OPEN Foundation

G. Sanacora

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)


Objective: To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation.
Methods: This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate.
Results: Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence.
Conclusions: These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent.
Fu, D. J., Ionescu, D. F., Li, X., Lane, R., Lim, P., Sanacora, G., … & Canuso, C. M. (2020). Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). The Journal of clinical psychiatry81(3), 0-0.,
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Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression


This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., … & Stahl, S. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. American Journal of Psychiatry, appi-ajp.,
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Ketamine: A Paradigm Shift for Depression Research and Treatment


Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.
Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron101(5), 774-778., 10.1016/j.neuron.2019.02.005
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Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic


Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.
Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.
Krystal, J. H., Abdallah, C. G., Averill, L. A., Kelmendi, B., Harpaz-Rotem, I., Sanacora, G., … & Duman, R. S. (2017). Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Current Psychiatry Reports19(10), 74. 10.1007/s11920-017-0829-z
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Ketamine as a Treatment for Adolescent Major Depressive Disorder


Nearly 1 in 4 adolescents will experience major depressive disorder (MDD). Suicide is the 3rd leading cause of death in this age group. 40% of adolescents with MDD fail to respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs). Of that SSRI-resistant population, nearly half remain depressed despite alternate medication and psychotherapy. Thus, better treatments for adolescent depression are urgently needed. Subanesthetic doses of ketamine, an NMDA antagonist, produce rapid antidepressant and anti-suicidal effects in depressed adults. There are few case reports and no prospective controlled trials of ketamine for the treatment of adolescent MDD.

Dwyer, J., Sanacora, G., & Bloch, M. (2017). 1002-Ketamine as a Treatment for Adolescent Major Depressive Disorder. Biological Psychiatry, 81(10), S405. 10.1016/j.biopsych.2017.02.729
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Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression


Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine’s antidepressant effects.
Patients who were pursuing ketamine infusion therapy for treatment-resistant depression were invited to participate in the study. If enrolled, the subjects initiated a 12-session, 10-week course of CBT concurrently with a short 4-treatment, 2-week course of intravenous ketamine (0.5 mg/kg infused over 40 min) provided under a standardized clinical protocol.
Sixteen participants initiated the protocol, with 8 (50%) attaining a response to the ketamine and 7 (43.8%) achieving remission during the first 2 weeks of protocol. Among ketamine responders, the relapse rate at the end of the CBT course (8 weeks following the last ketamine exposure) was 25% (2/8). On longer-term follow-up, 5 of 8 subjects eventually relapsed, the median time to relapse being 12 weeks following ketamine exposure. Among ketamine remitters, 3 of 7 retained remission until at least 4 weeks following the last ketamine exposure, with 2 retaining remission through 8 weeks following ketamine exposure. Ketamine nonresponders did not appear to benefit from CBT.
CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine’s antidepressant effects.
Wilkinson, S. T., Wright, D., Fasula, M. K., Fenton, L., Griepp, M., Ostroff, R. B., & Sanacora, G. (2017). Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression. Psychotherapy and Psychosomatics86(3), 162-167. 10.1159/000457960
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A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders


Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Sanacora, G., Frye, M. A., McDonald, W., Mathew, S. J., Turner, M. S., Schatzberg, A. F., … & Nemeroff, C. B. (2017). A consensus statement on the use of ketamine in the treatment of mood disorders. Jama psychiatry74(4), 399-405. 10.1001/jamapsychiatry.2017.0080
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Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion


New and encouraging findings regarding the use of ketamine for depression in the context of psychotic symptoms have been published by Pennybaker et al. (1). In their analysis, patients with bipolar disorder without a history of psychosis had a more robust response to ketamine, and patients with a history of psychosis had a significant response compared with placebo as well. Concerning dissociative symptoms, even though patients with a history of psychosis endorsed more symptoms, these were not maintained after a 40-minute period, and no full psychosis was induced in their sample.

da Frota Ribeiro, C. M., Sanacora, G., & Ostroff, R. (2017). Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion. Biological Psychiatry. 10.1016/j.biopsych.2017.01.012
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Ketamine’s Mechanisms of Rapid Antidepressant Activity: Evidence from Preclinical Studies


Enthusiasm over the growing series of reports describing ketamine’s rapid onset of robust antidepressant activity in clinical trials has ignited a large number of back-translational efforts attempting to employ rodent models to better characterize the antidepressant properties of the drug and to improve our understanding of its underlying mechanisms of antidepressant action. On balance, these preclinical studies have yielded fairly consistent findings demonstrating that ketamine has a broad range of behavioral effects consistent with antidepressant activity in a variety of rodent models. Many of these studies further suggest that ketamine’s effects are unique from other classic antidepressant drugs in producing more durable effects in some models and more rapidly reversing the behavioral effects of chronic stressor exposure in other models. The preclinical studies are also beginning to elucidate the drug’s mechanisms of antidepressant activity, with the majority of recent studies suggesting that increased levels of regional alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor activation and brain-derived neurotrophic factor (BDNF) expression, as well as enhanced synaptic plasticity, are critical components of the response. However, there remain several points of disagreement and inconsistency in the preclinical literature that require additional investigation, including the effectiveness of other NMDA receptor-targeting drugs and the specific targets of ketamine’s proximal effects. This chapter provides an overview and critical review of this preclinical literature. It is anticipated that a more complete understanding of ketamine’s mechanisms of antidepressant action will allow for a safer and more efficient use of ketamine in the clinical setting and afford us new opportunities for novel drug development.

Hermes, G., & Sanacora, G. (2016). Ketamine’s Mechanisms of Rapid Antidepressant Activity: Evidence from Preclinical Studies. In Ketamine for Treatment-Resistant Depression (pp. 73-98). Springer International Publishing. 10.1007/978-3-319-42925-0_6

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The use of ketamine for the treatment of depression in the context of psychotic symptoms


Mounting evidence from a series of small clinical trials and case series suggests ketamine can have rapid and robust antidepressant(1), and possibly anti-suicidal effects(2) in patients who had not responded to standard treatment options. However, due to ketamine’s variable psychotomimetic effects in healthy volunteers and exacerbation of previously experienced positive symptoms in schizophrenic volunteers(3,4), patients previously experiencing psychotic features have been excluded from the reported studies and trials.

da Frota Ribeiro, C. M., Sanacora, G., Hoffman, R., & Ostroff, R. (2015). The use of ketamine for the treatment of depression in the context of psychotic symptoms. Biological Psychiatry.
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