SUMMARY  

• There are no systematically collected data to specifically address the appropriate equivalent dosing regimen between intravenous (IV) ketamine and intranasal (IN) esketamine (ESK) (the Senantiomer of racemic ketamine) or vice versa for treatment-resistant depression (TRD) or for the treatment of depressive symptoms with acute suicidal ideation or behavior (MDSI).
• A retrospective case series (n=10) found that most patients with TRD who switched from IV ketamine to SPRAVATO either maintained or showed clinical improvement in depressive symptoms. No serious adverse reactions were observed.¹

product labeling

• SPRAVATO nasal spray is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, respiratory depression, and abuse and misuse.²
  • For additional information or questions about the REMS, call 1-855-382-6022 or visit www.SPRAVATOrems.com.

BACKGROUND

SPRAVATO

• The efficacy and safety of SPRAVATO is supported by 3 short-term studies and 3 long-term studies evaluating maintenance of effect and safety up to 4.5 years, respectively. The 6 trials evaluated the following SPRAVATO doses: 28 mg (elderly only), 56 mg, and 84 mg.^3-8
• In clinical trials, TRD was defined as a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of major depressive disorder (MDD) in patients who have not responded adequately to at least 2 different antidepressants of adequate dose and duration in the current depressive episode.^3-7
• The efficacy and safety of SPRAVATO 84 mg for MDSI is supported by 2 identically designed phase 3 studies.^9,10

KETAMINE

• Ketamine  is not approved by regulatory authorities for depression-related conditions in any formulation, such as intravenous (IV), intramuscular (IM), subcutaneous (SC), or compounded intranasal (IN), oral, or sublingual (SL).¹¹
• The IV ketamine dose most often used in the completed studies in patients with TRD is 0.5 mg/kg administered over a 40-minute infusion.^12-15

CLINICAL DATA

KETAMINE (IV) to SPRAVATO (IN) SWITCH

Banov et al (2021)¹ in a retrospective case series assessed the antidepressant effects of SPRAVATO in maintaining effectiveness and tolerability of patients with TRD who showed clinical improvement with IV ketamine.

• Six females and 4 males (mean age, 41 years) were all patients of a private psychiatric clinic with current depressive episodes lasting between 5 and 20 years. Most had psychiatric comorbidities and were receiving concomitant medications, including central nervous system (CNS) stimulants, antipsychotics, selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, anticonvulsants, mood stabilizers, benzodiazepines, and norepinephrine/dopamine reuptake inhibitors.
• Patients were initiated on IV ketamine 0.5 mg/kg with an option to titrate up to 1 mg/kg based on response and tolerability. Upon transition to SPRAVATO, 9 patients received an initial dose of 56 mg while 1 patient received an initial dose of 28 mg; all were titrated to 84 mg. Seven patients completed 6 initial infusions of ketamine over 14-21 days and 5 patients continued at least 1 maintenance infusion before switching to SPRAVATO.
• The antidepressant effect was either maintained or improved in 9 patients who transitioned to SPRAVATO. One had worsening of depression due to an acute psychosocial stressor but still improved from baseline ketamine treatment.
• Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total scores were 32 before ketamine administration, 25.6 at SPRAVATO administration (before dose), and 20.2 at the final observation.
• Mean Patient Health Questionnaire (PHQ-9) scores were 21.6 prior to ketamine administration, 15.4 at SPRAVATO administration (before dose), and 14.6 at final observation. Clinical Global Impression-Improvement (CGI-I) scores were maintained or improved.
• The number of SPRAVATO administrations varied among the 10 patients from 6 to 37 and varied in treatment duration from 2.1 weeks to 55 weeks.
• Four patients had persistent suicidal ideation that resolved during ketamine treatment and did not return when transitioned to SPRAVATO. For one patient, their thoughts of suicide were greatly reduced in frequency and intensity but did not fully resolve.
• All patients developed dissociation with both ketamine and SPRAVATO, but it was tolerable with no discontinuations. The authors noted that ketamine was titrated to induce a level of dissociation based on reports that it may be associated with treatment response. All other adverse events resolved by the end of the ketamine infusions except in 1 patient who had ongoing anxiety that resolved with SPRAVATO treatment, and another patient who had anxiety and hypertension that resolved while on SPRAVATO treatment. One patient developed new onset nausea with SPRAVATO that resolved over the course of treatment.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENTDrug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 19 June 2024.

A small retrospective case series (n=15) examined a group of patients with TRD and comorbid PTSD who did not respond adequately to SPRAVATO and had an improved response after a switch to IV ketamine. Eight of the fifteen patients had previous exposure to IV or IM ketamine, which may have affected results. Patients were administered at least 3 doses of SPRAVATO 84 mg before they switched to IV ketamine 0.5 mg/kg and then titrated up to 1 mg/kg accordingly based on their response.¹⁶