developer: Neuralstem Inc.

NSI-189 is an experimental medication under development by Neuralstem Inc. for the treatment of major depressive disorder, cognitive impairment, and neurodegenerative disorders. An interesting fact is that NSI-189 was developed via phenotypic screening of over 10,000 compounds to identify which induced the greatest degree of neurogenesis in-vitro (cells). NSI-189 appeared efficacious both in-vitro and rodents, and would thereafter be tested in humans with major depressive disorder.

I’ve written about the therapeutic potential of NSI-189 for depression, however, it’s unclear as to whether the medication will ever receive FDA approval as a treatment (standalone or adjunct) for major depressive disorder. In phase II clinical trials, NSI-189 failed to meet its primary endpoint via reducing scores on the MADRS in 220 patients with major depressive disorder. That said, substantial improvements were observed across secondary trial endpoints for depression and cognitive function.

As a result of its failure in phase II clinical trials, it remains unknown as to whether it will undergo further clinical trial testing as an antidepressant (e.g. as an adjunct) – or if its investigation for the treatment of depression will be discontinued. Still, NSI-189 will continue undergoing evaluation for the treatment of neurological and CNS disorders, including: neuropathy, ischemic stroke, and cognitive impairment. Because NSI-189 appears to provide benefit in ameliorating some depressive symptoms and cognitive deficits (as evidenced by secondary endpoints), it’s reasonable to speculate that it may prove useful as an adjunct therapy among those with depression.

Source: https://www.neuralstem.com/pipeline/ns-189

PH10 nasal spray

Mechanism: Chemoreceptor cell modulator

Status: Phase II

Developer: Pherin Pharmaceuticals

PH10 is a medicine in development by Pherin Pharmaceuticals for the treatment of major depressive disorder. Pherin Pharmaceuticals focuses specifically on developing treatments for human diseases and disorders using “pherines” (pherine molecules), hence their name. Pherines, also classified as vomeropherines, are odorless synthetic neuroactive steroids that interact with nasal chemosensory receptors (and other receptors in the CNS) to induce dose-dependent and reversible physiologic effects.

The medication PH10 was formulated as small-molecule nasal spray. In small phase II clinical trials, PH10 appeared to facilitate rapid antidepressant effects whereby depressive symptoms were significantly reduced in less than 1 week. Although the phase II trial was small, the effect sizes (Cohen’s d) were substantial: 1.01 (for high-dose PH10 vs. placebo) and 0.71 (for low-dose PH10 vs. placebo).

Among those who received the PH10 nasal spray, between 60% and 80% exhibited remission from depressive symptoms. The PH10 spray caused a few side effects such as: somnolence, nasal irritation (this should be expected), and headache, however, it was considered well-tolerated. This is certainly a unique antidepressant in the early stages of development; more information regarding its pharmacodynamics would provide more insight regarding its antidepressant action.

Source: http://www.pherin.com/products.html

Rapastinel (GLYX-13)

Mechanism: NMDA receptor modulator

Status: Phase III

Developer: Allergan

Rapastinel (formerly known as GLYX-13) is a medication being developed by Allergan (formerly tested by Naurex before Allergan’s acquisition) as an adjunct intervention for treatment-resistant depression (or depression that doesn’t respond to 2 or more first-line interventions). The medication is inactive when administered orally and was specifically engineered for intravenous administration. It functions as a selective, modest partial agonist (mixed antagonist/agonist) at an allosteric site upon the glycine subunit of the NMDA receptor complex.

Preliminary evidence suggests that Rapastinel is rapid-acting and yields a long-term antidepressant response. What’s more, it appears as though Rapastinel robustly enhances cognitive function via inhibition and enhancement of signal transduction mediated by NMDA receptors. Administration of Rapastinel to animals enhances memory and learning abilities – regardless of the animal age, and also facilitates a neuroprotective effect.

Rapastinel is classified as a glyxin compound derived from modifying the structure of a monoclonal antibody that modulates NMDA receptors, known as “B6B21.” Based on preliminary trial data, Rapastinel is among the most promising interventions for refractory depression in development. That said, Apimostinel (another medicine in development by Allergan that was already discussed) is intended to serve as an improved version of Rapastinel in terms of potency. (Read more about: “GLYX-13 for depression“).

Source: https://www.allergan.com/research-and-development/allergan-pipeline

RP-5063

Mechanism: Serotonin & dopamine partial agonist

Status: Phase I

Developer: Reviva Pharmaceuticals

RP-5063 is a substance being investigated by Reviva Pharmaceuticals for the treatment of major depressive disorder, as well as other neuropsychiatric conditions like: schizophrenia and schizoaffective disorder. Clinical trials of RP-5063 for the treatment of major depressive disorder are currently in phase I. However, RP-5063 is already in phase III clinical trials as a treatment for schizophrenia.

Pharmacodynamic evaluations indicate that RP-5063 functions as a “dopamine-serotonin system stabilizer.” Specifically, it acts as a: D2, D3, and D4 receptor partial agonist; 5-HT1A and 5-HT2A receptor partial agonist; and a 5-HT6 and 5-HT7 receptor antagonist. RP-5063 exhibits high affinity for: D2, D3, D4, 5-HT1A, 5-HT2A, 5-HT7, and H1 receptors – and moderate affinity for: D1, D5, 5-HT3, and 5-HT6 receptors; SERT; and alpha-1B adrenergic receptors.

Pharmacodynamics considered, it seems as though RP-5063 will likely be more useful as an antipsychotic than an antidepressant. Nevertheless, because the medication interacts with a host of different serotonin receptors and transporters, it may alleviate symptoms of many neuropsychiatric conditions – including depression.

Source: http://revivapharma.com/clinical-trails/

SAGE-217

Mechanism: GABAA receptor modulator

Status: Phase II

Developer: Sage Therapeutics

SAGE-217 is an investigational chemical being developed by the company Sage Therapeutics for the treatment of major depressive disorder and postpartum depression – as well as essential tremor in Parkinson’s, insomnia, and epilepsy. According to Sage Therapeutics, SAGE-217 is a synthetic pregnane neurosteroid that functions as a positive allosteric modulator of the GABAA receptor. SAGE-217 is intended to be an improvement upon, and pharmaceutical successor to, Brexanolone – another Sage Therapeutics development for depression that’s further along in clinical trials.

As of February 2018, SAGE-217 is in phase II clinical trials for major depressive disorder and postpartum depression. SAGE-217 exhibits a high bioavailability when administered orally, and considering its half-life, many speculate that SAGE-217 will be administered once daily. Given its primary action upon GABAA receptors, it’s reasonable to speculate that SAGE-217 would be more useful in the treatment of anxiety disorders – compared to depressive disorders.

Source: https://www.sagerx.com/programs.php

Brexanolone (Allopregnanolone)

Mechanism: GABAA receptor modulator

Status: Phase III

Developer: Sage Therapeutics

Brexanolone (allopregnanolone) is a medication being investigated by Sage Therapeutics for the treatment of major depressive disorder and postpartum depression. It is understood that allopregnanolone is an endogenous inhibitory pregnane neurosteroid synthesized from progesterone. The mechanism of Brexanolone’s action involves positive allosteric modulation of GABAA receptors.

Research suggests that allopregnanolone levels can significantly influence the pathophysiology of mood disorders. Administration of Brexanolone is thought to yield a combination of: antidepressant, antiaggressive, anxiolytic, pro-social, pro-sexual, and pro-sleep effects – each of which may help to enhance mood in persons with major depressive disorder. Of interest is the fact that there’s a biphasic “U-shaped” action of Brexanolone at the GABAA receptors.

Moderate increases in allopregnanolone (1.5-2 nM/L) inhibit the GABAA receptor, whereas concentrations that are either lower or higher – stimulate the receptor and can cause negative effects such as: depression, anxiety, irritability, and aggression. Reflecting upon its mechanism of action, it may come as surprise that Brexanolone is being investigated for depression – rather than anxiety. Nevertheless, there’s a possibility that it may alleviate postpartum depression and/or “anxiodepressive” conditions.

Source: https://www.sagerx.com/programs.php

Viloxazine (SPN-809)

Mechanism: NRI

Status: Phase I

Developer: Supernus Pharmaceuticals

Viloxazine is a substance being investigated by Supernus Pharmaceuticals for the treatment of major depressive disorder. Interestingly, Viloxazine is not a new chemical – it was first marketed in 1976 by Imperial Chemical Industries. Furthermore, Viloxazine was prescribed as an antidepressant medication throughout various European countries from the 1970s through the early 2000s – but was never approved by the FDA.

In the year 2002, worldwide production of Viloxazine was discontinued for business reasons. As an antidepressant, Viloxazine functions as a selective norepinephrine reuptake inhibitor (NRI) whereby it increases extracellular concentrations of norepinephrine. It is said that Viloxazine generates a stimulatory effect akin to amphetamines without signs of dependence.

In 2015, Supernus Pharmaceuticals began developing formats of Viloxazine for the treatment of major depressive disorder (SPN-809) and ADHD (SPN-812). Though Viloxazine does interact with serotonin, its serotonergic actions are very minimal. Because the mechanism of Viloxazine’s action has been well-researched for depression, I’d be surprised if it ends up effective as an antidepressant – but less surprised if it receives approval to treat ADHD.

Source: https://www.supernus.com/research-development#supernus-pipeline

Sirukumab

Mechanism: IL-6 inhibitor

Status: Phase II

Developer: Janssen

Sirukumab is a human monoclonal antibody medication designed primarily for the treatment of rheumatoid arthritis. However, the company Janssen (a subsidiary of Johnson & Johnson), is investigating the safety and efficacy of Sirukumab for the treatment of depression. Sirukumab functions as an inhibitor of interleukin-6 (IL-6), a proinflammatory cytokine.

Longstanding evidence has linked systemic inflammation with major depressive disorder. For this reason, it was thought that reducing inflammation via inhibiting IL-6 signaling may reverse physiological processes implicated in depressive disorders and ultimately enhance mood. A systematic review of Sirukumab indicates that it appears safe, tolerable, and effective in modulating both immune system activation and inflammatory responses.

Researchers speculate that Sirukumab may exert a myriad of favorable effects among individuals with depression such as: ameliorating anhedonia; mitigating cognitive deficits; and decreasing negative valence disturbances. Perhaps individuals with major depressive disorder could undergo testing for IL-6 elevations prior to using Sirukumab. If a person’s IL-6 is elevated and potentially implicated as a primary cause of his/her depression, Sirukumab may be a useful therapy.

Source: https://clinicaltrials.gov/ct2/show/NCT02473289

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216059/

Strada (Ademetionine)

Mechanism: Methylation modulator

Status: Phase II

Developer: MSI Methylation Sciences

Strada is a new antidepressant formula being developed that contains Ademetionine (a form of the amino acid methionine) also referred to as S-adenosylmethionine (SAMe). It is understood that the human body typically produces adequate ademetionine to maintain general health, however, things like: methylation problems or deficiencies in methionine, folate, and vitamin B12 can cause ademetionine levels to plummet. Low concentrations of ademetionine have been linked to depression, whereas supplementing with ademetionine is sometimes effective in treating depression.

Because ademetionine can’t be attained from diet, it is sold as an over-the-counter dietary supplement to help increase ademetionine concentrations in persons who are thought to be deficient. When compared with SAMe, Strada differs in that the formulation significantly enhances ademetionine bioavailability. The enhanced bioavailability of ademetionine associated with Strada administration may deliver a more potent and/or targeted antidepressant effect than SAMe.

Data from early clinical trials of Strada indicate that the formula is safe, tolerable, and significantly more bioavailable than current-market methylation modulators. Strada is intended to be ingested orally once per day, and developers believe that will prove therapeutic as an adjunct treatment for depression. Though not a development I’m particularly excited about, it may be an upgrade over SAMe.

Source: http://methylationsciences.com/index.php/strada/

SUVN-911

Mechanism: nAChR antagonist

Status: Phase I

Developer: Suven Life Sciences

SUVN-911 is a chemical being investigated by Suven Life Sciences for the treatment of major depressive disorder. Preliminary research indicates that SUVN-911 functions as a selective alpha-4-beta-2 nicotinic acetylcholine receptor (nAChR) antagonist. Antagonism of the alpha-4-beta-2 nAChR is believed to interfere with acetylcholine signaling that induces nAChR desensitization.

Because desensitization of nAChR sites is associated with depressive symptoms, it is thought that the administration of SUVN-911 may reverse these symptoms via counteracting nAChR desensitization. Animal models of depression exhibit antidepressant-like effects following the administration of nAChR antagonists – in both tail suspension tests (TST) and forced-swim tests (FST).

Developers of SUVN-911 claim that it has excellent antidepressant properties like rapid onset of action and no unwanted side effects such as: weight gain, sexual dysfunction, and cognitive deficits. As of February 2018, SUVN-911 is in early phase I clinical trials.

Source: http://www.suvenincusa.com/suvn-911/

Travivo (Gepirone ER)

Mechanism: 5-HT1A selective partial agonist

Status: Pending FDA approval

Developer: Fabre-Kramer Pharmaceuticals

Travivo (Gepirone ER) is an antidepressant medication that was initially rejected multiple times by the FDA due to concerns of efficacy. It was first rejected in 2004, then again in 2007. That said, the FDA reviewed data for Gepirone in 2015 and reversed their initial rejection of the drug – giving it a favorable review. As of January 2018, Gepirone is awaiting pre-approval from the FDA and is likely to hit markets within the next year under the brand name “Travivo.”

I’ve already written about using Travivo for depression and anxiety disorders. The drug is in the same azapirone classification as Buspar (buspirone) but functions slightly differently in that exerts a greater effect upon 5-HT1A receptors as a partial agonist – and has limited interaction with the D2 receptor. Essentially, Travivo may be like a slightly altered version of Buspar for anxiety with a much stronger antidepressant effect.

Considering its mechanism of action, it’s reasonable to speculate that Travivo will be useful for anxious-depression (i.e. anxiodepressive disorders). What’s more, research suggests that Travivo exhibits pro-sexual effects whereby it may reverse sexual dysfunction in men and women; these pro-sexual effects are independent of its antidepressant and anxiolytic action. Though not a new medication, I suspect that Travivo will be one of the safer psychiatric drugs if and when it hits the market.

Source: http://www.fabrekramer.com/?page_id=416

TS-121

Mechanism: Vasopressin (V1B) receptor agonist

Status: Phase II

Developer: Taisho Pharmaceutical

TS-121 is a chemical being developed by Taisho Pharmaceutical for the treatment of major depressive disorder. According to Taisho Pharmaceutical, TS-121 is an orally-active medication that functions as a selective vasopressin receptor antagonist. Specifically, TS-121 antagonizes vasopressin-1B (V1B) receptors.

Animal model data indicate that activation of vasopressin receptors may be viable target for the treatment of depression. Blocking the vasopressin-1B receptor in animal models of depression yields antidepressant-like and anxiolytic effects. In animals, blockade of V1B receptors yields decreased plasma concentrations of ACTH, likely via inhibition of HPA axis activation.

In humans, it is known that a major SNP haplotype of the arginine vasopressin-1B receptor protects against major depression. Moreover, human research suggests that V1B receptor antagonism appears to reverse dysphoria during drug withdrawal and modulates HPA axis activation. TS-121 is a unique antidepressant in the clinical trial pipeline. As of May 2017, the chemical entered phase II clinical trials as an intervention for depression.

Source: http://www.taisho-holdings.co.jp/en/ir/finance/development/

Other antidepressant adjuncts in clinical trials (2018)

In addition to the above list of antidepressants in clinical trials for depression, 2 medications that are already approved for other neuropsychiatric conditions – are undergoing additional trials as potential adjuncts in the treatment of major depressive disorder. I am of the opinion that these medications carry significantly greater risk and side effects than most current-market non-antipsychotic, antidepressant medications and adjuncts.

That said, many people with major depression don’t respond well to current antidepressants and adjuncts – so tacking on an antipsychotic can prove beneficial for some individuals as a last-resort mood enhancer. It’s likely that each of these will be approved as antidepressant adjuncts – helping respective companies rake in some major profits.

Nuplazid® (Pimavanserin)

Mechanism: 5-HT2A & 5-HT2C receptor modulator

Status: Phase II

Developer: ACADIA Pharmaceuticals

Nuplazid is currently the first and only medication that’s received FDA approval for the treatment of Parkinson’s-related psychosis. Specifically, Nuplazid treats hallucinations (e.g. hearing voices) and delusions (i.e. thoughts that don’t accurately reflect reality) among patients with Parkinson’s disease. Compared to other antipsychotics, what’s unique about Nuplazid is that it is devoid of dopaminergic effects.

Pharmacodynamic assessments of the drug indicate that it functions predominantly as a highly selective 5-HT2A receptor modulator (inverse agonism and antagonism), and to a lesser extent, a modulator of 5-HT2C receptors. Though it negligibly interacts with sigma-1 receptors, it has no significant interaction with serotonin, muscarinic acetylcholine, histamine, or adrenergic receptors. It is believed that Nuplazid will have fewer side effects and greater efficacy than other antipsychotics.

I guess the one thing I like about Nuplazid is that it doesn’t interact with dopamine (D2 and D3) receptors. Its lack of dopaminergic effect should make it better tolerated than most current-market antipsychotics being used as adjuncts for depression.

Source: http://www.acadia-pharm.com/product/

Vraylar™ (Cariprazine)

Mechanism: D2 & D3 receptor partial agonist + 5-HT1A receptor modulator

Status: Phase III

Developer: Allergan

Vraylar is an antipsychotic medication that’s approved by the FDA for the treatment of schizophrenia and bipolar mania. It functions as a D3 receptor and D2 receptor partial agonist – with high selectivity for the D3 receptor. As of current, it is in phase III clinical trials as an adjunct treatment for major depressive disorder.

Like other similar-acting antipsychotics, the most common side effects of Vraylar include: akathisia, insomnia, and weight gain. Other side effects observed with short-term use include: extrapyramidal symptoms, sedation, nausea, dizziness, vomiting, anxiety, and constipation. Allegedly, Vraylar doesn’t seem to alter metabolic levels, prolactin, or ECG QT intervals.

Source: http://www.vraylar.com/

Thoughts on new antidepressants (2018) in clinical trials

Of all the new antidepressant medications in development, I’m most interested in ALKS-5461, Apimostinel, Rapastinel, CERC-301, CERC-501, PH10 nasal spray, JNJ-39393406, BTRX-246040, Seltorexant, SUVN-911, Travivo, and TS-121. Most of the aforementioned agents exhibit markedly different mechanisms of action when compared to current-market antidepressants. Pharmacologic targets of these medications include: opioid receptors; NMDA receptor complexes; NOC receptors; nicotinic acetylcholine receptors; orexin receptors; and chemoreceptors.

Assuming some of these medications are deemed safe and efficacious in the treatment of depression, persons with major depressive disorder will have a greater variety of unique medication types to test in effort to alleviate depressive symptoms. As of current, most antidepressant medications function via modulating concentrations of monoamines – primarily serotonin and norepinephrine. While monoaminergic modulation can prove helpful for some – clearly not everyone derives benefit; hence individuals with treatment-resistant or refractory depression.

If and when FDA approved, it’ll be interesting to determine whether some of these medications provide a sustained (i.e. long-term) antidepressant effect without tolerance onset (e.g. the need for dosage increases after a year or two because the “antidepressant stopped working”). Because most companies aren’t advanced enough to engineer a medication devoid of tolerance (e.g. developing a chemical that modulates intracellular signaling cascades such that physiologic adaptation to the medication is prevented), most of the aforementioned substances will induce tolerance. While tolerance isn’t necessarily a big deal if it’s not significant or emerges after a long-term, it may be a problem if tolerance onset is quicker than expected.

That said, the speed of tolerance onset of each agent remains unknown and will likely vary in accordance with mechanism of action. In any regard, I’m of the mindset that the greater the total number of unique antidepressant medications that survive clinical trials (i.e. are safe and effective) to receive FDA approval for retail – the greater the odds that individuals with major depression will find a medication or medication combination that actually alleviates their symptoms – at least over a short-term. Considering that the neurochemical underpinnings of depression are subject to some degree of individual variation – new medications should help address depressive subtypes that didn’t respond to monoaminergic modulators (which have currently saturated the market).

On a final note, although the substance NSI-189 failed its clinical trial for depression, many anecdotal accounts continue circulating throughout the internet from NSI-189 users reporting substantial mood enhancement. To me, it seems as though even if the investigation of NSI-189 as a standalone treatment for depression is discontinued, it may yield substantial benefit as an antidepressant adjunct.

What are the next steps in antidepressant development?

A majority of pharmaceutical companies have finally shifted away from developing monoaminergic modulators for the treatment of depression and are focusing developing novel medications that exert unique neurochemical effects. Although monoaminergic modulators work well for some individuals, they are suboptimally effective or difficult to tolerate for others. Personally, I think the next step in antidepressant development is to target intracellular signaling cascades associated with short-term and long-term medication tolerance.

Unfortunately, it may take much longer that you’d expect for this to happen – in part because pharmaceutical companies, medical professionals, and most researchers don’t acknowledge that tolerance to antidepressants occurs. Failing to acknowledge tolerance development to antidepressants is partly due to the fact that most medications don’t induce prototypical rapid tolerance like drugs of abuse (e.g. cocaine, amphetamine, opioids, etc.). Moreover, inability to admit tolerance development to antidepressants is also partly due to the fact that tolerance and its mechanisms (e.g. receptor re-regulation, altered enzyme expression, etc.) haven’t been adequately investigated; research is desperately needed in this area.

In any regard, assuming a pharmaceutical company aims to develop either: a new antidepressant medication that enhances mood while counteracting physiologic feedback loops that lead to medication tolerance – or an adjunct medication that can be administered to counteract tolerance to preexisting antidepressant medications – this would be a major step forward in antidepressant development. There are many people who’ve benefitted from antidepressants for a while (e.g. a year or two), but found that the efficacy waned, they stopped working, or became intolerable due to side effects stemming from necessary (tolerance-related) dosage increases.

Creating an antidepressant devoid of tolerance would not be an easy accomplishment, however, it’s certainly worth attempting. Such a medication could be administered indefinitely at the same fixed-dosage dosage without any change in its efficacy over a period of decades; there would be no end to the mood enhancing “honeymoon phase.”

Another idea to consider in antidepressant development would be to create a medication that can be administered once to modulate physiology so profoundly, that secondary administration wouldn’t be necessary for weeks or months after the initial dose. In other words, this wouldn’t be like an extended-release medication that stays in your body – this would be like a substance that you take once, it profoundly alters neurophysiology, and is excreted. Ultimately, you’d be left in a protracted altered state (compared to depressive homeostasis) whereby depressive symptoms would be kept in remission.

Although this is already being done with some of the NMDA receptor modulators in clinical trials, but could be expanded upon – particularly with novel targets. Assuming we can get medication developers to create drugs that are devoid of tolerance and/or yield sustained long-term effects from a single dose, we’ll be substantially upgrading our ability to treat depression. In the future, there may be effective vaccines are developed to either prevent major depressive disorder – or minimize depressive symptoms among persons prone to the condition.

In the far future, I believe that depression will be targeted on a completely individualized basis. A person’s complete genome, epigenome, brain anatomy (e.g. size, structure, grey matter, white matter, damage, etc.), and brain chemistry (e.g. neurotransmitter levels, connectivity, etc.) will be analyzed and treatments will be administered that are contingent upon the person. A combination of: brain augmentation (e.g. hardware chips); nanotechnology; RNA interference; gene editing; stem-cells (to repair or enhance brain regions); and bio-specific designer drugs (developed specifically for the individual with depression) – will eradicate depressive symptoms.

Which new antidepressants (2018) in development are you most excited about?

Of all the medications in development (as of 2018) for the treatment of depression, which are you most excited about? Are there any particular mechanisms of action associated with medications in development that you believe will prove more effective in alleviating depressive symptoms (compared to others)? Are there any medications that you think may be effective for a short-term but cause tolerance and/or deleterious effects over a long-term?

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