Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study

Correia-Melo, Fernanda S.; Leal, Gustavo; Vieira, Flávia; Jesus-Nunes, Ana Paula; Mello, Rodrigo P.; Magnavita, Guilherme; Caliman-Fontes, Ana Teresa; Echegaray, Mariana V.F.; Bandeira, Igor D.; Silva, Samantha S.; Cavalcanti, Diogo Esmeraldo; Araújo-de-Freitas, Lucas; Sarin, Luciana Maria; Tuena, Marco Aurélio; Nakahira, Carolina; Sampaio, Aline Santos; Del-Porto, José Alberto; Turecki, Gustavo; Loo, Colleen; Lacerda, Acioly L.T.; Quarantini, Lucas C.

doi:10.1016/j.jad.2019.11.086

Cited by 117 publications

(67 citation statements)

References 45 publications

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“…Racemic ketamine is being used off-label in the community and evidence to date suggests noninferiority to IV esketamine. 8 For these reasons, CANMAT organized a task force to review the evidence and provide updated recommendations for the clinical use of ketamine as a pharmacological treatment in adults with MDD. We limited the scope of the task force review to racemic ketamine because intranasal esketamine (Spravato®) has been approved by Health Canada, the United States Food and Drug Administration (FDA), and the European Medicines Agency for patients with TRD, and other reviews are available for its use.…”

Section: Introductionmentioning

confidence: 99%

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L’humeur Et De L’anxiété (Canmat) Concernant L’utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur

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Objective: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice. Methods: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question–answer format. Results: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response. Conclusions: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.

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Section: Introductionmentioning

confidence: 99%

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L’humeur Et De L’anxiété (Canmat) Concernant L’utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur

et al. 2020

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“…Our results are based on the effects of ketamine that is a racemic mixture containing equal amounts of the enantiomers esketamine and arketamine. A dose of 0.25 mg/kg esketamine had a similar short-term antidepressant effects and a similar safety profile to 0.5 mg/kg ketamine, suggesting that esketamine is the active enantiomer (Correia-Melo et al, 2020). However, there is preliminary evidence that arketamine might provide a more prolonged antidepressant response than esketamine with less side effects, particularly with no dissociative and hemodynamic effects.…”

Section: Discussionmentioning

confidence: 84%

Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study

et al. 2020

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Conventional antidepressants have several important limitations, including a lack of direct effects on negative self-schema, which is at the core of Beck's cognitive theory of depression. Based on previous studies showing a positive effect of ketamine on negative cognition, we compared reductions in negative self-schema between responders and non-responders to a single infusion of ketamine. In an open-label study, 26 participants with treatment-resistant depression received 0.5 mg/kg ketamine via infusion. Depression symptoms were assessed at baseline, 24 h, and 7 days after treatment with Montgomery-Åsberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI-II). Nine of the 26 participants fulfilled response criteria after 24 h. Of these, eight still fulfilled response criteria after 7 days. Response was defined as a reduction in MADRS total score of 50% or more. Responders improved significantly more than non-responders both 24 h and 7 days after ketamine treatment on the following BDI-II items: item 1 ("Sadness"), item 7 ("Self-Dislike"), and item 8 ("Self-Criticalness"). These results suggest an important therapeutic effect of ketamine on negative self-schema, which is a fundamental cognitive aspect of depression. This effect is unique and might be associated with ketamine's profound effects on neuroplasticity. Small sample size and lack of a placebo control group are the major limitations of this study.

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“…Moreover our findings are consistent with recent studies that examined different esketamine delivery routes, such as i.v. (Correia-Melo et al, 2020;Singh et al, 2016) and i.n. (Canuso et al, 2018;Daly et al, 2018Daly et al, , 2019Popova et al, 2019) administration.…”

Section: Discussionmentioning

confidence: 99%

“…Esketamine administered via the i.v. route was also investigated in two studies (Correia-Melo et al, 2020; Singh et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression

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Introduction and objectives: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. Methods: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient’s response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. Results: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30–45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. Conclusions: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.

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Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study

Cited by 117 publications

References 45 publications

Sustained Improvement of Negative Self-Schema After a Single Ketamine Infusion: An Open-Label Study

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression

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