There is rapidly escalating interest in drugs that target the glutamatergic neurotransmitter system, especially NMDA receptor modulators. The hope is that they will fill the large unmet need for rapid-acting antidepressant medications with efficacy in treatment-resistant patients.
Although we have made significant advances in the treatment of mood disorders, studies such as the STAR*D and STEP-BD have made us increasingly aware of the limitations of the effectiveness of our current treatment strategies.1,2
Moreover, the fact that the currently existing antidepressant treatments require several weeks to produce a clinically meaningful improvement leads to high rates of discontinuation, extended hospital stays, prolonged suffering-and possibly even increased rates of suicidal behavior.
A series of studies completed over the past 12 years suggest that a novel class of drugs that directly target the glutamatergic neurotransmitter system may produce rapid and robust antidepressant effects in patients who had previously not responded to the standard monoaminergic antidepressant medications. Here I discuss the clinical studies that demonstrate the antidepressant effect of ketamine and other glutamatergic drugs, review the risks associated with some of these medications, and highlight the many still unanswered questions regarding the treatments. I also present information on several ongoing clinical trials in this area and encourage use of the NIH-sponsored registry of clinical trials, http://clinicaltrials.gov, when treatment options are being considered for patients with treatment-resistant mood disorders.
Glutamate receptors in the mammalian CNS
Glutamate is by far the most abundant and ubiquitous neurotransmitter in the mammalian CNS (Figure 1). Although it is known to serve as the major excitatory neurotransmitter in the brain, it was only recognized as a true neurotransmitter less than 30 years ago.3 Since that time, accumulated evidence has demonstrated glutamate’s central role in mediating nearly all forms of brain function, including cognition, perception, learning, and emotion. There is increasing evidence that disrupted glutamatergic signaling can contribute to the pathophysiology of a large variety of neuropsychiatric disorders. Preclinical studies are beginning to elucidate the connections between impaired function of glutamatergic synapses and stress-related conditions, such as mood disorders.4
The earliest evidence that a glutamatergic drug could have antidepressant effects was presented by George Crane5 in the late 1950s, long before the recognition of glutamate as a neurotransmitter. He noted the rapid antidepressant effects of cycloserine-now known to be a partial agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor-when it was used to treat patients with tuberculosis. He specifically remarked on the rapid improvement of insomnia, anorexia, and tension in those patients.
Although he noted “cycloserine may become a valuable agent in psychopharmacological research considering the fact that its chemical structure and mode of action are different from those of most drugs with psychic effects,” there was little follow-up until the late 1980s, when Phil Skolnick’s laboratory at the NIH began to seriously examine the role of the NMDA receptor in the pathology of depression and as a target for antidepressant drug development.6 A series of studies throughout the 1990s further identified the critical role of NMDA receptors in eliciting stress-related behavioral deficits and in the generation of antidepressant-like effects in rodent models while postmortem studies in humans reported specific abnormalities in NMDA receptor function in the brains of depressed patients and suicide victims.7
In 2000, Berman and colleagues8 were the first to demonstrate the rapid onset of antidepressant effects with an NMDA receptor antagonist. In a small, placebo-controlled, proof-of-concept, crossover study of 7 patients, they found that a subanesthetic dose of ketamine (0.5 mg/kg) administered via a 40-minute infusion elicited robust antidepressant effects within hours of administration that lasted for several days.
However, it was a follow-up study of 17 treatment-resistant patients with MDD by Zarate and colleagues9 that truly ignited interest in the NMDA receptor as a viable target for antidepressant drug development. This placebo-controlled, randomized, crossover study found 71% of the participants to have a greater than 50% reduction in depressive symptoms within 24 hours of ketamine administration, while the same participants showed almost no change in symptoms following the placebo saline injection. Moreover, the response was sustained for the 1-week follow-up in approximately one-third of the participants. There have been 3 additional placebo-controlled crossover studies that showed very similar findings of rapid onset of robust antidepressant activity lasting for several days to weeks after a single subanesthetic dose of ketamine in the treatment of major depressive episodes associated with both MDD and bipolar disorder.10-12
Numerous open-label studies and case series provide additional evidence of ketamine’s antidepressant effect and further characterize its effects in unique patient populations. Rapid reductions in suicidal ideation in depressed patients who received ketamine have been reported.13,14 Other studies have begun to examine the potential benefits of adding ketamine to the anesthetic regimen of patients undergoing ECT. While some early reports suggest benefits, the proper use of the drug in this situation may need to be more clearly detemined.15,16 Still other reports have begun to evaluate the potential use of ketamine in palliative care settings, where the drug’s pain-reducing effects may provide an additional benefit.17,18
Phelps and colleagues19 report that individuals with a family history of alcohol dependence had significantly greater mood improvement following ketamine infusion than those who had no family history of alcohol dependence. On the basis of these findings, a study (clinicaltrials.gov identifier: NCT01551329) is evaluating the efficacy of ketamine in reducing depressive symptoms in patients with a comorbid major depressive episode and alcohol dependence. In an attempt to examine the potential benefits of ketamine treatment outside of mood disorders, a recent study in patients with obsessive-compulsive disorder showed ketamine to have sustained effects on comorbid mood symptoms but only very transient effects on obsessions and compulsions.20 Another recently initiated study (NCT00749203) is attempting to investigate whether ketamine decreases symptoms of PTSD.
Unresolved issues and concerns
The aforementioned studies with ketamine have generated great interest from both academic centers and the pharmaceutical industry. However, there remain several unresolved issues with the studies and concerns about the drug’s safety in this setting that need to be better addressed before widespread implementation in clinical practice. First, there is the concern that none of the studies published to date have been able to maintain a true blind. Since the effects of ketamine on perception and cognition are usually evident to both the patient and the investigators, the blind is likely compromised in studies in which saline is used as the placebo control. Attempts are now under way to more effectively institute blinding by using midazolam as the comparator in a randomized clinical trial (NCT00768430).
Second, the optimal dose and route of delivery have yet to be determined. Most studies use the 0.5 mg/kg dose delivered by IV infusion over 40 minutes, as initially reported in the Berman study over a decade ago. Studies are under way that examine both the optimal dose range (NCT01558063 and NCT01441505) and alternative routes of administration (NCT01304147).
Third, and perhaps the most clinically important unknown, is whether it will be possible to maintain the ketamine-induced antidepressant response for a sustained period. A recent study found that a single sub-anesthetic dose of ketamine provides a moderate antidepressant effect over a 28-day follow-up period and that 27% of ketamine responders maintain improvement for 4 weeks fol-lowing a single ketamine infusion, The average time to relapse was approximately 2 weeks, however.21 This result has prompted a search for novel ways of extending the antidepressant response. A few preliminary studies that attempted to extend the response with oral medication strategies have not yet shown success, but results of a study of 6 open-label ketamine infusions over 12 days suggest that the effect can be safely extended with a limited number of repeated doses.22 Other studies investigating the value of repeated ketamine dosing in sustaining the antidepressant response are now under way (NCT01582945 and NCT00548964).
The use of repeated dosing underscores the potential safety concerns of ketamine. Ketamine has been used in hundreds of thousands of patients worldwide for surgical anesthesia and emergency medical procedures since 1965, and it is considered to have a “high degree of safety” when used for procedural sedation.23 However, there remain safety concerns surrounding the drug’s acute and chronic physiological and psychological effects, its abuse liability, its effects on the kidneys and liver, and also its potential neurotoxicity.
NMDA receptor antagonists
The adverse effects of long-term treatment need to be carefully considered when evaluating the risk to benefit ratio associated with ketamine. Would other NMDA antagonists provide a similar benefit without the same level of potential risks? Memantine, a relatively weak NMDA receptor antagonist did not show efficacy superior to that of placebo in several small proof-of-concept studies in MDD, bipolar disorder, and late-life depression.24-26 However, the full dose range of the drug had not been tested in the studies and final results from several ongoing studies have not been reported yet.
A large, phase 2, multisite clinical trial (NCT00781742) of another nonselective NMDA antagonist-AZD6765-that enrolled 152 participants was recently completed. The results of this study that examined the safety and efficacy of 2 drug doses administered multiple times over a 3-week period and results of 2 smaller studies (NCT00491686 and NCT00986479) that examined the safety and efficacy of a single infusion of AZD6765 should be available soon. A second, larger, phase 2, repeated-dosing study (NCT01482221) with this drug is currently under way. Its aim is to recruit more than 280 participants internationally.
Other studies have begun to investigate the effects of more selective NMDA receptor drugs. A positive study was reported with traxoprodil (CP-101,606), an NMDA receptor antagonist with relative selectivity for the NR2B-containing subset of NMDA receptors. The study of 30 patients who had not responded to a prospective, 6-week, open-label trial of paroxetine showed a 60% response rate at day 5 compared with a 20% response rate for placebo. The data suggest that the antidepressant effects are not limited to some unique properties of ketamine.27 However, not all doses used in this study were free of psychotomimetic effects. A small proof-of-concept study (NCT00472576) that examined the effects of orally administered MK-0657, another selective NR2B NMDA antagonist, was also recently completed and the results should be available shortly.
Following on the exciting findings in fear extinction and phobia treatment, there are a number of studies on the effects of D-cycloserine-the same partial agonist at the NMDA receptor-glycine site reported on by Crane in the 1950s-in a variety of neuropsychiatric disorders, including depressive symptoms.28 A phase 2 study (NCT01234558) currently enrolling 80 participants to investigate the safety and efficacy of single-dose administration of a novel NMDA receptor glycine-site functional partial agonist, GLYX-13, should be completed in the near future.
Glutamatergic neurotransmitter system
In addition to studies specifically examining the potential antidepressant efficacy of drugs that target the NMDA receptor, there are several ongoing early-phase clinical trials evaluating the efficacy of drugs that target other components of the glutamatergic neurotransmitter system. (Figure 2illustrates some of these pharmacological targets.)
Interest in the novel glutamatergic drug riluzole, which appears to modulate both glutamate release and clearance and is currently FDA-approved for the treatment of amyotrophic lateral sclerosis, was fueled by evidence of its antidepressant-like and neuroprotective properties in humans and rodent models. Several small open-label studies have reported positive results in a variety of mood and anxiety disorders.29 The first large, multisite, placebo-controlled, randomized clinical trial in treatment-resistant MDD (NCT01204918) is under way and actively recruiting. A second, smaller, randomized clinical trial in bipolar depression (NCT00376220) has been completed recently, and results should be available shortly. Other studies that are evaluating riluzole’s effects in a variety of disorders as well as in the pediatric population are also currently under way.
Based on preclinical evidence that demonstrates that mGluR5 antagonists possess antidepressant and anxiolytic effects, a phase 2 clinical trial (NCT00809562) with a novel mGluR5 antagonist, RO4917523, examined safety and efficacy in a population of patients with treatment-resistant MDD. The trial was recently completed, but the results are not yet available. Similarly, a study (NCT01457677) evaluating the antidepressant properties of an mGluR2/3 antagonist, RO4995819, was recently initiated on the basis of strong evidence that suggests that this class of drugs has potent antidepressant effects in rodent models. A second drug, BCI-838, that acts as an mGluR2/3 antagonist is currently in phase 1 studies (NCT01548703).
Finally, there is growing interest in the effects of N-acetylcysteine (NAC) on glutamate neurotransmission and in NAC as treatment of a variety of neuropsychiatric disorders. In addition to its function as a glutathione precursor, NAC modulates glial glutamate release through its actions on the glutamate/cystine antiporter and can modulate extracellular levels in specific brain regions. Preliminary studies suggest that NAC may be an effective augmentation strategy for the treatment of bipolar depression, but follow-up studies are needed.30
There is rapidly escalating interest in drugs that target the glutamatergic neurotransmitter system, especially NMDA receptor modulators. The hope is that they will fill the large unmet need for rapid-acting antidepressant medications with efficacy in treatment-resistant patients.31 While early-phase clinical studies provide strong evidence that this novel class of drugs may advance our ability to treat mood disorders, the treatments remain in the realm of experimental therapeutics. Several important questions still need to be answered related to dosage, efficacy compared with a truly blinded placebo, and duration of effect of these drugs.
There are several known potential risks associated with ketamine administration, including physiological and psychological effects, substance abuse liability, cystitis, and hepatotoxicity, that should be seriously considered before initiating a trial of ketamine for the treatment of a mood disorder. At the present time, consideration of ketamine or similar drugs should be limited to patients with well-documented treatment-resistant depressive episodes.
Whenever possible, it is prudent to consider enrolling a patient in one of the multiple ongoing clinical trials that are available in many locations around the country. Scrutiny of the study protocols by institutional review boards before trial initiation helps ensure patient safety in these clinical trials. In addition, it is important to remember that patient participation in these well-controlled and well-documented clinical trials is required to ultimately provide answers to the many questions regarding the ultimate safety and efficacy of this novel class of medications.
Clinicaltrials.gov is a valuable resource to guide clinicians and patients to local clinical trials or studies allowing for longer-term inpatient stays, and should serve as a primary reference for clinicians considering these novel treatments for patients.
1. National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. http://www.nimh.nih.gov/trials/practical/stard/index.shtml. Accessed April 27, 2012.
2. National Institute of Mental Health. Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). http://www.nimh.nih.gov/trials/practical/step-bd/index.shtml. Accessed April 27, 2012.
3. Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J Neurochem. 1984;42:1-11.
4. Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011;13:22-37.
5. Crane GE. Cycloserine as an antidepressant agent. Am J Psychiatry. 1959;115:1025-1026.
6. Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185:1-10.
7. Paul IA, Skolnick P. Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci. 2003;1003:25-272.
8. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
9. 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;63:856-864.
10. 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;67:793-802.
11. Valentine GW, Mason GF, Gomez R, et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res. 2011;191:122-127.
12. 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;71:939-946.
13. 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;71:1605-1611.
14. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66:522-526.
15. Kranaster L, Kammerer-Ciernioch J, Hoyer C, Sartorius A. Clinically favourable effects of ketamine as an anaesthetic for electroconvulsive therapy: a retrospective study. Eur Arch Psychiatry Clin Neurosci. 2011;261:575-582.
16. Abdalla CG, Fasula M, Kelmendi B, et al. The rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. J ECT. In press.
17. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 2010;13:903-908.
18. Kerr C, Holahan T, Milch R. The use of ketamine in severe cases of refractory pain syndromes in the palliative care setting: a case series. J Palliat Med. 2011;14:1074-1077.
19. Phelps LE, Brutsche N, Moral JR, et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009;65:181-184.
20. Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. In press.
21. Ibrahim L, Diazgranados N, Frnaco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double blind, placebo-controlled study. Neuropsychopharmacology. 2012;37:1526-1533.
22. 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;67:139-145.
23. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults [published correction appears in Am J Emerg Med. 2009;27:512]. Am J Emerg Med. 2008;26:985-1028.
24. Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163:153-155.
25. Anand A, Gunn AD, Barkay G, et al. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord. 2012;14:64-70.
26. Lenze EJ, Skidmore ER, Begley AE, et al. Memantine for late-life depression and apathy after a disabling medical event: a 12-week, double-blind placebo-controlled pilot study. Int J Geriatr Psychiatry. 2011 Dec 16; [Epub ahead of print].
27. Preskorn SH, Baker B, Kolluri S, et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refratory major depressive disorder. J Clin Psychopharmacol. 2008;28:631-637.
28. Davis M, Ressler K, Rothbaum BO, Richardson R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol Psychiatry. 2006;60:369-375.
29. Pittenger C, Coric C, Banasr M, et al. Riluzole in the treatment of mood and anxiety disorders. CNS Drugs. 2008;22:761-786.
30. Berk M, Dean O, Cotton SM, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011;135:389-394.
31. Sanacora G, Zarate CA Jr, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7:426-437.