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SPRAVATO® (esketamine)

Medical Information

Effect of SPRAVATO on Cognition

Last Updated: 09/24/2025

SUMMARY

  • Results of a phase 1, double-blind (DB), placebo-controlled (PBO-controlled), crossover study in healthy volunteers showed that a single SPRAVATO 84 mg dose produced a transient decline in cognitive function (attention, visual and working memory, reaction time, and executive functioning) at 40 minutes post-dose, which resolved by 2 hours post-dose.1 See PHASE 1 STUDY.
  • Across the short-term, phase 3 studies2-4 of SPRAVATO in adult patients with treatment-resistant depression (TRD), cognition generally remained stable.5
  • Consistently, in long-term studies5-8, performance on each of the cognitive tests relative to baseline showed slight improvement or remained stable in each treatment phase in all age groups. In the elderly subgroup (≥65 years of age) of SUSTAIN-2 and SUSTAIN-3, small increases of simple and choice reaction time occurred during the optimization/maintenance phase.8
  • A case series of 8 patients with TRD treated with SPRAVATO over 6 months reported improvements in attention, memory, and executive functions, with some cognitive gains correlating with reduced depression severity.9
  • A case series of 8 patients with TRD treated with SPRAVATO reported improvement in cognitive symptoms over 12 weeks of treatment.10

BACKGROUND

Cogstate

The Cogstate tests are validated computerized cognitive assessment tests that measure specific areas of cognition and are grouped together to form customized batteries based on the unique requirements of a given study design and population.1,5,11 Patients are encouraged to work through the tests as quickly and accurately as they can. The tests included in the esketamine trials assessed psychomotor function, attention, visual learning, working memory, and executive function:

  • Detection Test – measures processing speed using a simple reaction time paradigm.
  • Identification Test – assesses attention using a choice reaction time paradigm.
  • One Card Learning Test – evaluates visual memory using a pattern separation paradigm.
  • One Back Test – measures working memory using an n-back paradigm.
  • Groton Maze Learning – assesses executive function using a maze learning paradigm.

Hopkins Verbal Learning Test Revised (HVLT-R)

The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. Administration includes 3 learning trials, a delayed recall (20-minute) trial, and a 24-word recognition list (including 12 target and 12 foil words). The test administrator reads instructions and word lists aloud, and records words recalled/recognized by the subject. Scores include learning, delayed recall, and recognition. The HVLT-R is a well-validated and widely used measure of verbal episodic memory.12

Clinical Data


Clinical Studies in Treatment-Resistant Depression
PHASE 3 STUDIES
Short-Term Clinical Trials
Trial Design
Effect on Cognition
TRANSFORM-1 (3001)2, TRANSFORM-2 (3002)4, and TRANSFORM-3 (3005)3 were 4-week, randomized, DB, active-controlled, multinational studies comparing the efficacy and safety of fixed (3001) or flexibly (3002; 3005) dosed SPRAVATO nasal spray plus a newly initiated oral AD (SPRAVATO+Oral AD) vs. a newly initiated oral AD plus PBO nasal spray (Oral AD+PBO) in adult patients (18-64 years; 3001/3002) and ≥65 years (3005) with TRD.5  
 
Study Treatment
Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. 
 
A new open-label (OL) oral AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily for the duration of the DB phase following a fixed titration schedule. 
 
Study Groups
TRANSFORM-1 (3001)
  • 56 mg SPRAVATO+Oral AD (n=115) 
  • 84 mg SPRAVATO+Oral AD (n=114); SPRAVATO was started on day 1 at 56 mg 
  • Oral AD+PBO (n=113) 

TRANSFORM-2 (3002) 
  • 56 or 84 mg SPRAVATO+Oral AD (n=114); SPRAVATO was started on day 1 at 56 mg for all 
  • Oral AD+PBO (n=109) 

TRANSFORM-3 (3005)
  • 28, 56, or 84 mg SPRAVATO+Oral AD (n=72); SPRAVATO was started on day 1 at 28 mg 
  • Oral AD+PBO (n=65) 
Cognitive Evaluation
Cogstate and HVLT-R were performed predose at baseline, at the end of the double-blind treatment period (day 28), at the last observation carried forward (LOCF) endpoint, at Week 2 of the follow-up phase, and at the early withdrawal visit.
 
Effect on Cognition
TRANSFORM-1 (3001) and TRANSFORM-2 (3002):
  • Performance on all cognitive tests for the SPRAVATO+Oral AD arm showed improvement from baseline or remained at levels similar to baseline at day 28 of the DB phase and at study endpoint. All but verbal memory (HVLT-R Total Recall) and delayed recall (HVLT-R_D) improved for patients in the Oral AD+PBO arm.
  • Between-group differences observed at day 28 were small but statistically significant in favor of SPRAVATO+Oral AD for attention (IDN; Cohen’s d = 0.224, 95% CI: 0.051-0.398), verbal memory (HVLT-R Total Recall; d = 0.222, 95% CI: 0.043-0.401), and delayed recall (HVLT-R_D; d = 0.245, 95% CI: 0.056-0.434).
  • At study endpoint, statistically significant between-group differences continued to favor SPRAVATO + Oral AD for attention (IDN; d = 0.186, 95% CI: 0.015-0.357), verbal memory (HVLT-R Total Recall; d = 0.198, 95% CI: 0.026-0.370), and delayed recall (HVLT-R_D; d = 0.190, 95% CI: 0.003-0.377).
  • Correlations between MADRS total scores and cognitive results at day 28 and study endpoint were small.5

TRANSFORM-3 (3005):  There were no significant between-group differences in any of the cognitive measures at day 28 of the DB phase or at study endpoint.5
Long-Term Clinical Trials
Trial Design
Effect on Cognition
SUSTAIN-1 (3003)6 was a long-term, DB, active-controlled, multicenter, randomized-withdrawal study to assess the efficacy of flexibly-dosed SPRAVATO plus an oral AD compared with an oral AD plus PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and remitters after an initial 16 weeks of treatment with SPRAVATO+Oral AD.5   
 
Study Treatment 
During the induction phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the optimization (12 weeks) and maintenance (variable duration) phases, nasal spray medication was administered weekly for the first 4 weeks, then individualized to once weekly or once every other week based on severity of depression symptoms. 
 
A new oral OL AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily for the duration of the DB phase following a fixed titration schedule during the induction phase and remaining unchanged during the maintenance phase. 
 
Study Groups 
56 or 84 mg SPRAVATO+Oral AD (n=152); SPRAVATO was started on day 1 at 56 mg 
Oral AD+PBO (n=145) 
Cognitive Evaluation
Cogstate and HVLT-R were performed predose at baseline, day 28, at 12-week intervals from week 32 of the maintenance phase through the study endpoint or last study visit in the event of early withdrawal.5
 
Effect on Cognition
Cognitive performance in the SPRAVATO + Oral AD group improved or remained stable across all phases. At the end of the maintenance phase, statistically significant between-group differences were observed for the following, in favor of SPRAVATO + Oral AD:
  • Attention (IDN): d = 0.300; 95% CI: 0.002-0.598
  • Visual learning (OCL): d = 0.288; 95% CI: 0.027-0.550
  • Working memory (ONB): d = 0.367; 95% CI: 0.118-0.615
  • Verbal memory (HVLT-R Total Recall): d = 0.274; 95% CI: 0.040-0.508
  • Delayed recall (HVLT-R_D): d = 0.459; 95% CI: 0.229-0.688

Cognitive measures generally improved from baseline at week 32, 44, and 56 for both treatment groups. At week 56, performance in the SPRAVATO + Oral AD group was slightly lower for visual learning (OCL), but the difference was not statistically significant.
SUSTAIN-2 (3004)7 was an OL, multicenter study to evaluate the long-term (up to 1 year of exposure) safety and efficacy of flexibly-dosed SPRAVATO nasal spray (28, 56, or 84 mg) plus a newly initiated oral AD in patients with TRD. 
 
Study Treatment 
During the induction phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the optimization and maintenance phases (48 weeks), nasal spray medication was reduced to once weekly for the first 4 weeks, and then individualized to once weekly or once every other week based on severity of depression symptoms. 
 
A new oral OL AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily following a fixed titration schedule during the induction phase and remained unchanged during the maintenance phase. 
 
Study Groups 
28, 56, or 84 mg SPRAVATO+Oral AD (n=802); SPRAVATO was started on day 1 at 28 mg for patients ≥65 years and at 56 mg for patients <65 years. Adjustments for subsequent doses (<65 years: 56 or 84 mg; ≥65 years: 28, 56, or 84 mg) were allowed based on efficacy and tolerability per the investigator’s judgement. 
Cognitive Evaluation
Cogstate and HVLT-R were performed predose baseline and at specified pre-dose timepoints (day 28 and weeks 20, 32, 44, and endpoint).
 
Effect on Cognition
Mean performance on all tests (Cogstate and HVLT-R), including measures of simple and choice RT, visual and verbal learning and memory, working memory, and executive function, either improved from baseline or remained stable through week 44 in all patients.
Performance on all cognitive tests either remained stable or slightly improved from baseline in patients <65 years. In those ≥65 years, mean performance on visual and verbal learning and memory, working memory, and executive function improved or remained stable, while mean performance on simple and choice RT (DET and IDN on Cogstate) slowed down from baseline, starting at week 20 (n=72) and continuing through week 44 (n=28).
  • DET, mean change from baseline to week 44: -0.1032
  • IDN, mean change from baseline to week 44: -0.0587
SUSTAIN-3 (3008)8 was an OLE study to evaluate the long-term safety and efficacy of individualized, intermittently-dosed SPRAVATO+Oral AD in patients with TRD.
Study Treatment
During the induction phase (initial 4 weeks), patients self-administered a flexible-dose of SPRAVATO twice-weekly. In the optimization/maintenance phase (variable duration), patients were administered SPRAVATO weekly, every other week, or every 4 weeks based on the assessment of Clinical Global Impression-Severity Scale (CGI-S) rating and tolerability.
Study Groups
Starting dose of 28 (patients aged ≥65 years), 56, or 84 mg SPRAVATO (N=1148): induction phase, n=458; optimization/maintenance phase, n=1110 (690 directly enrolled; 420 continued from the induction phase)
Cognitive Evaluation
Cogstate and HVLT-R were performed.
Effect on Cognition
Mean performance on all tests (Cogstate and HVLT-R), including attention (simple and choice RT), visual and verbal learning and memory, and executive function, remained stable for the total population and for patients aged <65 years, without changes over time.
In patients aged ≥65 years, performance on the tests of higher cognitive function remained stable or slightly improved; small increase in simple and choice RT occurred during the optimization/maintenance phase.
PHASE 1 STUDY
Morrison et al (2018)1 conducted a DB, randomized, PBO-controlled, two-period crossover study in healthy men and women to evaluate the effect of SPRAVATO on cognitive functioning in healthy participants.
 
Study Design/Methods
  • The study consisted of 3 phases. A screening phase for up to 3 weeks, a DB phase lasting 2 weeks, and a follow-up phase for 1 week.
  • Subjects were excluded if they had: systolic BP <90 or >140 mmHg and diastolic BP >90 mmHg, clinically significant abnormalities in ECG, significant medical conditions (including primary sleep disorder), abnormal laboratory values or abnormal physical/nasal examination, current or prior diagnosis of psychosis/psychotic disorder, or performance >1 standard deviation below the mean on any of the five tests of Cogstate® during a training session.
  • The Cogstateconsisted of a 5-test battery (detection, identification, one-card learning, one card memory, and Groton maze learning).

Study Group
Subjects received SPRAVATO 84 mg followed by nasal PBO spray in sequence 1 (n=12) and nasal PBO followed by SPRAVATO 84 mg in sequence 2 (n=12) in a two-way crossover design.  
Cognitive Function Results
  • Primary Endpoint - Cognitive performance for all 5 Cogstate® tests declined to a greater extent with SPRAVATO 84 mg vs PBO on each test 40 minute post-dose (Detection: P=0.0011; Identification: P=0.0006; One-Card Learning: P=0.0040; One Back: P=0.0017; Groton Maze Learning Test: P<0.0001) and was comparable to PBO at 2, 4, and 6 hours post-dose.
  • Secondary Endpoints - Greater effort was required to complete the cognitive test battery versus PBO at 40 minutes post-dose (mean [SE] Mental Effort Scale: 2.74 [0.35] for PBO vs 7.01 [0.358, P <0.0001] for SPRAVATO. The cognitive test results returned to normal levels vs PBO at 2, 4, and 6 hours post-dose.
  • Increased sleepiness was observed after SPRAVATO administration compared to PBO. Significant differences in KSS was observed at 40 minutes and 2 hours post-dose.
    • KSS mean [SE] after 40 minutes: 3.85 [0.344] for PBO and 6.32 [0.344] for SPRAVATO; P <0.0001)
    • KSS mean [SE] after 2 hours: 3.53 [0.270] for PBO and 5.46 [0.283] for SPRAVATO; P <0.0001).  
    • Levels were comparable to PBO by 4 hours post-dose.

Safety Results
  • Most common TEAEs after SPRAVATO (n=24) administration included dizziness (67%), nausea (38%), disturbance in attention (29%), fatigue (29%), and somnolence (25%), and feeling abnormal (25%). The majority of the TEAEs were mild in severity and resolved at the end of the study.
Abbreviations: AD, antidepressant; BP, blood pressure; Cogstate, computerized cognitive test battery; DB, double-blind; DET, detection; GML, Groton Maze Learning HVLT-R, Hopkins Verbal Learning Test Revised; IDN, identification; KSS, Karolinska Sleepiness Scale; MA, maintenance; OCL, one-card learning; OL, open-label; OLE, open-label extension; ONB, one-back memory; PBO, placebo nasal spray; RCI, reliable change index; RT, reaction time; SD, standard deviation; TEAE, treatment-emergent adverse event; TRD, treatment-resistant depression. 

CASE SERIES

Sobreiro et al (2025)9 investigated the long-term cognitive effects of SPRAVATO in 8 adult patients with treatment-resistant depression (TRD) over a 6-month period. During induction, SPRAVATO was administered twice a week for 4 weeks, with an initial dose of 28 mg or 56 mg. Dose adjustments to 56 mg or 84 mg were made based on clinical judgment. This was followed by weekly dosing for one month (maintenance phase) and then either weekly or biweekly administration depending on remission status.

Cognitive performance was assessed using a comprehensive neuropsychological battery of tests over a 6-month period, including assessments of attention, memory and working memory, processing speed, visual-motor coordination, visual-spatial and organizational processing abilities, verbal, intellectual, and problem-solving abilities, and executive function. Fourteen of the 21 tests did not show significant changes over time, while 7 tests were significantly improved. These included the Trail Making Test-A (TMT-A) for attention, Rey Auditory Verbal Learning Test (RAVLT; Correct and Immediate) for memory, Logical Memory II for episodic memory, Digit Span Backward for working memory, Stroop Color for inhibition control, and the Wisconsin Card Sorting Test (WCST) – Total Correct for cognitive flexibility.

A significant reduction in depression severity was observed over 6 months of adjunct SPRAVATO treatment. Improvements from baseline to six months in attention, delayed episodic memory, working memory, cognitive flexibility, and inhibitory control were significantly correlated with reductions in depression severity. In contrast, improvements in abstract thinking, set-shifting, and immediate memory were not associated with changes in mood.

Pepe et al (2023)10 described changes in cognition after 12 weeks of treatment with SPRAVATO in 8 patients with TRD (female, n=3; male, n=5; mean age, 52.9 years). Patients received SPRAVATO 56 mg twice-weekly for the first month followed by 84 mg once-weekly over the next 8 weeks. All patients received concomitant medications, including atypical antipsychotics, benzodiazepines, antidepressants, and mood stabilizers.

A reduction in cognitive symptoms was reported in all patients during treatment, as assessed by the Digit Symbol Substitution Test (DSST), the Trail Making Test-B (TMT-B), and the Perceived Deficits Questionnaire for Depression 5-item test (PDQ-D5). Symptoms of mild dissociation, nausea, and small increases in blood pressure were reported in all patients during the 2 hours after SPRAVATO administration and resolved over the course of the observation period. No clinically relevant side effects were reported throughout the treatment period.

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, and DERWENT® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 August 2025.

 

References

Show
1 Morrison RL, Fedgchin M, Singh J, et al. Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology. 2018;235(4):1107-1119.  
2 Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630.  
3 Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-141.  
4 Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.  
5 Morrison RL, Singh J, Daly E, et al. Effect of esketamine nasal spray on cognition in patients with treatment-resistant depression: results from four phase 3 studies. Int J Neuropsychopharmacol. 2024;27(11):pyae046.  
6 Daly EJ, Trivedi MH, Janik A, et al. Supplement to: Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.  
7 Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891.  
8 Zaki N, Chen LN, Lane R, et al. Long-term safety and maintenance of response with esketamine nasal spray in treatment-resistant depression: final results of the SUSTAIN-3 study. Poster presented at: the Psych Congress; September 6-10, 2023; Nashville, TN.  
9 Sobreiro MFM, Silveira PSP, Cavenaghi VB, et al. Long-term cognitive outcomes of esketamine nasal spray in treatment-resistant depression: a preliminary report. Pharmaceuticals (Basel). 2025;18(2):173.  
10 Pepe M, Bartolucci G, Marcelli I, et al. Reduction in cognitive symptoms following intranasal esketamine administration in patients with chronic treatment-resistant depression: a 12-week case series. J Psychiatr Pract. 2023;29(4):325-332.  
11 Cogstate Computerized Cognitive Assessment. Accessed August 20, 2025. https://www.cogstate.com/clinical-trials/computerized-cognitive-assessment/
12 Benedict RHB, Schretlen D, Groninger L, et al. Hopkins Verbal Learning Test – Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol. 1998;12(1):43-55.