Not So Fast: Recent Successes and Failures in Treating Depression

Historically, rapid antidepressant effects within days to weeks were seen in response to electroconvulsive therapy (ECT). In contrast, antidepressant medications took 4 to 6 weeks to exert their antidepressant effects. However, trials with novel, rapid-acting antidepressant medications—including the glutamatergic modulator ketamine—have revolutionized our expectation of when antidepressant effects could be expected, that is, in a matter of hours or days instead of weeks or months. This paradigm shift has instilled hope in individuals struggling with depression, particularly treatment-resistant depression (TRD). The unmatched robustness of ketamine’s effects, the notable recent FDA approval of its derivative esketamine for adults with TRD, and the recent approval of brexanolone for postpartum depression (PPD) underscore the first exemplars of a mechanistically novel and distinct antidepressant agent in decades. Yet, despite tremendous progress, challenges have arisen in our investigation of many promising, novel, and rapid-acting (as well as non-rapid-acting) antidepressant interventions for depression. Here, we briefly assess some of these recent successes and setbacks.

Ketamine

Initial preclinical studies in the 1990s implicated the glutamatergic system in the etiology of mood disorders.1 The first small clinical study of intravenous subanesthetic-dose (0.5 mg/kg) ketamine, administered over 40 minutes, showed that this agent had unusually rapid and robust antidepressant effects.2 Since then, multiple double-blind, placebo-controlled, randomized trials have established ketamine’s antidepressant efficacy for TRD, both in individuals with major depressive disorder (MDD)3,4 and in those with bipolar depression.5,6 Meta-analyses subsequently corroborated these findings.7-11 A single ketamine infusion was also found to have significant and rapid (1 to 4 hours) antisuicidal ideation effects.12-15 Furthermore, while the robust antidepressant effects of subanesthetic-dose ketamine were found to be transient, researchers were able to successfully prolong these effects with repeated infusions.16-18 These groundbreaking findings led to the development of intranasal esketamine, the stereoisomer derived from racemic ketamine. Positive phase 3 clinical trials established its efficacy,19-21 which led to the recent (March 2019) FDA approval of intranasal esketamine for adults with TRD.22

Despite these advances, ketamine’s underlying mechanisms of action remain largely unknown. The prevailing hypothesis is one of direct and indirect antagonism at the N-methyl-d-aspartate receptor (NMDAR) as well as AMPA throughput modulation.23,24 These converging mechanisms appear to induce rapid and sustained changes in synaptic plasticity that result in increased synaptic spine turnover that, in turn, propagates ketamine’s antidepressant-like effects over time.25 Studies suggest that a cascade of several mechanisms triggered by ketamine’s unique pharmacodynamic profile might be critical to its antidepressant effects.23

As our theoretical understanding of ketamine’s mechanisms of action grew, several preclinical candidate drugs whose mechanistic processes were purported to overlap with those of ketamine (eg, lanicemine, GLYX-13, and 4-chlorokynurenine [4-Cl-KYN]) were explored to investigate whether these would mimic ketamine’s rapid and robust antidepressant properties while avoiding its dissociative and psychotomimetic side effects. Although some promising agents emerged, other early phase 2 or 3 clinical studies failed to show clinical efficacy.26 While a comprehensive review of this topic is beyond the scope of this article, below we highlight a handful of candidate examples. For additional information, the interested reader is referred to recent review articles on this subject.23,27

“Ketamine-Like” Agents

Lanicemine. Lanicemine (AZD6765) is a low-trapping, noncompetitive NMDAR channel blocker whose mechanism of action was thought to be similar to that of ketamine but without ketamine’s dissociative or psychotomimetic side effects. Though early clinical studies were promising,28 a subsequent 3-week, placebo-controlled trial of repeated-dose adjunctive lanicemine found that this agent had antidepressant effects but that these were not rapid.29 A larger, 6-week, phase 2b study of adjunctive repeated-dose (50 mg and 100 mg) lanicemine then found that this agent did not separate from placebo on primary endpoint measures30; clinical development of the compound was terminated due to lack of efficacy.30

GLYX-13. GLYX-13 is an intravenously administered tetrapeptide whose mechanism of action has yet to be fully elucidated. However, recent findings suggest its mechanism of action is pharmacologically unique and may involve NMDAR activation via a novel binding domain, even in the absence of glycine.31 Building on several initially promising preclinical studies showing mechanistic overlap with ketamine,32 phase 1 and 2 clinical trials found that GLYX-13 was well tolerated and exhibited rapid-acting lasting antidepressant properties in TRD participants without producing psychotomimetic effects.33 However, GLYX-13 failed to meet primary or secondary endpoints in subsequent large phase 3 trials.34 Several ongoing studies are assessing the long-term antidepressant properties of GLYX-13 in individuals with MDD—both as adjunctive treatment and as monotherapy.

4-Chlorokynurenine. 4-Cl-KYN is a prodrug of an NMDAR glycine B site antagonist. In preclinical models, 4-Cl-KYN induced rapid and sustained antidepressant effects without ketamine-related side effects,35 suggesting that directly targeting the glycine B site with an antagonist might be a viable antidepressant strategy. However, a recent phase 2, placebo-controlled, crossover study evaluating a 2-week course of 4-Cl-KYN monotherapy in 19 TRD participants found that this agent failed to improve participants’ overall depressive symptomatology, nor did it engage the primary target in brain.36 A multisite study in TRD is currently underway.

Other Novel Interventions for Depression

Brexanolone (SAGE-547). In March 2019, the FDA approved brexanolone (SAGE-547), the first drug specifically indicated for PPD. Brexanolone is a synthetic formulation of allopregnanolone and a known positive allosteric modulator of γ aminobutyric acid type A (GABAA) receptor function.37 In 2 large, phase 3 trials, 138 women with moderate to severe PPD were randomly assigned to a single 60-hour infusion of either brexanolone (60 or 90 µg/kg/h) or placebo. Mean reductions in depression rating scale scores from baseline were greater in the group receiving brexanolone versus placebo, and the proportion of participants achieving remission was also significantly higher for the brexanolone groups.38,39

Relatedly, SAGE-217 is an analogue of allopregnanolone similar to brexanolone but intended for once-daily oral dosing. A previous phase 3 trial found that SAGE-217 met primary and secondary endpoints for PPD,40 and an earlier, double-blind, phase 2 trial found that daily administration of SAGE-217 reduced depressive symptoms at day 15.41 However, in a recent phase 3 trial in MDD, SAGE-217 was not superior to placebo at its primary endpoint at day 15.42

Theta burst stimulation and electroconvulsive therapy. Device-based treatments are another source of rapid antidepressant effects. In August 2018, the FDA approved intermittent theta burst stimulation (iTBS). The iTBS protocol can be delivered in 3 minutes (versus 37 minutes for the conventional repetitive transcranial magnetic stimulation [rTMS] protocol) and has been shown to facilitate cortical excitability.43 In a multicenter clinical trial of 400 participants randomized to receive either iTBS or standard 10 Hz rTMS, iTBS had equivalent antidepressant efficacy to rTMS.44 Furthermore, a recent, open study45 of 22 TRD participants demonstrated the feasibility of using an accelerated high-dose resting-state functional connectivity MRI-guided iTBS protocol for TRD. Ongoing studies are investigating ways to shorten the time of each treatment session as well as accelerate response.46

Another notable development in this area is that the FDA reclassified ECT in December 2018, downgrading its risk category from Class III (high risk) to Class II (moderate risk). Despite ECT’s superior clinical efficacy—it has the largest effect size of all available treatments for depression47—its use is both limited and declining,48 typically because of its potential to cause adverse cognitive effects. Alternative approaches and novel technologies may soon allow for more individualized and selective targeting with ECT, including the use of multichannel stimulation systems and computational electric field models to characterize intracranial current flow.

Conclusion

The evidence reviewed above suggests that a complex drug like ketamine, though responsible for a considerable therapeutic breakthrough, may have a somewhat unique pharmacologic profile that is difficult to reproduce. The recent failure of several novel therapies for depression deserves thorough reflection by the scientific community; in particular, the importance of bench-to-bedside translational paradigms that lead from basic science research to clinical trials deserves scrutiny. Perhaps attempts to “sanitize” the side effect profile of ketamine-like agents could serve as a learning example for the entire field, helping to reconceptualize the challenging and complex process that drug discovery in psychiatry is facing. In this context, the scientific community might reconsider its traditional path of translating animal models for novel drug testing and re-examine ways to address particular study design and phase-to-phase feasibility challenges when designing or testing novel therapeutics.

Despite these setbacks, we wish to stress that the situation is not bleak. Indeed, the discovery of ketamine’s rapid antidepressant effects ushered in a new era of paradigm-shifting research focused on developing or repurposing new antidepressant therapies capable of working within hours or days versus weeks or months. Most notably, the recent FDA approval of esketamine for TRD and brexanolone for PPD marks the first time in 50 years that 2 antidepressants with distinct novel mechanisms of action have reached the market. Along these lines, in 2018 the FDA also cleared the iTBS protocol. The approval of 3 new treatments—esketamine, brexanolone, and theta burst stimulation—for the treatment of depression over the course of a single year is a singular achievement that highlights the possibility of developing urgently needed next-generation treatments based on an improved understanding of the precise mechanistic processes underlying their therapeutic properties. As a field, we continue to learn from both our successes and our failures to enhance study design and move promising agents forward from bench to bedside.

Published online: May 26, 2020.

Potential conflicts of interest: Dr Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. Drs Deng and Lisanby have an issued patent on TMS technology, assigned to Columbia University, not licensed, and with no renumeration. Dr Lisanby has received grant support from the Brain and Behavior Research Foundation, the Stanley Medical Research Foundation, Neosync, Nexstim, National Institutes of Health, and Brainsway. Drs Kadriu and Kraus and Ms Henter have no conflict of interest to disclose, financial or otherwise.

Funding/support: Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927), by a NARSAD Independent Investigator Award to Dr Zarate, by a Brain and Behavior Mood Disorders Research Award to Dr Zarate, and by a NARSAD Young Investigator Award to Dr Deng.

Role of the sponsor: The National Institute of Mental Health had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Disclaimer: The views expressed are the authors’ own and do not necessarily represent the views of the National Institutes of Health or the United States Government.

Acknowledgment: The authors thank the 7SE research unit and staff for their support.

REFERENCES

1.Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185(1):1-10. PubMed CrossRef

2.Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354. PubMed CrossRef

3.Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. PubMed CrossRef

4.Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. PubMed CrossRef

5.Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793-802. PubMed CrossRef

6.Zarate CA Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939-946. PubMed CrossRef

7.Caddy C, Giaroli G, White TP, et al. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014;4(2):75-99. PubMed CrossRef

8.Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459-1472. PubMed CrossRef

9.McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693-704. PubMed CrossRef

10.Newport DJ, Carpenter LL, McDonald WM, et al; APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950-966. PubMed CrossRef

11.Romeo B, Choucha W, Fossati P, et al. Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res. 2015;230(2):682-688. PubMed CrossRef

12.DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-d-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71(12):1605-1611. PubMed CrossRef

13.Murrough JW, Soleimani L, DeWilde KE, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015;45(16):3571-3580. PubMed CrossRef

14.Price RB, Nock MK, Charney DS, et al. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522-526. PubMed CrossRef

15.Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150-158. PubMed CrossRef

16.aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67(2):139-145. PubMed CrossRef

17.Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176(5):401-409. PubMed CrossRef

18.Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256. PubMed CrossRef

19.Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620-630. PubMed CrossRef

20.Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):139-148. PubMed CrossRef

21.Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903. PubMed CrossRef

22.US Food & Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression. US Food and Drug Administration website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm. 2019.

23.Kadriu B, Musazzi L, Henter ID, et al. Glutamatergic neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Int J Neuropsychopharmacol. 2019;22(2):119-135. PubMed CrossRef

24.Zarate CAJ Jr, Machado-Vieira R. Ketamine: translating mechanistic discoveries into the next generation of glutamate modulators for mood disorders. Mol Psychiatry. 2017;22(3):324-327. PubMed CrossRef

25.Moda-Sava RN, Murdock MH, Parekh PK, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364(6436):eaat8078. PubMed

26.Wilkinson ST, Sanacora G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Drug Discov Today. 2019;24(2):606-615. PubMed CrossRef

27.Zanos P, Thompson SM, Duman RS, et al. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32(3):197-227. PubMed CrossRef

28.Zarate CA Jr, Mathews D, Ibrahim L, et al. A randomized trial of a low-trapping nonselective N-methyl-d-aspartate channel blocker in major depression. Biol Psychiatry. 2013;74(4):257-264. PubMed CrossRef

29.Sanacora G, Johnson M, Khan A, et al. Adjunctive lanicemine (AZD6765) in patients with major depressive disorder and a history of inadequate response to antidepressants: primary results from a randomized, placebo controlled study (PURSUIT). 53rd Meeting of the ACNP. 2014; Hollywood, FL.

30.Sanacora G, Johnson MR, Khan A, et al. Adjunctive lanicemine (AZD6765) in patients with major depressive disorder and history of inadequate response to antidepressants: a randomized, placebo-controlled study. Neuropsychopharmacology. 2017;42(4):844-853. PubMed CrossRef

31.Donello JE, Banerjee P, Li YX, et al. Positive N-methyl-d-aspartate receptor modulation by rapastinel promotes rapid and sustained antidepressant-like effects. Int J Neuropsychopharmacol. 2019;22(3):247-259. PubMed CrossRef

32.Moskal JR, Burch R, Burgdorf JS, et al. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs. 2014;23(2):243-254. PubMed CrossRef

33.Preskorn S, Macaluso M, Mehra DO, et al; GLYX-13 Clinical Study Group. Randomized proof of concept trial of GLYX-13, an N-methyl-d-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21(2):140-149. PubMed CrossRef

34.Allergan announces phase 3 results for rapastinel as an adjunctive treatment of major depressive disorder (MDD). BioSpace website. https://www.biospace.com/article/releases/allergan-announces-Phase-3-results-for-rapastinel-as-an-adjunctive-treatment-of-major-depressive-disorder-mdd-/. 2019.

35.Zanos P, Piantadosi SC, Wu HQ, et al. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J Pharmacol Exp Ther. 2015;355(1):76-85. PubMed CrossRef

36.Park LT, Kadriu B, Gould TD, et al. A randomized trial of the N-methyl-d-aspartate receptor glycine site antagonist prodrug 4-chlorokynurenine in treatment-resistant depression. Int J Neuropsychopharmacol. Published online March 31, 2020. PubMed CrossRef

37.Majewska MD, Harrison NL, Schwartz RD, et al. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986;232(4753):1004-1007. PubMed CrossRef

38.Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390(10093):480-489. PubMed CrossRef

39.Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-1070. PubMed CrossRef

40.Sage Therapeutics. Sage announces pivotal Phase 3 trial status for SAGE-217 in major depressive disorder and postpartum depression based on FDA breakthrough therapy meeting. Sage Therapeutics website. https://investor.sagerx.com/news-releases/news-release-details/sage-announces-pivotal-phase-3-trial-status-sage-217-major. June 12, 2018.

41.Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019;381(10):903-911. PubMed CrossRef

42.Taylor NP. Sage crushed by MOUNTAIN as phase 3 depression data fall short. Fierce Biotech website. https://www.fiercebiotech.com/biotech/sage-crushed-by-mountain-as-phase-3-depression-data-fall-short. Published December 5, 2019.

43.Huang Y-Z, Edwards MJ, Rounis E, et al. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201-206. PubMed CrossRef

44.Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391(10131):1683-1692. PubMed CrossRef

45.Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for treatment-resistant depression. Am J Psychiatry. Published online April 7, 2020. PubMed

46.Fitzgerald PB, Hoy KE, Elliot D, et al. Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Neuropsychopharmacology. 2018;43(7):1565-1572. PubMed CrossRef

47.Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649-659. PubMed CrossRef

48.Wilkinson ST, Agbese E, Leslie DL, et al. Identifying recipients of electroconvulsive therapy: data from privately insured Americans. Psychiatr Serv. 2018;69(5):542-548. PubMed CrossRef

aExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

*Corresponding author: Bashkim Kadriu, MD, Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Dr, Room 7-5545, Bethesda, MD 20892 ([email protected]).

J Clin Psychiatry 2020;81(4):19ac13138

To cite: Kadriu B, Deng Z-D, Kraus C, et al. Not so fast: recent successes and failures in treating depression. J Clin Psychiatry. 2020;81(4):19ac13138.

To share: https://doi.org/10.4088/JCP.19ac13138

© Copyright 2020 Physicians Postgraduate Press, Inc.