Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder (2015)

Another interest of mine is quickly reviewed in the following article:

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder (2015)

Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments—especially for treatment-resistant depression (TRD)—are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.

The article covers:

Glutamatergic modulators

1. Ketamine

“…ketamine has been shown to decrease depressive symptoms in the typically difficult-to-treat subtype of patients with unipolar and bipolar anxious depression. Further, it has also been shown to rapidly decrease suicidal ideation and anhedonia – two symptoms of depression that are particularly difficult to treat.”

  •  A recent report confirmed intravenous ketamine’s favorable safety and tolerability profile treating patients with depression and there were no cases of persistent psychotomimetic effects, adverse medical effects or increased substance use in a subgroup of long-term follow-up patients
  • Several randomized, double-blind, placebo-controlled trials have further demonstrated ketamine’s rapid (within 110min), robust (across a variety of symptoms) and relatively sustained (approximately 7 days) antidepressant efficacy at subanesthetic intravenous doses (typically, 0.5mg/kg over 40min) in well-characterized patients with TRD
  • A proof-of-concept trial of intranasal ketamine (50mg) significantly reduced depressive symptoms within 24h of administration compared with placebo in 18 completers with TRD, though its antidepressant effects were no longer significant at 72h posttreatment.

“Ketamine is classified as a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, though its antidepressant mechanism of action remains largely unknown. Modulation of synaptogenesis likely has a role in its antidepressant properties. As recently reviewed by Zunszain et al., actions on glutamatergic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors stimulate translation pathways for proteins involved in neuronal plasticity. Specifically, the stimulation of mammalian target of rapamycin (an essential kinase in regulating proteins involved in synaptic plasticity) may have a role in ketamine’s antidepressant effects. Furthermore, ketamine potentiates brain-derived neurotrophic factor (BDNF)—a factor implicated in neurogenesis and synaptic remodeling. Ketamine has also been shown to decrease inflammation via inhibition of inflammatory responses. Needless to say, ketamine’s mechanism of antidepressant action is likely complex; several trials are underway to understand its unique mechanis.”

2. Lanicemine (AZD6765)—is a moderate-affinity low-trapping NMDA-receptor blocker that has been tested as an antidepressant in both preclinical and clinical settings.

  • “Following a single intravenous infusion of lanicemine 150mg, MADRS scores significantly decreased compared with placebo within 80min in medication-free patients (n=22) with TRD.This rapid antidepressant onset, though similar to ketamine, remained significant only through 110min.”
  • “Though the antidepressant action of lanicemine was short-lived, its psychotomimetic and dissociative side effects did not differ compared with placebo, underscoring lanicemine’s superior safety profile compared with ketamine.”

3. Memantine is a low-to-moderate affinity NMDA-receptor antagonist already approved for Alzheimer’s dementia

  • Unfortunately, trials examining the antidepressant effects of memantine have been largely negative.

4. Riluzole, an approved medication for amyotrophic lateral sclerosis, inhibits glutamate release via sodium channel inactivation, while blocking NMDA-receptor activation and enhancing AMPA expression.

  • One small (n=19) open-labeled study of riluzole monotherapy for TRD showed significant improvements in depression symptoms.
  • Riluzole augmentation to antidepressant therapy has resulted in significant improvements in both depression and anxiety symptoms.
  • “…it has been hypothesized that oral riluzole could extend the antidepressant properties of a single ketamine infusion by continuing to influence the glutamatergic system without requiring intravenous medication, while simultaneously avoiding ketamine’s unwanted side effects. In one trial, patients (n=42) were randomized in a double-blind manner to receive either riluzole or placebo following an open-label infusion of ketamine. After 28 days, no significant differences were seen between placebo versus riluzole with regards to antidepressant symptoms, suggesting that riluzole does not significantly alter the course of antidepressant response to ketamine. Furthermore, in this same sample, riluzole did not have antidepressant efficacy in ketamine non-responders. A larger clinical trial is currently underway to examine the efficacy and tolerability of adjunctive riluzole in the treatment of resistant depression (ClinicalTrials identifier: NCT01204918).”

5. MK-0657 is an antagonist at the NR2B (also known as GluN2B) subunit of the NMDA receptor, originally developed by Merck.

  • “One small (n=21), randomized, double-blind, placebo-controlled, crossover pilot study examined the antidepressant efficacy and tolerability of oral MK-0657 monotherapy (4–8mg/day) in medication-free patients with TRD. Unfortunately, no significant mood improvements were seen on the MADRS (the primary outcome measure), though no serious or dissociative adverse events were appreciated.”

6. Nitrous oxide, or ‘laughing gas’, is similar to ketamine in that it is a non-competitive antagonist of the NMDA receptor.

  • “One recently published randomized, blind, placebo-controlled crossover pilot study compared the antidepressant effects of inhaled nitrous oxide (administered over 1h) with placebo in patients with TRD (n=20). Nitrous oxide rapidly decreased symptoms of depression within 2h; these effects were sustained for at least 24h. Response to nitrous oxide was 20%, and remission was 15%. Side effects were mild to moderate in nature, with no dissociation or psychotomimetic side effects appreciated. A Phase II trial is currently underway ( identifier: NCT02139540).”

Interestingly, on nitrous oxide:

“In Germany, Zádor, from the Department of Psychiatry and Neurology, University of Greifswald, popularized the psychiatric use of laughing gas scientifically and therapeutically through systematic investigations on healthy subjects and patients. In England, Rogerson  used laughing gas inhalation as a valuable method of disinhibition during narcoanalysis. Lindner, a physician at the Department of Psychiatry and Neurology in Nuremberg, Germany, confirmed the possibility of achieving cathartic revelations in patients with anxiously guarded delusions with the aid of the cheerfulness produced by laughing gas intoxication. Regarding his observations in patients with psychosis, he wrote: “While the deep endogenous depressivity within the cyclothymia could not be penetrated and at most a certain mood brightening was to be achieved, a marked brightening, disinhibition and euphoria occurred in almost all schizophrenics”. As is known, the pharmacologic support of psychoanalytical procedures (diagnostic and therapeutic) and psychopathologic diagnostics is rarely applied today.”

That said:

“…a case of chronic laughing gas intoxication was described in the English-speaking literature in 1906. It involved a young chemist in Boston who inhaled laughing gas several times a day “for his own pleasure” and later experienced a cheerful state of arousal lasting for a period of months, which was accompanied by disorientation, pleasant hallucinations, and a marked loquaciousness. In that case, the antidepressant effects and the harmful psychotic experiences persisted for a long period of time, which exemplifies the delayed and chronic psychotropic effects of N2O. Ultimately, inpatient psychiatric treatment was necessary “

7. GLYX-13 is a functional partial agonist at the NMDA-receptor glycine site that has been shown to produce antidepressant effects in rats, without the unwanted side effects that accompany ketamine

“It is thought to work by activating the NR2B receptor of the NMDA channel, causing calcium influx and increasing the expression of AMPA receptors. This increases learning and memory and is thought to contribute to its antidepressant effects.”

  • TRD patients in the Phase IIa study (n=116) received either intravenous GLYX-13 or placebo in a randomized, double-blind manner. Depression scores improved within hours; this improvement was sustained for 1–2 weeks. Furthermore, no serious treatment-associated adverse events were observed, including psychotomimetic effects

8. AVP-786 is a novel combination of deuterium-modified dextromethorphan hydrobromide (DXM) and low-dose quinidine sulfate.

“Deuterium (a nonradioactive isotope of hydrogen) incorporation enhances the DXM molecule to decrease hepatic metabolism on first pass, which allows for more active drug to reach the brain; quinidine has been found to also increase its bioavailability. DXM is a low-to-moderate affinity NMDA-receptor antagonist, in addition to having serotonin and norepinephrine reuptake properties and sigma-1 receptor agonism—all thought to contribute to its potential antidepressant properties.”

9. Org 26576 “is an AMPA positive allosteric modulator (AMPA PAM) in development. Because ketamine is thought, in part, to exert its mechanism of action via enhancing AMPA-receptor throughput of glutamate (thereby increasing BDNF, neuronal plasticity, and neurogenesis—all processes thought to be disrupted in depression), AMPA PAMs hold theoretical promise for treating depression.”

  • “A  Phase I trial (n=36) showed that Org 26576 was well tolerated in healthy volunteers. Phase Ib testing (n=54) confirmed its positive tolerability profile, established 450mg/day as the maximum tolerated dose and improved clinically relevant cognitive measures of executive functioning and speed of processing—domains all relevant to depression. Furthermore, symptomatic improvements on depression scores were greater in the Org 26576 group compared with placebo. With regard to biomarkers, Org 26576 was associated with increases in growth hormone and decreases in cortisol at the end of treatment; prolactin and BDNF levels were not influenced.”

Metabotropic glutamate receptor modulators

“…several compounds are currently in clinical and preclinical testing that work on the metabotropic glutamate receptors (mGluRs). Specifically, mGluR2 and mGluR3 modulators (that is, LY341495, MGS0039) are of particular interest, as antagonism of these autoreceptors may lead to antidepressant responses. Significant preclinical data demonstrating their antidepressant effects is promising, though no large clinical trials in humans have been completed.”

“Antagonism of the mGluR5 postsynaptic receptor by basimglurant (1.5mg/day) as an adjunctive treatment to antidepressant treatments showed consistent antidepressant efficacy across primary and secondary end points in one 9-week double-blind, placebo control study in 333 patients with TRD, with good tolerability and safety. However, the study just missed statistical significance on the primary outcome measure (clinician rated MADRS) (P=0.061), likely due to a sizeable placebo response rate (approximately 14 point mean score reduction).”

Anticholinergic modulators

1. Scopolamine

“It has been hypothesized that depression may be due to, in some cases, a hypercholinergic state. Scopolamine, often used for motion sickness, is a competitive antimuscarinic (specifically, at the muscarinic M1 receptor) compound. It has been found to rapidly (within 3 days) and robustly decrease symptoms of depression and anxiety in both unipolar and bipolar patients with treatment-naive and resistant depression, though those with treatment-naive depression showed greater improvements. Interestingly, though both men and women experience rapid antidepressant and anxiolytic effects following scopolamine, effects appear to be greater in women. However, similar with ketamine, studies on how to maintain short-term gains seen with intravenous scopolamine are lacking.”

2. Mecamylamine and dexmecamylamine (TC-5214)

“Excessive nicotinic-receptor stimulation may also contribute to the hypercholinergic state that results in depression in some cases; therefore, nicotinic antagonists may have a role to play in the treatment of depression. One such nicotinic-receptor antagonist, mecamylamine, was superior to placebo in improving primary and secondary depression outcomes when augmented to citalopram treatment in incomplete responders with depression”

3. CP-601,927 is a high-affinity, selective nicotinic acetylcholine receptor (α4β2) partial agonist developed by Pfizer after it showed antidepressant qualities in animal models of depression.

  • Unfortunately, it failed to show superior antidepressant efficacy to placebo as an augmentation agent to selective serotonin reuptake inhibitors (SSRIs) in one Phase II randomized trial. However, post hoc analyses showed a drug–placebo separation in non-obese patients, suggesting that the overall findings were adversely affected by obesity.

Opioid system modulators

“ALKS 5461—combines buprenorphine (a μ-opioid receptor partial agonist and functional kappa-opioid receptor antagonist) with samidorphan (a potent μ- opioid receptor antagonist) in an attempt to create a functional kappa receptor antagonist. A recently published study has yielded positive efficacy and safety data, with no abuse with withdrawal concerns. Phase III clinical trials are ongoing ( identifier: NCT02085135; NCT02218008; NCT02158546; NCT02158533).”


  • Vortioxetine
  • Lisdexamfetamine dimesylate
  • Edivoxetine (LY2216684)
  • Pramipexole

Neutraceuticals and exercise

1. L-methylfolate and S-adenosyl-methionine (SAMe)

  • “outpatients with TRD (n=148) on an SSRI antidepressant regimen were randomized to placebo for 60 days, L-methylfolate (7.5mg/day) for 30 days followed by 15mg/day for 30 days) or a combination of placebo for 30 days followed by L-methylfolate (7.5mg/day) for 30 days as adjunctive therapy” No significant differences between the groups were observed
  • A trial with 75 depressed patients found statistically significant antidepressant efficacy for adjunctive L-methylfolate at 15mg/day compared with placebo, with comparable safety profiles. Further post hoc testing showed that certain inflammatory biomarkers and genetic markers associated with the synthesis and metabolism of L-methylfolate may be useful predictors for adjunctive treatment response
  • SAMe (800–1600mg/day) was safe and effective as an augmentation agent to serotonin reuptake inhibitors

2. Exercise


  • Erythropoietin (EPO)
  • Testosterone


  • Infliximab
  • Celecoxib

Transcranial magnetic stimulation (TMS)

To conclude:

“…explorations into experimental treatments for resistant depression have broken away from the monoaminergic antidepressant ‘dogma’ of the late twentieth century and into a wider realm of possibilities. Throughout all this excitement of novel therapeutics, we must keep in mind that the modulation of the monoaminergic system through medications with primary mechanisms of action outside of the monoaminergic system (and vice versa) is very possible. In fact, given the that brain’s intricate highway system of neurocircuitry and neurotransmission are intimately connected, the consideration of neurotransmitter systems and circuits in isolation and the excessive reliance on a ‘rational’ development of ‘single-target’ designer drugs seems unrealistic. The role of serendipity coupled with meticulous clinical observation in drug development in medicine should be emphasized.

Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far. As seen with the ketamine story, patients with difficult-to-treat depression have been observed to respond and remit within hours—an incredible finding from both a clinical and research perspective. The discovery of ketamine’s rapidly acting antidepressant properties also reminds us of the importance of serendipity in antidepressant research. Maintaining the ability to uncover breakthroughs by creatively re-examining ‘knowns’ is a crucial part of drug discovery. Serendipity combined with biomarkers’ breakthroughs, target-engagement research and neuroscience-driven discovery are the keys to the future of antidepressant research.”

Not mentioned in the article: acetyl-L-carnitine [1,2], sarcosine [3], negative allosteric modulators of α5 subunit-containing GABAA receptors [4] and 4-chlorokynurenine [5].

See also:

Faster, better, stronger: Towards new antidepressant therapeutic strategies

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