New Antidepressants 2022 (Clinical Trials)

Antidepressants: (1) They help some, (2) they don’t do much for others (maybe cause emotional blunting/numbness), and (3) they worsen preexisting depression and/or cause new-onset symptoms such as anxiety for another subset of users.

The treatment of depression is essentially one big neurochemical crapshoot (i.e. gamble) that involves trial and error. Give people meds that “should work” for 4-8 weeks and assess response.

If the first med doesn’t work, follow a psychiatric decision tree for subsequent meds to try – and hope those work.

Because the neurobiological/genetic underpinnings of depression are highly individualized – medications that work well for some do NOT work at all for others.

Zhdanava et al. (2021) estimate that ~30.9% of adults (2.8 million individuals) with major depression have treatment-resistant cases wherein they don’t respond to any treatment. (R)

Then consider things like: (1) tolerability (i.e. side effects/adverse events); (2) tachyphylaxis & tolerance (i.e. meds stop working with time); (3) withdrawal symptoms; and/or (4) adverse long-term effects – and most would agree that we desperately need alternative options to what’s currently available.

New Antidepressants in Clinical Trials (2022)

So what is “big pharma” (and perhaps little pharma) cooking up in the lab?

Clinical trials (Phases)

• Phase 1 (Pharmacology): Evaluate safety. Determine safe dosage. Identify side effects.
• Phase 2 (Exploratory): Test efficacy. Continued safety evaluation.
• Phase 3 (Confirmatory): Confirm efficacy. Monitor side effects. Compare to other treatments. Collect information.
• FDA approval: Treatment determined safe and effective for mainstream use.
• Phase 4 (Post-marketing): Provide additional information post-approval including risk/benefits.

I’ve sorted the antidepressants in development in order of clinical trial progress.  The drugs that are furthest along in clinical trials are listed above those that are still in early stages of trials.

Note #1: I did not attempt to analyze specific progression of each drug within specific phases – so intra-phase listings should not be regarded as being listed in order of development.

Note #2: I included 2 drugs in this list that are being investigated specifically for the treatment of “bipolar 1 depression” – which differs from other forms of depression in that it is specific to patients with bipolar 1 disorder.

Gepirone

• Mechanism of action: 5-HT1A receptor partial agonist
• Indication: Major depressive disorder
• Developer: Fabre-Kramer
• Stage of development: Marketing

Gepirone (proposed names: Travivo & Variza) is a chemical that was first synthesized by Bristol-Myers Squibb in 1986 and subsequently out-licensed to Fabre-Kramer in 1993.

The FDA rejected gepirone for approval twice as a treatment for anxiety and depression: (1) first in 2004 and (2) again in 2012 (after more information was added from clinical trials).

In 2015, the FDA gave gepirone a “negative review” for depression due to concerns of effectiveness – but for whatever reason(s), the FDA reversed its stance in 2016 and gave gepirone a “positive review” – enabling Fabre-Kramer to market the drug as a treatment.

Gepirone is a medication in the “azapirone” class that functions primarily as a selective partial agonist of the 5-HT1A receptor (but it does have distinct effects on the presynaptic and postsynaptic sites).

Many consider gepirone to be extremely similar to buspirone (i.e. Buspar) based on the fact that it’s in the same “azapirone” class and generates the same principal 1-(2-pyrimidinyl)piperazine metabolite.

Gepirone differs mechanistically from buspirone in that it activates 5-HT1A receptors to a greater extent and interacts with D2 receptors to a lesser extent (~30-to-50-fold less) than buspirone.

Randomized, double-blind, placebo-controlled trials have found gepirone extended-release to be effective in the treatment of both major depressive disorder and generalized anxiety disorder. (R)

Compared to SSRIs, gepirone activates 5-HT1A receptors to a greater extent and doesn’t cause sexual dysfunction (which many would consider a major advantage).

At one point Fabre-Kramer began marketing gepirone under the brand “Travivo ER” (posting digital advertisements, etc.) but it remains unknown as to whether this drug will eventually hit the market or remain eternally shelved.

Zuranolone

• Mechanism of action: GABA-A receptor PAM
• Indication: Major depressive disorder
• Developer: Sage Therapeutics + Biogen (R)
• Stage of development: Registration

Zuranolone (SAGE-217) is a drug in development by Sage Therapeutics for the treatment of major depressive disorder.

It is also being investigated as a treatment for postpartum depression; treatment-resistant depression; generalized anxiety disorder; and bipolar depression.

Zuranolone is a synthetic, orally active, inhibitory pregnane neurosteroid that functions as a positive allosteric modulator (PAM) at GABA-A receptors.

Evidence suggests that GABAergic deficits/dysfunction may be involved in some cases of major depressive disorder. (R)

Administration of zuranolone daily for 14 days reduced depressive symptoms in patients with major depression relative to a placebo control. (R)

Tangentially-related is that Sage Therapeutics recently received FDA approval to market the drug zulresso (brexanolone) for the treatment of postpartum depression – and it has the same mechanism of action as zuranolone (PAM of GABA-A receptors).

A problem with zulresso (brexanolone) is that it requires I.V. administration via long and slow infusion with medical supervision – hence the creation by Sage Therapeutics of an orally-administered version called “zuranolone.”

This is essentially the same mechanism of action as benzodiazepines… which makes me wonder how zuranolone differs in effect from benzos.

Sage and Biogen plan to seek FDA approval for zuranolone in late 2022 and plan to file for a new drug application (NDA) in 2023.

Bupropion/Dextromethorphan (AXS-05)

• Mechanism of action: NDRI; nAChR antagonist; sigma-1 receptor antagonist; NMDAR antagonist; SNRI
• Indication: Treatment-resistant depression (Fast Track); MDD
• Developer: Axsome Therapeutics (R)
• Stage of development: Phase 3

Fixed-dose bupropion/dextromethorphan (AXS-05) is a combination of 2 well-known drugs: (1) bupropion (i.e. Wellbutrin/Zyban) and (2) dextromethorphan (DXM).

Bupropion is already approved for the treatment of major depressive disorder (Wellbutrin) and for the support of smoking cessation (Zyban).

Dextromethorphan is used primarily as a cough suppressant for the temporary relief of cough caused by minor throat and bronchial irritation.

The combined mechanism of action will involve: (1) norepinephrine-dopamine reuptake inhibition + nicotinic acetylcholine receptor antagonism (bupropion) + (2) sigma-1 receptor agonism + NMDA receptor antagonism, and serotonin-norepinephrine reuptake inhibition (dextromethorphan).

An interesting aspect of this combination drug is that bupropion potently inhibits CYP2D6 enzymes in the liver which metabolize/break down dextromethorphan (DXM) into its bioactive metabolite dextrorphan (DXO).

This increases dextromethorphan exposure and reduces the ratio of DXM to DXO in the body.

One might argue that since bupropion is effective for depression on its own – it might be facilitating all or a majority of the antidepressant effect associated with this combination drug.

Obviously dextromethorphan elicits its own psychoactive effects, but these may not necessarily contribute to the treatment of depression. Essentially, bupropion could be effective for depression in spite of the dextromethorphan.

Nonetheless, the entirety of the pharmacological effects will differ than either drug used in isolation and the cost will likely be high.

Theoretically, one could already test this out by: (A) getting a bupropion prescription and (B) buying dextromethorphan – and administering at appropriate ratios.

JNJ-42165279

• Mechanism of action: FAAH inhibitor
• Indication: Major depressive disorder with anxiety
• Developer: Janssen Pharmaceuticals
• Stage of development: Phase 3

JNJ-42165279 is a drug under development by Janssen Pharmaceuticals for the treatment of major depressive disorder with comorbid anxiety.

It functions as a slowly reversible inhibitor of FAAH (fatty acid amide hydrolase) – the enzyme responsible for the metabolism/degradation of fatty acid amides (FAAs) including:

• Anandamide (AEA)
• Palmitoylethanolamide (PEA)
• N-oleoylethanolamide (OEA)

FAAH inhibition produces antidepressant-like effects in mice when exposed to acute stress. (R)

Elevated brain fatty acid amide hydrolase induces depressive-like behaviors in rodent models. (R)

Chronic inhibition of FAAH reduces depressive-like behavior after chronic unpredictable stress exposure. (R)

Preliminary evidence suggests that JNJ-42165279 elicits a significant anxiolytic effect in persons with social anxiety disorder relative to a placebo – and that it is well-tolerated. (R)

In 2016 Janssen paused trials of JNJ-42165279 due to a different FAAH inhibitor under development by Bial (10-2474) causing adverse events including death – but trials resumed in 2018 with no indication of serious adverse events.

Ansofaxine HCL (Toludesvenlafaxine)

• Mechanism of action: DSNRI
• Indication: Moderate-to-severe depression
• Developer: Luye Pharma
• Stage of development: Phase 3

Ansofaxine (Toludesvenlafaxine), also known as Ansofaxine or 4-methylbenzoate desvenlafaxine, is a triple reuptake inhibitor under development by Luye Pharma for the treatment of moderate-to-severe depression.

As you may have been able to deduct, it is a prodrug of desvenlafaxine. And for reference, desvenlafaxine (i.e. Pristiq) is the primary bioactive metabolite of venlafaxine (i.e. Effexor).

Unlike desvenlafaxine which exhibits IC50 values of: 53 nM for SRI and 538 nM for NRI – toludesvenlafaxine exhibits IC50 values of 723 nM for SRI; 763 nM for NRI; and 491 nM for DRI.

In other words, toludesvenlafaxine functions as a dopamine-serotonin-norepinephrine reuptake inhibitor (DSNRI) – if we list monoamines in the mechanism in order from highest-to-lowest magnitude of reuptake inhibition.

Ansofaxine HCL will be manufactured as an “extended-release” drug such as to provide sustained antidepressant effect for a prolonged duration (i.e. 24 hours).

In China, Ansofaxine reached the primary endpoint and showed good response rate/remission rate – and showed potential for improving symptoms of anxiety and cognitive deficits. (R)

Seltorexant

• Mechanism of action: OX2R antagonist
• Indication: Major depressive disorder & insomnia
• Developer: Janssen R&D + Minerva Neurosciences
• Stage of development: Phase 3

Seltorexant (MIN-202 & JNJ-42847922) is a substance under joint development by Janssen R&D and Minerva Neurosciences for the treatment of major depressive disorder and insomnia – and was formerly tested as a treatment for sleep apnea.

It functions as a selective antagonist of the orexin OX2 receptor (2-SORA) – wherein it prevents the endogenous ligand orexin (i.e. hypocretin), a wakefulness-promoting neuropeptide, from binding to and activating OX2 receptor sites.

Preliminary evidence suggests that seltorexant is more effective than a placebo for the treatment of depression – particularly in persons with comorbid insomnia. (R)

Evidence suggests that seltorexant improves: sleep onset; total sleep time; time awake after sleep onset; and sleep efficiency in individuals with major depressive disorder and/or insomnia.

Interestingly, seltorexant is rapidly absorbed and peaks within 20 minutes to 1.5 hours – and has a short duration of effect with an elimination half-life of just 2-3 hours.

Cyclurad (Cycloserine & Lurasidone)

• Mechanism of action: NMDAR modulator + D2/D3R antagonist; 5-HT2AR, 5-HT7R antagonist; a2C-adrenergic receptor antagonist; 5-HT1AR partial agonist
• Indication: Bipolar 1 depression & suicidal ideation (Fast Track)
• Developer: NeuroRx (R)
• Stage of development: Phase 3

Cyclurad a.k.a. D-cycloserine/Lurasidone (NRX-100/101) is a fixed-dose combination drug under investigation by NeuroRx for the treatment of bipolar depression and suicidal ideation.

The cycloserine component functions primarily as an NMDA receptor modulator wherein it alters activity at NMDA receptors in response to glutamate. (R)

Cycloserine also functions as an antimicrobial agent wherein it inhibits bacteria cell-wall biosynthesis – but it’s unknown as to whether this mechanism might also improve depressive symptoms such as via the gut-brain axis (GBA) or immunomodulation.

The lurasidone (i.e. Latuda) component functions primarily as a: D2/D3 receptor antagonist, 5-HT2A receptor antagonist, 5-HT7 receptor antagonist, alpha-2C adrenergic receptor antagonist, and 5-HT1A receptor partial agonist.

Lurasidone received FDA approval in 2013 for the treatment of bipolar depression – and is considered effective as a standalone agent for bipolar depression.

Preliminary evidence suggests that D-cycloserine maintains antidepressant and antisuicidal effects resulting from low-dose ketamine infusion in patients with treatment-resistant depression. (R)

Technically it’s already possible to utilize lurasidone and cycloserine in combination as an experimental intervention (just get a prescription for each), however, the cost would be high – and due to lack of strong evidence most doctors would be unwilling to try it.

This combination drug has received “Fast Track” status from the FDA.

Aramisulpride/Esamisulpride (SEP-4199)

• Mechanism of action: 5-HT7 antagonist (85%) + D2/D3 receptor antagonist (15%)
• Indication: Bipolar 1 depression
• Developer: Sunovion Pharmaceuticals + Otsuka Pharmaceutical Co.
• Stage of development: Phase 3

Aramisulpride/Esamisulpride (SEP-4199) is a drug under joint investigation by Sunovion Pharmaceuticals and Otsuka Pharmaceutical Co. for the treatment of bipolar depression.

Chemically, it is a benzamide and is a non-racemic mixture (85:15 ratio) of amisulpride enantiomers: aramisulpride (85%) & esamisulpride (15%).

For reference, amisulpride received FDA approval in 2020 for the prevention of postoperative nausea/vomiting – and is marketed under the brand name “Barhemsys.”

Amisulpride functions primarily as a D2/D3 dopamine receptor antagonist with dose-dependent effects: (1) low doses = preferentially block inhibitory presynaptic autoreceptors vs. (2) high doses = inhibit dopaminergic neurotransmission.

There’s evidence that amisulpride also binds to the high-affinity GHB receptor at concentrations that are therapeutically-relevant.

Amisulpride also appears to function as a potent 5-HT7 receptor antagonist – which may be an important mechanism (possibly the most important mechanism) behind its antidepressant action. (R)

Interestingly this drug was first introduced by Sanofi-Aventis in the 1990s and its patent expired in 2008 whereafter genetic formulations became available.

In any regard, a non-racemic version of amisulpride (85% aramisulpride + 15% esamisulpride) a.k.a. SEP-4199 seems to have slightly different pharmacological effects which may be preferable/superior for bipolar depression.

The aramisulpride component is more potent at 5-HT7 receptors as an antagonist than esamisulpride (Ki 47 vs. 1900 nM) and the esamisulpride component is more potent as a D2 receptor antagonist (Ki 4.0 vs. 140 nM).

Researchers believe a non-racemic mixture of 85% aramisulpride and 15% esamisulpride should maximize: (1) potential antidepressant benefit via increased 5-HT7 receptor antagonism and (2) reduce bipolar symptoms via a more optimized D2 receptor antagonism (less significant albeit still sufficient activation and thus fewer extrapyramidal reactions with adequate relief). (R)

Preliminary evidence suggests that SEP-4199 appears useful in the treatment of bipolar 1 depression.

Zelquistinel (GATE-251)

• Mechanism of action: NMDA receptor modulator
• Indication: Major depressive disorder (Fast Track)
• Developer: Gate Neurosciences (R)
• Stage of development: Phase 2A (completed)

This chemical was formerly known as “AGN-241751” while under development with Allergan – but was eventually acquired by Gate Neurosciences.

It aims to treat depression by interacting with a unique binding site of the NMDA receptor (independent of the glycine site) to: (1) modulate NMDA receptor activity and (2) enhance NMDA receptor-mediated synaptic plasticity.

Its mechanism of action is similar to the substance Rapastinel (GLYX-13) which failed to be more effective than a placebo in Phase 3 clinical trials.

Unlike Rapastinel, Zelquistinel is: (A) orally bioavailable; (B) more potent; and (C) has superior overall qualities/properties. It has also received “Fast Track” status from the FDA.

4-CI-KYN (AV-101)

• Mechanism of action: NMDA receptor antagonist
• Indication: Major depressive disorder (Fast Track); MDD (post-ketamine/esketamine); suicidal ideation
• Developer: VistaGen Therapeutics (R)
• Stage of development: Phase 2

4-CI-KYN (L-4-Chlorokynurenine) a.k.a. AV-101 was first synthesized at Marion Merrell Dow and its biological activity explored at the University of Maryland.

It underwent initial development by Artemis Neuroscience which was acquired by VistaGen in 2003.

4-CI-KYN is an orally-active small molecule prodrug of 7-chlorokynurenic acid, an NMDA receptor antagonist.

In other words, 4-CI-KYN (the prodrug) is metabolized into 7-chlorokynurenic acid (metabolite) whereafter the metabolite functions as a potent and selective full antagonist of the glycine co-agonist site of the NMDA receptor.

Unlike other NMDA receptor antagonists such as ketamine – 4-CI-KYN does not block NMDA receptor function.

In clinical trials, 4-CI-KYN has been observed to be orally bioavailable, well-tolerated, and devoid of dissociative/hallucinogenic psychological side effects/concerns associated with other NMDA antagonists.

A Phase 2 clinical trial failed to show any significant antidepressant effect vs. placebo for refractory depression, however, it remains in development.

BI-1358894

• Mechanism of action: TRPC 4/5 inhibitor
• Indication: Major depressive disorder
• Developer: Boehringer Ingelheim (R)
• Stage of development: Phase 2

BI-1358894 is a chemical under investigation by Boeringer Ingelheim for the treatment of major depressive disorder (MDD).

It functions as an inhibitor of TRPC (transient receptor potential channels) 4 & 5 (TRPC4 & TRPC5).

Preliminary evidence suggests that TRPC4 & TRPC5 inhibition yields both antidepressant and anxiolytic effects in mice. (R)

As of current (Phase 2 clinical trials), researchers are evaluating how BI-1358894 (at different dosage increments) compares in efficacy to a placebo and quetiapine.

NMRA-140

• Mechanism of action: Selective KOR antagonist
• Indication: Major depressive disorder
• Developer: Neumora Therapeutics, Inc. (R)
• Stage of development: Phase 2

NMRA-140 (formerly BTRX-335140 & CYM-53093) is a novel compound under investigation by Neumora Therapeutics for the treatment of major depressive disorder.

It aims to treat major depressive disorder via action as a potent and selective kappa-opioid receptor (KOR) antagonist. (R)

Kappa-opioid receptors have been proposed to influence the stress system, pathophysiology of depression, and reward dysfunction. (R)

Endogenous ligands known as “dynorphins” stimulate/activate kappa-opioid receptors under stress which induces dysphoria, aversion, and hallucinations in humans. (R)

Preclinical evidence from animal models indicates that kappa-opioid antagonism generates antidepressant-like effects.

FKB01MD (TGBA01AD)

• Mechanism of action: Serotonin modulator (Serotonin reuptake inhibition; 5-HT2 receptor agonism; 5-HT1A receptor agonism; 5-HT1D autoreceptor agonist)
• Indication: Major depressive disorder
• Developer: Fabre-Kramer Pharmaceuticals (R)
• Stage of development: Phase 2

FKB01MD is a substance under investigation by Fabre-Kramer Pharmaceuticals for the treatment of major depressive disorder.

FKB01MD functions via multiple mechanisms including: (1) serotonin reuptake inhibition; (2) 5-HT2 receptor agonism; (3) 5-HT1A receptor agonism; (4) 5-HT1D central terminal autoreceptor agonist.

Fabre-Kramer states that this drug exhibits: “the 5HT reuptake blockade found in tricyclic antidepressants, 5-HT2 receptor blockade found in trazodone, and 5-HT1A interactions found in azapirones.”

They add: “It is anticipated that interactions of FKB01MD with multiple subtypes of 5-HT2 receptors will produce earlier and greater adaptation of serotonergic systems than other antidepressants, and this will in turn result in a more rapid onset and greater degree of antidepressant efficacy.”

Interestingly this chemical has been in Phase 2 clinical trials since 2009… progress seems to have stalled – with no explanation as to why.

Although the pharmaceutical company hypes this drug as being like “3 drugs in 1” – someone might be able to generate a similar effect via: a conventional tricyclic antidepressant (e.g. amitriptyline) + azapirone (e.g. buspirone) + trazodone – although maybe it does something unique and/or has fewer side effects.

Aticaprant

• Mechanism of action: KOR antagonist
• Indication: Major depressive disorder
• Developer: Janssen Pharmaceuticals
• Stage of development: Phase 2

Aticaprant (JNJ-67953964, CERC-501, LY-2456302) is a substance under investigation by Janssen Pharmaceuticals for the treatment of major depressive disorder.

It functions as a potent, selective, short-acting kappa-opioid receptor (KOR) antagonist with binding affinities of: 0.81 nM (KOR); 24 nM (MOR); 155 nM (DOR) – indicating that its activity primarily involves kappa receptors.

The oral bioavailability of aticaprant is ~25% and it’s rapidly absorbed – reaching maximum concentrations ~1-2 hours post-administration.

Steady-state levels are reached around 6-8 days of dosing.  Its elimination half-life ranges from 30 to 40 hours in healthy subjects.

Eli Lilly (LY-2456302) was the first developer of aticaprant – and it first appeared in scientific literature in 2010.

Cerecor Inc. acquired rights to aticaprant in 2015 and changed its developmental moniker to “CERC-501.”

It was initially investigated as a substance to promote smoking cessation/nicotine withdrawal in heavy smokers – but it failed to meet Phase 2 clinical trial endpoints for this indication in 2016.

Janssen Pharmaceuticals acquired rights to the drug in 2016 from Cerecor Inc. where it remains in development as a potential antidepressant.

Liafensine

• Mechanism of action: SNDRI
• Indication: Depression
• Developer: Denovo Biopharma (R)
• Stage of development: Phase 2

Liafensine (DB104 or BMS-820836) is a drug under investigation by Denovo Biopharma for the treatment of depression.

It functions as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) – or a “triple reuptake inhibitor” based on its ability to inhibit the reuptake of all monoamines simultaneously.

Simultaneous reuptake inhibition of serotonin, norepinephrine, and dopamine may prove superior in efficacy to standalone reuptake inhibition of serotonin or dual reuptake inhibition (serotonin + norepinephrine vs. norepinephrine + dopamine vs. serotonin + dopamine).

Liafensine was previously under investigation by Bristol-Myers Squibb for the treatment of major depressive disorder and demonstrated comparable efficacy to escitalopram (i.e. Lexapro) and duloxetine (i.e. Cymbalta) in Phase 2 clinical trials.

Its development was terminated based on: (1) lack of superior effect to escitalopram & duloxetine; (2) side effect profile (increased capacity); and/or (3) abuse potential (due to the dopaminergic action).

Nevertheless, Denovo Biopharma acquired rights to liafensine and has reinitiated its clinical development (which may prove to be a lucrative decision).

SNDRIs have been hyped up as “next-generation antidepressants” the early 2000s (R) – but in my opinion the hype is not warranted… all they do is add a dopaminergic component to the equation.

Similar effects can likely be achieved by combining a SSRI + Bupropion or Methylphenidate.

MIJ821

• Mechanism of action: NMDA-2BR NAM
• Indication: Major depressive disorder + suicidal ideation
• Developer: Novartis Pharmaceuticals
• Stage of development: Phase 2

MIJ821 is a drug in development by Novartis Pharmaceuticals for the treatment of major depressive disorder with acute suicidal ideation.

It functions as a NMDA-2B receptor negative allosteric modulator (NAM) – wherein it antagonizes agonist-induced activation of NMDA-2B receptors (i.e. decreases the affinity and/or effect of agonists for receptor sites).

So essentially because the NMDA receptors are agonized by the excitatory neurotransmitter “glutamate” – the administration of MIJ821 counteracts its effect specifically at the 2B site.

Antagonism of the NR2B subunit of NMDA receptors induces increased connectivity of the prefrontal and subcortical regions regulating reward behavior.

Research indicates that NR2B-selective compounds (e.g. ketamine) upregulate reward circuitry which might facilitate an antidepressant and/or anti-anhedonic effect. (R)

NV-5138

• Mechanism of action: mTORC1 protein stimulant
• Indication: Major depressive disorder
• Developer: Navitor Pharmaceuticals
• Stage of development: Phase 2

NV-5138 is an orally active small-molecule drug under development by Navitor Pharmaceuticals for the treatment of major depressive disorder.

It functions as a direct and selective activator/stimulant of mTORC1 (mammalian target of rapamycin complex 1) signaling pathway by binding to and modulating sestrin-2, a leucine amino acid sensor and upstream regulatory pathway.

The mTORC1 pathway is the same signaling pathway that the NMDA receptor antagonist ketamine activates in the medial prefrontal cortex (mPFC) to induce rapid-onset antidepressant effect. (R)

A single oral dose of NV-5138 has been shown to increase mTORC1 signaling and induce synaptogenesis (i.e. growth of new synapses) in the medial prefrontal cortex (mPFC) and to induce rapid-onset antidepressant effect in animal models.

Interestingly, the antidepressant effects after just one dose of NV-5138 are long-lasting – with a duration of up to ~7 days (analogous to ketamine).

Preliminary evidence from human trials suggests that NV-5138 is safe, tolerable, and effective for the treatment of depression.

PDC-1421

• Mechanism of action: NET inhibitor
• Indication: Major depressive disorder
• Developer: BioLite Inc.
• Stage of development: Phase 2

PDC-1421 is a drug in development by BioLite Inc. for the treatment of major depressive disorder and attention-deficit hyperactivity disorder (ADHD).

It functions as a norepinephrine transporter (NET) inhibitor wherein it blocks action of the norepinephrine transporter – which in turn yields increased extracellular concentrations of norepinephrine and epinephrine to increase adrenergic neurotransmission.

In other words, PDC-1421 is essentially a norepinephrine reuptake inhibitor (NRI) without appreciable interaction with other monoaminergic systems (e.g. serotonin & dopamine).

To date, there’s only one drug that functions as a standalone norepinephrine reuptake inhibitor (NRI) that has received approval to treat depression (reboxetine) – but its efficacy is considered controversial.

Evidence for the involvement of norepinephrine in depression is abundant and various studies on neuronal pathways and systems suggest a specific role of norepinephrine in major depressive disorder. (R)

Although a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pro-noradrenergic action may enhance the effectiveness of other non-noradrenergic antidepressants via normalization of attention, arousal, and motor activity. (R)

Itruvone (PH10)

• Mechanism of action: Chemoreceptor cell stimulant
• Indication: Major depressive disorder
• Developer: VistaGen Therapeutics (R)
• Stage of development: Phase 2B

Itruvone (PH10) also referred to as “pregn-4-en-20-yn-3-one” is a substance under development by VistaGen Therapeutics for the treatment of major depressive disorder.

It was developed from proprietary compounds called “pherines” (i.e. vomeropherines) – odorless synthetic neuroactive steroids that engage nasal chemosensory receptors and induce dose-dependent and reversible pharmacological/behavioral effects.

Itruvone will be administered intranasally (as a “nasal spray”) wherein it’ll stimulate nasal chemosensory cells in nasal passages to trigger a subset of neurons in the olfactory bulb to stimulate neurons in the limbic amygdala.

This cascade of actions will increase activity of the limbic-hypothalamic- sympathetic nervous system and increase the release of catecholamines (epinephrine, norepinephrine, dopamine).

Because itruvone will be administered intranasally, it’s capable of delivering a rapid-onset antidepressant action within the brain while having potentially reduced risk of side effects/adverse events (due to lack of systemic uptake/distribution).

A small, Phase 2A clinical trial for major depressive disorder found that a 6.4 mcg dose of itruvone generated rapid-onset antidepressant effects that were sustained for ~8 weeks – without psychological side effects or safety concerns as are observed with other intranasal antidepressants (e.g. ketamine).

Pramipexole

• Mechanism of action: D2S receptor full agonist; D2L receptor partial agonist; D3 receptor partial agonist; D4 receptor partial agonist
• Indication: Major depressive disorder
• Developer: Chase Therapeutics
• Stage of development: Phase 2

Pramipexole (brand: Mirapex) is a medication used primarily for the treatment of Parkinson’s disease (PD) and restless legs syndrome (RLS).

Although it’s not a “new drug” (it was first approved for medical in 1997) – it is being investigated by Chase Therapeutics as a potential treatment for major depressive disorder.

It functions primarily as a dopamine receptor modulator: D2S full agonist; D2L partial agonist; D3 partial agonist; D4 partial agonist – but it may also modulate concentrations of inflammatory cytokines secondary to dopamine receptor interactions. (R)

A systematic review and meta-analysis suggests that pramipexole may be helpful for some episodes of major depressive disorder. (R)

That said, I’m unsure of how Chase Therapeutics will financially benefit/profit if pramipexole is found effective – as doctors can just prescribe the widely available generic version (~$5-30 for 30 tablets).

Esmethadone

• Mechanism of action: NMDAR antagonist
• Indication: Major depressive disorder (Fast Track)
• Developer: Relmada Therapeutics (R)
• Stage of development: Phase 2

Esmethadone (REL-1017) a.k.a. dextromethadone, is chemically the (S)-enantiomer of the popular opioid-dependence medication “methadone.”

It functions primarily as a low-potency/low-affinity NMDA receptor antagonist with preferential activity at hyperactive GluN1-GluN2D channels.

It also negligibly interacts with the mu-opioid receptor (MOR), serotonin transporter (SERT), and delta-opioid receptor (DOR).

The actions of esmethadone differ significantly from methadone’s (R)-enantiomer “levomethadone” which is ~50-fold more potent and exhibits higher selectivity for the mu-opioid receptor (MOR) as an agonist.

Preliminary evidence from animal models suggests that a single-dose of esmethadone exerts antidepressant-like activity that is similar to or stronger than that of ketamine with rapid-onset of effect. (R)

In Phase 1 of a clinical trial, esmethadone was observed to increase circulating BDNF (brain-derived neurotrophic factor) concentrations. (R)

It is currently in Phase 2 of clinical trials and has received “Fast Track” status from the FDA.

Ketamine (Transdermal Patch)

• Mechanism of action: NMDAR antagonist
• Indication: Major depressive disorder
• Developer: Shenox Pharmaceuticals (R)
• Stage of development: Phase 2B

Ketamine as a transdermal patch is under development by Shenox Pharmaceuticals, a subsidiary of GDB (Dazhou Biomed), for the treatment of major depressive disorder.

This company seems to be specializing in creating already-available medications in patch format for transdermal administration – as evidenced by other pipeline developments like donepezil patch and methylphenidate patch.

Ketamine functions as an NMDA receptor antagonist wherein it: alters NMDA receptor-mediated signaling, inhibits extrasynaptic NMDA receptor activity, and blocks NMDA receptors in the synapse.

Ketamine is already approved as an intranasal spray (i.e. Spravato) for the management of treatment-resistant depression in adults.

It is unclear as to whether a transdermal patch delivery method for ketamine is superior, inferior, or analogous to intranasal ketamine administration.

Strada (Ademetionine)

• Mechanism of action: Transsulfuration, transaminopropylation, methylation
• Indication: Major depressive disorder
• Developer: MSI Methylation Sciences
• Stage of development: Phase 2

Strada (ademetionine) is a version of SAMe (S-Adenosyl methionine) under investigation by MSI Methylation Sciences as a treatment for major depressive disorder.

SAMe is involved in transsulfuration (synthesis of glutathione); transaminopropylation (development of polyamines); and methylation (synthesis of sarcosine; conversion of norepinephrine to epinephrine; catabolism/anabolism of monoamines).

It is thought that administration of ademetionine (i.e. SAMe) will modulate: (1) transsulfuration; (2) transaminopropylation; and (3) methylation – to enhance mood via subsequent neurochemistry changes. (R)

Some evidence suggests that SAMe enhances gene expression of BDNF (brain-derived neurotrophic factor) which could be another mechanism of its antidepressant action.

TS-121

• Mechanism of action: V1BR antagonist
• Indication: Major depressive disorder
• Developer: Taisho Pharmaceutical
• Stage of development: Phase 2

TS-121 is a substance under development by Taisho Pharmaceutical for the treatment of major depressive disorder.

It is an orally-active medication that functions as a selective vasopressin V1B receptor antagonist.

The idea for targeting V1B receptors with an antagonist to treat depression likely comes from research in rodents wherein rodents without V1B receptors due to gene knockout exhibit: reduced aggression; antidepressant-like behaviors; and anxiolytic-like behaviors.

Research suggests that V1B antagonists exert antidepressant-like effects in several animal models via attenuating hyperactivity of the HPA axis and reducing basal cortisol levels. (R)

Based on these findings, it is thought that TS-121 may prove most therapeutic among depressed patients specifically with HPA axis hyperactivity and/or elevated basal cortisol levels.

A preliminary study found TS-121 safe, tolerable, and effective (relative to a placebo) for the treatment of major depressive disorder. (R)

JNJ-54175446

• Mechanism of action: P2X7 receptor antagonist
• Indication: Major depressive disorder
• Developer: Janssen R&D
• Stage of development: Phase 1

JNJ-54175446 is a novel compound under development by Janssen Research & Development for the treatment of major depressive disorder.

It aims to alleviate depression by acting as a P2X7 purinergic receptor antagonist – which should reduce neuroinflammation and inflammatory mediators (e.g. IL-1B).

P2X7 is an ATP-activated ion channel that is expressed abundantly on microglia and peripheral immune cells and is a critical mediator of neuroinflammation via release of NLRP3-dependent IL-1B and IL-18. (R)

Preclinical models demonstrate that an activated NLRP3-IL1B pathway is “pro-inflammatory” and associated with psychiatric diseases – and that P2X7 ion channel antagonism can counteract this activation to potentially improve mood.

Research suggests this drug’s pharmacological profile is “compatible with potential mood-modulating effect.” (R)

Essentially this would be a neuroimmunological intervention for depression.

Scopolamine (Intranasal)

• Mechanism of action: mAChR antagonist (M1, M2, M3, M4)
• Indication: Major depressive disorder
• Developer: Repurposed Therapeutics
• Stage of development: Phase 1

Scopolamine a.k.a. “hycosine” – colloquially referred to as “Devil’s Breath” – is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is primarily used to treat motion sickness, nausea, and vomiting.

Pharmacologically, scopolamine acts as a non-specific antagonist at M1, M2, M3, and M4 muscarinic acetylcholine receptors.

Scopolamine may provide rapid-onset antidepressant action as a result of convergent activation of synaptic plasticity, synaptogenesis, and glutamate modulation – occurring via antagonism of muscarinic acetylcholine receptors (mAChRs). (R)

Preliminary evidence suggests that scopolamine produces a “rapid and robust” antidepressant response. (R)

Intranasal scopolamine should theoretically be more potent and faster-acting than other versions – and may carry fewer side effects due to lack of peripheral effect.

SEP-378614

• Mechanism of action: N/A
• Indication: Treatment-resistant depression
• Developer: Sunovion Pharmaceuticals + Otsuka Pharmaceutical Co. (R)
• Stage of development: Phase 1

SEP-378614 is a compound under joint investigation by Sunovion Pharmaceuticals and Otsuka Pharmaceutical Co. for the treatment of treatment-resistant depression.

At this stage there isn’t much known about how SEP-378614 works, however, it was reported that Sunovion discovered this compounds with a mechanism-independent approach using the in vivo phenotypic SmartCube platform and associated artificial intelligence algorithms.

Ropanicant

• Mechanism of action: a4B2 nAChR antagonist
• Indication: Major depressive disorder
• Developer: Suven Neurosciences (R)
• Stage of development: Phase 1

Ropanicant (SUVN-911) is a compound under investigation by Suven Neurosciences (a subsidiary of Suven Life Sciences Ltd.) for the treatment of major depressive disorder.

It functions as an alpha-4-beta-2 (a4B2) nicotinic acetylcholine receptor (nAChR) antagonist.

Evidence suggests that depressed patients have lower availability of nAChR-B2 than healthy subjects – and modulation of this receptor site with ropanicant might prove therapeutic. (R)

Preliminary research suggests ropanicant exhibits antidepressant-like properties in animal models of depression wherein it reduced anhedonia, increased serotonin, increased BDNF, and reduced Iba1 (ionized calcium binding adaptor molecule-1) activity. (R)

TAK-653

• Mechanism of action: AMPA receptor potentiator
• Indication: Treatment-resistant depression
• Developer: Takeda + Neurocrine Biosciences
• Stage of development: Phase 1

TAK-653 is a substance under joint investigation by Takeda and Neurocrine Biosciences for the treatment of refractory depression.

It functions by potentiating AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors without any agonistic activity.

It also seems to activate mTOR (mechanistic target of rapamycin) signaling pathways and promotes increases in BDNF (brain-derived neurotrophic factor).

In rats, subchronic administration of TAK-653 for 6 days produced a strong antidepressant-like effect – with seemingly fewer side effects than ketamine.

TAK-653 may also improve cognition for both working memory and recognition memory. (R)

TS-161 (TP0473292)

• Mechanism of action: mGlu2/3R antagonist
• Indication: Depression
• Developer: Taisho Pharmaceutical
• Stage of development: Phase 1

TS-161 (TP0473292) is a substance under development by Taisho Pharmaceutical for the treatment of major depressive disorder.

It functions primarily as a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist.

Research suggests that mGlu2/3 receptor antagonists exert similar synaptic/neural effects as ketamine to induce rapid and sustained antidepressant activity. (R)

It is thought that mGlu2/3 receptor antagonists may generate an antidepressant effect in part via AMPA receptor stimulation in the medial prefrontal cortex (mPFC) which then increases activation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). (R)

Preclinical side effect, tolerability, and toxicology profiles of mGlu2/3 antagonists are not concerning. (R)

The prodrug of TS-161 known as “TP0473292” is safe, well-tolerated, and orally-bioavailable in humans with extensive conversion into the bioactive metabolite “TP0178894” which penetrates the CSF to exert pharmacological effects. (R)

NSI-189 (Benzylpiperazine-aminopyridine neurogenic)

• Mechanism of action: Neurogenesis (hippocampal)
• Indication: Major depressive disorder (adjunct)
• Developer: N/A
• Stage of development: Unknown

NSI-189 is an experimental compound originally developed by Neuralstem Inc. for the treatment of major depressive disorder and cognitive impairment/neurodegeneration.

The compound was discovered using phenotypic screening with a library of 10,000+ compounds to identify agents that promoted neurogenesis in vivo.

Although the specific biochemical target(s) of the compound remained unclear, it is understood to function by promoting hippocampal neurogenesis (i.e. growth of new brain cells in the hippocampus region of the brain).

The rationale for using a neurogenesis-inducing agent (NIA) in major depressive disorder is solid given that most conventional antidepressants promote hippocampal neurogenesis (and this might be a major reason as to why they’re effective).

Some evidence suggests that NSI-189 is safe and effective as an adjunct in patients with moderate depression – and that NSI-189 provides an additional pro-cognitive effect. (R)

However, a large study found that NSI-189 was ineffective relative to a placebo as a monotherapy in major depressive disorder. (R)

Neuralstem Inc., developer of NSI-189, changed its name to Seneca Biopharma Inc. in 2019 – and merged with Leading BioSciences in 2021 to form the company Palisade Bio Inc.

As of 2019, NSI-189 was still undergoing clinical trials as a potential treatment for major depressive disorder, however, Palisade Bio sold NSI-189 to an unknown buyer in 2021 for: $400,000 upfront cash payment and an additional $4.5M contingent upon development milestones, licensing, or sale of the asset within a specific timeframe.

At this time, it remains unknown as to which specific entity owns NSI-189 and whether they have plans to push NSI-189 through additional clinical trials – such that it could eventually hit the market.

Neurochemical targets for new antidepressants (Overview)

Included below is an overview of mechanisms of action associated with new antidepressants in development.

• NMDA receptor antagonist: NMDA receptor antagonism seems to have become the most popular mechanism for new antidepressants.
• Kappa opioid receptor (KOR) antagonist: Multiple substances in development aim to treat depression via antagonism of kappa-opioid receptors (KORs).
• Chemoreceptor cell stimulant
• Methylation modulator
• mTORC1 protein stimulant
• NET inhibitor: One substance in development aims to treat depression via standalone norepinephrine transporter/reuptake inhibition.
• SNDRI: One compound in development will function as a SNDRI with magnitude of reuptake inhibition greatest for serotonin, then norepinephrine, followed by dopamine.
• DSNRI: One compound in development will function as a DSNRI with magnitude of reuptake inhibition greatest for dopamine, then serotonin, followed by norepinephrine.
• Vasopressin 1B receptor antagonist
• P2X7 receptor antagonist
• mACh receptor antagonist
• TRPC 4/5 inhibitor
• 5-HT1A partial agonist
• OX2 receptor antagonist
• AMPA receptor potentiator
• mGlu2/3R antagonist
• Neurogenesis

Is mechanistic/pharmacodynamic saturation problematic?

My opinion: Only insofar as it stifles timely innovation.

Antidepressant development seems to happen in mechanistic historical “waves” wherein pharmaceutical companies all seem to gravitate towards one specific mechanism of action for decades before branching out and attempting to take on additional innovation risk.

• Wave #1: Monoamine oxidase inhibitors (MAOIs)
• Wave #2: Tricyclic antidepressants (TCAs)
• Wave #3: Selective-serotonin reuptake inhibitors (SSRIs)
• Wave #4: SRI + other actions (e.g. 5-HT1A; NRI; etc.)
• Wave #5: NMDA receptor modulators (?)

Sure there were some “atypical” antidepressants developed during these waves – but most of these atypical antidepressants were not “atypical” in the sense that they still targeted monoamines or monoamine receptors (serotonin, norepinephrine, dopamine).

For a while it seemed like every pharmaceutical company was focused on creating new SSRIs (selective-serotonin reuptake inhibitors).

Then many pharmaceutical companies pivoted from SSRI development to: (A) SNRIs (serotonin-norepinephrine reuptake inhibitors) or (B) serotonin reuptake inhibitors (SRIs) with additional action(s) at other neurochemical targets like 5-HT1A – because secondary actions reduce certain side effects (e.g. weight gain) and/or enhance antidepressant effect.

Additionally, some pharmaceutical companies would take an already-available drug (e.g. citalopram, venlafaxine, etc.) and “develop” a new drug using: (A) one enantiomer (escitalopram) of the old drug (citalopram) or (B) a bioactive metabolite (desvenlafaxine) of the old drug (venlafaxine).

Then they’d compile evidence suggesting that the newer compounds were either: safer, more effective, and/or more tolerable (with fewer side effects) relative to the predecessor compounds – and market them aggressively to medical doctors/patients as being “better.”

Although some people dislike these drug development tactics, I’m not entirely against them because it is possible that subtle improvements in safety, efficacy, and/or tolerability are significant with newer compounds in some cases.

Because it’s incredibly difficult to develop drugs that are effective for neuropsychiatric conditions like depression – most pharmaceutical companies want to “play it safe” with drug development by focusing on: proven mechanisms and safety/tolerability.

Why play it safe? Because a failed clinical trial can cost billions of dollars – and a lot of lost time (time/money could’ve been allocated towards testing something else).

As a result, when a new chemical class and/or mechanism for an antidepressant is discovered that is an improvement over an older class in: magnitude of effect; duration of effect; safety; tolerability; and/or onset of effect – it gets the attention of all pharma companies and many want in on the action.

Saturation of a specific mechanism isn’t necessarily a bad thing as evidenced by significant individual variability in responses to drugs within the same class (e.g. one SSRI works well yet another SSRI doesn’t work) likely due to interindividual differences in neurochemistry.

Although it’s possible that “Wave #5” of antidepressant development will not consist of one clear-cut mechanism of action (such that chemical classes and mechanisms for antidepressants will become increasingly heterogeneous) – there’s a current trend towards developing compounds that function as NMDA receptor antagonists/modulators.

Why? NMDA receptor antagonists/modulators seem to provide a faster and longer-lasting antidepressant effect than currently-available medications.  I’m expecting some degree of NMDAR modulator saturation in the 2030s.

Drugs I’m least excited about…

Below are the types of antidepressants I’m least excited about. However, just because I’m least excited about them doesn’t mean they won’t work well for some people or that they shouldn’t be approved.

Already-available: Fixed-doses & old

Any “fixed-dose” combination drugs (comprised of already-available drugs) or already-available drugs with administration modality tweaks (e.g. transdermal patch ketamine) are not very exciting to me.

If I start with a tolerable antidepressant like bupropion and combine it with another OTC drug like dextromethorphan (DXM) – and it proves effective in clinical trials, it’s possible that the efficacy is 100% due to the bupropion and that the DXM component was merely unnecessary added “novelty” for flash/marketing potential.

Moreover, many of these “fixed-dose” combination drugs are unnecessary given that if a pharmaceutical company receives FDA approval for their “combo” – doctors can simply prescribe patients the bupropion + OTC DXM to help patients save money.

The only rationale I can think of for putting a fixed-dose combination of readily-available compounds through clinical trials for depression – is that many patients/doctors will use the “patented” version to avoid certain risks/lawsuits and this will rake in big money for pharma.

It’s also possible that pharmaceutical companies manufacturing these “fixed-dose” combination drugs will tweak the release/formatting and thus pharmacokinetics to provide antidepressant relief that may not occur with administering each drug in non-combination format.

Older medications such as pramipexole are being evaluated for the treatment of depression – when it’s been approved by the FDA since 1997 for Parkinson’s disease.

It makes almost zero logical sense that any pharmaceutical company would waste time investigating this agent for depression because: if found effective – profits will likely be low/nonexistent due to availability as a generic.

The oddest drug in development to me is Strada (ademetionine) which is essentially a version of the dietary supplement “SAMe.” If Strada is proven effective, individuals who want to try it can simply purchase SAMe instead for what’ll likely be the same effect.

Same ole’ mechanisms – different drug/day…

Drugs in development that involve targeting the reuptake of monoamines (serotonin, norepinephrine, dopamine) are not particularly exciting to me because the market is oversaturated with drugs that have this mechanism.

I will acknowledge that if I had to pick one “triple reuptake inhibitor” that I hope is successful – I’d go with ansofaxine on the basis that its magnitude of monoamine reuptake inhibition in order of significance is dopamine (~2-fold the others) followed by serotonin then norepinephrine (modest differences between 5-HT/NA reuptake inhibition).

However, I’m of the mindset that “triple reuptake inhibitors” are unnecessary given that psychiatrists can simply mix/match currently available drugs (e.g. serotonin-reuptake inhibitors + dopamine-reuptake inhibitors + norepinephrine reuptake inhibitors) – at varying dosages – to achieve somewhat of a similar effect.

I’m not at all that excited about gepirone (buspirone’s relative) – because it targets 5-HT1A receptors almost identically to buspirone and many old antidepressants employ 5-HT1A receptor modulation as a mechanism of action.

A drug like PDC-1421 functions as a norepinephrine transporter/reuptake inhibitor (in isolation without serotonergic action) – and there are already medications with a similar mechanism (e.g. atomoxetine, reboxetine, etc.), so this isn’t anything “novel.”

Even the drug zuranolone doesn’t contain a unique mechanism of action – it acts as a positive allosteric modulator (PAM) at GABA-A receptors. (This mechanism is shared by nearly all benzodiazepines – and it’s unclear how it would be significantly different in effect.)

Moreover, some evidence suggests that megadosing of the hormone “progesterone” could be a cheap substitute for zuranolone – as zuranolone is basically synthetic allopregnanolone (a metabolite of progesterone). (R)

New formatting of available drugs…

Certain companies are looking to market reformatted versions of available drugs for the treatment of depression.

For example: transdermal ketamine… ketamine is already available as an intranasal spray (pretty convenient) and via intravenous infusions (inconvenient).

I guess one could argue that transdermal formatting is somehow superior to intranasal spray for safety/abuse potential or something.

Creating an orally-available version of zulresso (brexanolone) with zuranolone is probably smart (as intravenous infusions are invasive and require medical supervision – which increases patient costs)… but it’s still just another “spin” of an already-available substance.

Another example is intranasal scopolamine which will directly deliver scopolamine to the brain to antagonize mAChRs (1-4) without appreciable peripheral action.

Drugs I’m most interested in…

I’m interested primarily in antidepressants that function as: (1) NMDA receptor antagonists/modulators and (2) kappa opioid receptor (KOR) antagonists/modulators.

Why? They differ substantially in action from drugs that target monoamines (serotonin, dopamine, norepinephrine) and therefore provide something different for people who do not significantly benefit from monoamine modulating compounds (most drugs on the market).

NMDA receptor antagonists appear to provide: rapid-onset antidepressant activity and sustained antidepressant effect after short-term dosing – such that those with depression may not require long-term, daily administration of drugs for depression relief.

Due to potential for infrequent administration protocols – NMDA receptor modulators may enable patients to experience an antidepressant effect without any “ongoing” side effects (such as occurs during antidepressant treatment).

As of current ketamine and its enantiomer S-ketamine (esketamine) seem to be popular alternative antidepressants because they are rapid acting with sustained effect, but newer NMDA receptor modulators may further reduce some of the potentially-deleterious side effects associated with ketamine/esketamine.

Kappa opioid receptor (KOR) antagonists tend to be highly-selective for KORs are unique in that there are 2 types of KORs in development: (1) short-acting and (2) long-acting.

Short-acting KOR antagonists could be beneficial in that KOR responses could be quickly modified by altering the dosage – enabling treatment optimization.

Long-acting KOR antagonists could be beneficial in that they can inactivate KORs for weeks (i.e. “receptor inactivating antagonists) via c-Jun Kinase pathways – even after drug discontinuation.

Other mechanisms of action that are intriguing include: AMPA receptor potentiators; mGlu2/3 receptor antagonists; OX2 receptor antagonists; mTORC1 protein stimulants; chemoreceptor cell stimulants; neurogenesis inducers; P2X7 receptor modulators; FAAH inhibitors; and TRPC4/5 inhibitors.

My thoughts on new antidepressants in development…

Some antidepressant development is always better than none – even if there’s not significant mechanistic innovation.

I’m of the mindset that the more FDA-approved (safe/effective) options there are on the market – the more likely any particular individual with depression will be to find a drug that uniquely suits their specific biochemical signature/abnormalities to alleviate depressive symptoms.

As I mentioned, I’m most looking forward to seeing how NMDA receptor and kappa-opioid receptor – antagonists/modulators fare in clinical trials.

That said, I’m intrigued by any substance with a novel mechanism of action that receives FDA approval for the treatment of major depressive disorder.

Strategy/considerations for antidepressant development

If I could, I’d continue investigating novel potential mechanisms for depression treatment and developing compounds with highly selective actions.

• AI screening: Ideally one would have an algorithm/AI screen for chemical compounds that are likely to be: (A) safe in humans and (B) elicit a specific effect (many companies are already doing this).
• Action specificity (ultra-specific vs. multi-target): I prefer medications that have an ultra-specific mechanism of action (e.g. a specific subunit of a single receptor site rather than a random barrage of targets within a specific system). Ideal would be an action that is so specific/precise it doesn’t cause tolerance onset (assuming possible).
• Strategic multi-target mechanism: A strategic multi-target medication may be worth developing such that the primary mechanism could involve treating depression and the secondary mechanism could involve preventing adaptation/tolerance, side effects, and/or withdrawal symptoms.
• Sustained action (post-dosing): A sustained neuromodulatory action would involve administration of an antidepressant infrequently and “as needed” (e.g. every few months) without the drug remaining in systemic circulation. Essentially you figure out how a drug could leave a lasting/sustained effect on receptors even after cleared from circulation.
• Short-term action (post-dosing): It may be worth creating a shorter-acting compound to test efficacy in specific people prior to administering a compound with sustained action. This would help the person know whether the longer-acting drug is likely to provide benefit before they commit to a longer-term effect.
• Physiological adaptation/tolerance/tachyphylaxis prevention: This would involve researching specific neurobiological feedback loops associated with pharmacokinetic and pharmacodynamic tolerance – and either avoiding them with specific drug design OR designing adjunct compounds to prevent tolerance from occurring.
  • Pharmacodynamic tolerance: Examine neurochemical cascade effects of certain drugs and try to avoid or counteract them to prevent tolerance (assuming counteracting these cascades won’t diminish the efficacy of the antidepressant).
  • Pharmacokinetic tolerance: I’ve long thought that it might be useful to engineer a non-psychoactive substance that essentially modulates/regulates CYP450 expression to prevent potential pharmacokinetic tolerance (as is observed with certain drugs) – this might be relatively easy to do and could be a way to help reduce tachyphylaxis with currently-available antidepressants.

Futuristic antidepressant strategies?

• Gene editing: Perhaps editing multiple genes associated with depression.
• Epigenetic modulation: Modifying epigenetic correlates of depression.
• RNA interference: Reversible RNA interference to counteract depression.
• Immunomodulation: Analyze immune correlates with depression and evaluate whether specific forms of immunomodulation might alleviate depressive symptoms.
• Neural growth/connectivity modulators: Induce neurogenesis, synaptogenesis, etc. to alter brain connectivity and treat depression.
• Ultra-targeted brain surgeries: Brain surgeries might prove useful for certain cases of depression – particularly if they become more precise/targeted.
• External neuromodulator devices (electricity, magnets, etc.): It may be possible to improve significantly upon preexisting neuromodulator devices for depression.
• Brain implanted devices: Perhaps nanobots in the far future could be programmed in specific ways to modify brain chemistry to ensure that depression never occurs.
• Customized drugs: Would involve the development of designer compounds that are likely to prove safe, effective, etc. in one person but not necessarily another. First might be better to design drugs for depression with a specific gene set before getting more individualized.

What are your thoughts on new antidepressants in development?

If you have any specific thoughts on new antidepressants in development – feel free to leave a comment below.

• Which specific medication(s) are you most excited about? (Why?)
• Do you think any of these mechanisms are paradigm-shifting in the treatment of depression?
• Do you think any of these antidepressants will be an improvement over current options? (Why?)