From May 20th through May 24th approximately 11,000 clinicians, scientists, and industry professionals attended the 2017 Annual Meeting for the American Psychiatric Association (APA) in San Diego, California. For many of the attendees, off-label treatments for treatment-resistant depression (TRD), specifically ketamine, were topics of great interest and excitement.

TRD is often defined by physicians as those patients with major depressive disorder (MDD) who have failed two or more lines of therapy. Even though the antidepressant market is replete with effective and generically available agents, per DRG estimates, approximately one-third of the MDD population suffer from TRD (i.e., approximately 14 million of G7 patients in 2015). Typically, physicians will try to treat TRD with a combination regimen (e.g., an adjunctive atypical antipsychotic on a background of a baseline antidepressant) or even nonpharmacological approaches like electroconvulsive therapy (ECT). However, these methods of treatment do not always fully address TRD patients’ symptoms. Additionally, rapidly effective treatments for those TRD patients who are suicidal is a great unmet need according to interviewed physicians and physicians attending the APA conference; the onset of action of commonly prescribed antidepressants, such as serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs), ranges from four to six weeks.

The unmet need for rapidly effective TRD agents has, in part, contributed to the field’s investigation of ketamine. Ketamine is an NMDA receptor antagonist that U.S. clinicians have used as an anesthetic since the 1970s.[1] In the past seventeen years, research into the effectiveness of subanesthetic doses of intravenous ketamine in patients with MDD, specifically patients with TRD, has demonstrated that ketamine can rapidly reduce depressive symptoms in the majority of patients within 40 minutes to 24 hours after treatment administration.[2],[3],[4],[5],[6] Aligning with ketamine’s effects on general depressive symptoms, suicidal symptoms in patients with mood and anxiety disorders are also attenuated at 40 minutes, with these effects lasting only three to seven days post-administration.[7] Despite ketamine’s rapid efficacy, it possesses transient, but potentially serious intolerability, including the development of elevated blood pressure, dissociative symptoms, and psychotomimetic effects within two to four hours of infusion, which has precluded its widespread acceptance as an antidepressant treatment.3,4

Clinicians at the 2017 Annual Meeting for the APA hypothesized that ketamine’s rapid effectiveness can be attributed to its induction of synaptogenesis through the drug’s antagonism of the presynaptic-NDMA receptors, resulting in the downstream production of brain-derived neurotrophic factor (BDNF), a protein that contributes to synaptic plasticity by stimulating axonal growth of serotonergic neurons, especially within the hippocampus. [8],[9],[10],[11] With neuronal atrophy in the hippocampus being prevalent in patients with recurrent MDD and shown to promote depressive symptoms, the initiation of synaptogenesis by BDNF likely contributes to the alleviation of these symptoms and thus the efficacy of ketamine.[12],[13] Presently, the long-term synaptogenic effects of BDNF as a result of ketamine treatment are unknown, but physicians at the APA believed that ketamine’s non-sustained efficacy suggests that synaptogenic changes do not persist over the long-term.

Regardless of ketamine’s intolerability and its MDD clinical studies’ small patient size (e.g., 4-234 patients), the drug’s demonstrated acute efficacy in severe depression and TRD has, in part, driven a proportion of psychiatrists to incorporate this off-label therapy into their TRD treatment algorithm.2,3,4,5,6 The 2017 Annual Meeting’s sessions on ketamine highlighted this practice, with Mayo Clinic psychiatrists outlining their guidelines for the management of their inpatient/outpatient ketamine infusion center. At Mayo Clinic, eligible TRD patients (e.g., no history of psychosis and substance abuse disorder, no use of lorazepam), receive ketamine infusions to address their suicidal ideation and/or depressive symptoms at the hospital’s designated ketamine infusion center. Because of ketamine’s short-lived efficacy, patients are cycled through at least a six-week-long five-step process (i.e., acute phase infusion, continued phase infusion, optimization phase, and maintenance phase), in an effort to find an effective and infrequent dosing schedule that will control patients’ depressive symptoms over the long term.[14] In recognition of the drawbacks of long-term administration of an IV treatment, psychiatrists prescribe intranasal, oral, and/or sublingual ketamine to eligible TRD patients, as a way to control and maintain symptom remission over the long term because these formulations can be administered at home by the patient.[15] Anecdotal discussions at these conference sessions further confirmed that some psychiatrists across the United States are using oral, intranasal, and/or intravenous ketamine to attenuate select TRD patients’ symptoms. Notably, the presence of commercial ketamine clinics for depression maintenance treatment across the United States is indicative of the field’s continued support of ketamine’s use as an off-label therapy for TRD. The presence of commercial ketamine clinics across the United States will likely proliferate as a growing subset of psychiatrists incorporate ketamine into their treatment algorithm and as additional clinical data demonstrating the efficacy of repeated infusions of ketamine becomes available.

Given the field’s progress in use of ketamine as an off-label treatment for TRD, we expect that physicians will welcome emerging agents with similar mechanisms of action (i.e., NMDA receptor modulation)—in particular, esketamine (Janssen) and rapastinel (Allergan), both in Phase III trials—into their TRD treatment paradigm once these therapies enter the U.S. market. Indeed, Phase II data suggest that intravenous rapastinel reduces depressive symptoms within an hour of treatment, without the psychoactive side effects associated with ketamine, while esketamine (the S-entantiomer of ketamine) reduces depressive symptoms within four hours of administration.[16],[17] Thus, because of these emerging therapies’ relatively comparable time to onset of therapeutic effect to ketamine, psychiatrists would likely perceive esketamine and/or rapastinel to be viable treatment alternatives to ketamine, for multiple reasons. First, those psychiatrists who already prescribe ketamine will likely be comfortable managing the side effects associated with NMDA receptor modulators, such as transient dissociation—as mentioned, a known side effect of ketamine and also a side effect observed in esketamine’s Phase II trial.17 Second, despite oral therapies dominating the MDD treatment landscape, those psychiatrists who prescribe ketamine in its varied formulations have presumably familiarized them with prescribing and managing patients on intravenous and intranasal agents. Third, the development of commercial ketamine infusion clinics and in-hospital ketamine infusion clinics will provide the necessary infrastructure for the administration of intravenous rapastinel, likely facilitating and encouraging the integration of intravenous rapastinel into psychiatrists’ treatment paradigm. Fourth, despite ketamine’s use as a TRD treatment, its lack of formal regulatory approval for the treatment of MDD or TRD often precludes it from being reimbursed, limiting its use to patients who can afford the out-of-pocket costs. Thus, if esketamine and/or rapastinel obtain labelling for MDD and/or TRD from the FDA, the agents will likely be more favorably reimbursed than ketamine, incentivizing psychiatrists to switch their TRD patients from ketamine to esketamine or rapastinel for cost-saving purposes. Furthermore, psychiatrists who have been reluctant to prescribe ketamine because it is an off-label therapy, may be more willing to incorporate esketamine and/or rapastinel into their treatment algorithm for MDD and/or TRD because of the FDA’s potential approval of these agents for the treatment of MDD and/or TRD.

Because of the pressing unmet need for rapid and effective therapies for the TRD population and physicians’ ingenuity in utilizing subanesthetic doses of ketamine as an off-label TRD treatment, the MDD market is increasingly poised to incorporate fast-acting emerging therapies—once they are available. In the meantime, a subset of psychiatrists will likely continue to prescribe ketamine to their TRD patients. This use of ketamine will likely be further augmented once clinical research can determine how to efficiently maintain the drug’s therapeutic effect over the long term.

[1] Food & Drug Administration. Ketalar original approvals or tentative approvals. Accessed June 22, 2017.

[2] Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.

[3] Zarate CA, 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.

[4] Murrough JW, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. AM J Psychiatry. 2012;170:1134-1142.

[5] Kishimoto T, 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;46:1459-1472.

[6] Feifel D, et al. Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. J Affect Disord. 2017;221:283-288.

[7] Murrough JW, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015;45:3571-3580.

[8] Duman RS, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62:35-41.

[9] Duman RS, Nanxin L. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012;367:2475-2484.

[10] Bun-Lee H, Young-Ku K. The major roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig. 2010;7:231-235.

[11] Popova NK, et al. Neurotrophic factors (BDNF and GDNF) and the serotonergic system of the brain. Biochemistry (Moscow). 2017;82:308-317.

[12] Sheline YI, et al. Hippocampal atrophy in recurrent major depression. Proc. Natl. Acad Sci USA. 1993;93:3908-3913.

[13] Alves ND, et al. Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression. Transl Psychiatry. 2017;7:e1058.

[14] Developing a ketamine infusion therapy service for patients with treatment-resistant depression: lessons learned from the Mayo Clinic. 2017 Annual Meeting for the American Psychiatric Association. May 23, 2017; San Diego, CA.

[15] Ketamine for treatment-resistant chronic pain and depression. 2017 Annual Meeting for the American Psychiatric Association. May 23, 2017; San Diego, CA.

[16] Allergan, company presentation, August 11, 2015

[17] Janssen, press release, August 16, 2016

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