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SPRAVATO - Adverse Event - Suicidal Ideation and Behavior in Treatment-Resistant Depression Clinical Trials

Last Updated: 04/16/2025

summary

Antidepressants (AD) increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. SPRAVATO nasal spray is not approved for use in pediatrics.¹^,²
The Columbia-Suicide Severity Rating Scale (C-SSRS) was used to prospectively assess potential suicidal ideation and behavior in the SPRAVATO clinical trial program in patients with treatment-resistant depression (TRD). Patients with suicidal ideation were not excluded; however, patients with suicidal behavior in the past year and suicidal ideation with some intent to act in the previous 6 months were excluded.³^-⁶
Across all phase 2⁷ and phase 3 studies³^-⁵^,⁸^,⁹ for TRD, suicidal ideation, assessed by C-SSRS, showed a decrease from baseline to endpoint in the SPRAVATO treatment groups. There was no evidence of association between SPRAVATO and increased risk of treatment-emergent suicidal ideation and behavior.¹⁰ See CLINICAL TRIAL DATA
There have been 3 completed suicides reported in the SPRAVATO clinical program for TRD.⁶^,¹⁰^,¹¹ See Serious Adverse Events of Completed Suicide in Clinical Studies
Overall, across phase 2⁷ and 3,³^-⁵^,⁸^,⁹ suicidality-related AEs were uncommon, and most of the reported cases were those of suicidal ideation. Clinical review of suicidality-related treatment-emergent adverse events (TEAE) indicated that most of these events were likely associated with the underlying disease in the patient population studied.¹¹
In postmarketing safety data from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) and the SPRAVATO global medical safety databases from 5 March 2019 to 5 January 2023, suicidal ideation was reported in 10.2% (249/2437) of serious adverse events (SAEs) and 47 deaths were reported due to completed suicides.¹² In another analysis of REMS data from 5 March 2019 to 5 January 2024, suicidal ideation was reported in 3.6% (76/2096) of SAEs.¹³
In an analysis of postmarketing safety data (first quarter of 2019 to the first quarter of 2023) using the Food and Drug Administration Adverse Event Reporting System (FAERS), suicidal ideation (n=456) and suicide attempt (n=140) were reported under SPRAVATO-related AEs.¹⁴ In a recent analysis performed using the FAERS database (from the first quarter of 2019 to the fourth quarter of 2023), 720 cases of suicidal ideation (reporting odds ratio [ROR], 52.93), 205 cases of suicide attempt (ROR, 18.55), 16 cases of self-injurious ideation (ROR, 22.51), 9 cases of suicidal depression (ROR, 11.53), and 3 cases of suicide threat (ROR, 28.22) were reported.¹⁵

PRODUCT LABELING

Consider changing the therapeutic regimen, including possibly discontinuing SPRAVATO and/or the concomitant oral AD, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.¹⁶

BACKGROUND

The Columbia Suicide Severity Rating Scale (C-SSRS) was used to assess potential suicidal ideation and behavior during the SPRAVATO clinical trial program. It is a clinical interview providing a summary of both suicidal ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present.¹¹

clinical Trial data

The overall incidence of TEAEs of suicidality in completed phase 3 studies is summarized in Table: Treatment-Emergent Adverse Events of Suicidality in Phase 3 Studies in TRD

Treatment-Emergent Adverse Events of Suicidality in Phase 3 Studies in TRD⁵^,⁹^,¹¹^,¹⁷^a

Study	SPRAVATO (28 mg, 56 mg, or 84 mg) + AD (%, n/N)	AD+PBO (%, n/N)
Pooled TRANSFORM-1/2	0.9 (3/346)	0.9 (2/222)
TRANSFORM-3	1.4 (1/72)	-
SUSTAIN-1
IND Phase	1.1 (5/437)	N/A
OP Phase	0.2 (1/455)	-
MA Phase	2.0 (3/152)	0.7 (1/145)
SUSTAIN-2
IND Phase	2.4 (19/779)	N/A
OP/MA	3.8 (23/603)	N/A
Abbreviations: AD, oral antidepressant; IND, induction; MA, maintenance; N/A, not applicable; OP, optimization; PBO, placebo.^aTEAEs of suicidality includes completed suicide, depression suicidal, intentional overdose, intentional self-injury, multiple drug overdose intentional, poisoning deliberate, self-injurious behaviour, self-injurious ideation, suicidal behaviour, suicidal ideation, suicide attempt. Incidence is based on the number of subjects experiencing at least one adverse event, not the number of events.Note: TRANSFORM-1 and TRANSFORM-2 were short-term, double-blind, 4-week studies in patients <65 years of age who received treatment twice a week (TRANSFORM-1 was fixed-dose and TRANSFORM-2 was flexible-dose); the table reports pooled results from both studies; TRANSFORM-3 was a short-term, double-blind, flexible-dose, 4-week study in patients ≥65 years who received treatment twice a week. SUSTAIN-1 was a long-term, randomized withdrawal study to assess the efficacy of flexibly-dosed SPRAVATO+AD compared with AD+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+AD. Patients received treatment twice a week during the initial 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (optimization phase was the following 12 weeks followed by the maintenance phase). SUSTAIN-2 was an open-label, flexibly-dosed study to evaluate the long-term safety of SPRAVATO+AD. Patients received treatment twice a week for the first 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (48-week optimization/maintenance phase). Note: no comparator data is available based on the open-label design.

Baseline Suicidal Ideation and Behavior

In the phase 3 trials of SPRAVATO in TRD,³^-⁵^,⁸^,⁹ between 25% and 37% of patients across studies/treatment groups had a lifetime history of suicidal ideation, and 14% to 19% had a lifetime history of suicidal behavior prior to screening.¹¹

Postbaseline Suicidal Ideation based on C-SSRS

During the double-blind period of phase 3 clinical trials of SPRAVATO in TRD,³^-⁵^,⁸ the proportion of patients with no suicidal ideation at baseline who went on to report suicidal ideation at any time point postbaseline was similar in the SPRAVATO+AD group and in the AD+PBO group.¹⁰ See Table: Postbaseline Reported Treatment-Emergent Suicidal Ideation (Based On C-SSRS) in Patients with No Ideation at Baseline.

Postbaseline Reported Treatment-Emergent Suicidal Ideation (Based on C-SSRS) in Patients with No Ideation or Behavior at Baseline⁵^,⁸^-¹⁰^a

Study	SPRAVATO (28 mg, 56 mg, or 84 mg) + AD (%, n/N)	AD+PBO (%, n/N)
Pooled TRANSFORM-1/2	10.2 (26/254)	12.3 (20/162)
TRANSFORM-3	13.8 (8/58)	16.7 (9/54)
SUSTAIN-1
IND Phase	11.3 (41/362)	N/A
OP Phase	5.7 (22/387)	-
MA Phase	2.4 (3/126)	4.5 (6/133)
SUSTAIN-2
IND Phase	11.1 (71/637)	N/A
OP/MA	11.6 (59/509)	N/A
Abbreviations: AD, oral antidepressant; IND, induction; MA, maintenance; N/A; not applicable; OP, optimization; PBO, placebo. ^aFor each study, each subject is counted only once in the above table, based on the most severe postbaseline C-SSRS category Note: TRANSFORM-1 and TRANSFORM-2 were short-term, double-blind, 4-week studies in patients <65 years of age who received treatment twice a week (1 was fixed-dose and 2 was flexible-dose); the table reports pooled results from both studies; TRANSFORM-3 was a short-term, double-blind, flexible-dose, 4-week study in patients ≥65 years who received treatment twice a week. SUSTAIN-1 was a long-term, randomized withdrawal study to assess the efficacy of flexibly-dosed SPRAVATO+AD compared with AD+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+AD. Patients received treatment twice a week during the initial 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (optimization phase was the following 12 weeks followed by the maintenance phase). SUSTAIN-2 was an open-label, flexibly-dosed study to evaluate the long-term safety of SPRAVATO+AD. Patients received treatment twice a week for the first 4 weeks (induction phase), weekly for the next 4 weeks, and then once every 2 weeks or weekly thereafter (48-week optimization/maintenance phase). Note: No comparator data is available based on the open-label design.

Postbaseline Suicidal Behavior Based on C-SSRS

In patients who did not have suicidal ideation or behavior at baseline across the phase 3 trials, 5 patients treated with SPRAVATO+AD were assessed to have suicidal behavior at any time postbaseline:¹⁰

In SUSTAIN-1: 1 (0.3%) patient in the open label IND phase⁵^,¹⁰
In SUSTAIN-2 (open label study): 2 (0.3%) patients in IND phase and 2 (0.4%) patients in the OP/MA phase⁹^,¹⁰

In patients who had suicidal ideation at baseline, 5 were observed to have postbaseline suicidal behavior:

In the 2 short-term studies in patients <65 years of age: 1 (1.2%) patient³^,⁴^,¹¹
In the long-term safety study: 2 (1.6%) patients in the IND phase and 2 (2.2%) patients during the OP/MA phase^,⁹^,¹¹

All patients who reported suicidal behavior during the phase 3 trials based on C-SSRS had a lifetime history of suicidal ideation or suicidal behavior.¹¹

SAEs of Completed Suicides in Clinical Studies

Although death by suicide is always tragic, in the SPRAVATO TRD development program, the suicide completion rate (0.49 per 100 patient-years of treatment) was comparable to the background rate of 0.47 (95% CI: 0.22-1.00) completed suicides per 100 patient-years reported in a different study in a TRD population.¹⁸^,¹⁹ After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO. Additionally, safety data was reviewed every 6 months by an Independent Data Monitoring Committee (IDMC) to ensure the continuing safety of the patients enrolled in the phase 3 trials.²⁰^,²¹

There have been 3 completed suicides in the SPRAVATO clinical program for TRD, including in an ongoing phase 3 trial.⁶^,¹⁰^,¹¹ See Table: Serious Adverse Events of Completed Suicides in Clinical Studies of SPRAVATO in TRD

Serious Adverse Events of Completed Suicides in Clinical Studies of SPRAVATO in TRD¹⁰^,¹¹

Study	Age (years) /Gender	Narrative	Investigator’s Assessment of Relationship to SPRAVATO
SYNAPSE (Phase 2 adjunctive trial)	41; male	Died due to suicide on day 45, 20 days after receiving the last dose of study medication during the follow-up phase of the study. During the 2-week double-blind treatment phase, the patient was in the placebo/SPRAVATO 14-mg group, and during the open-label phase he received 4 doses of SPRAVATO 56 mg.¹¹	Not related
SUSTAIN-2 (Phase 3, long-term, open label safety trial)	55; female	Died due to suicide (ie, overdosed with zolpidem and oxazepam) on day 188, 12 days after receiving the last dose of SPRAVATO 84 mg.⁹ Of note, there were psychosocial stressors that were subsequently reported to have preceded the suicide.¹¹^,²⁰	Not related
SUSTAIN-3 (Long-term, open-label safety extension trial)	48; male	Died due to a suicide on day 26 of the induction phase. The patient had been receiving SPRAVATO 84 mg with the last dose administered 4 days prior to the event.¹¹	Not related

McIntyre et al (2024)²² conducted a secondary safety and tolerability analysis of the ESCAPE-TRD²³ study, a 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO (n=334) vs quetiapine extended-release (QUE-XR; n=336) for the treatment of TRD. Treatment-emergent suicidal ideation was reported in 5 patients (1.5%) in the SPRAVATO group and 7 patients (2.1%) in the QUE-XR group. Treatment-emergent suicide attempts were reported in 2 patients (0.6%) in the SPRAVATO group and 1 patient (0.3%) in the QUE-XR group.

postmarketing safety data

REMS Database

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies and a separate SPRAVATO global medical safety database (which includes AEs reported from the REMS) from 5 March 2019 to 5 January 2023.¹² Of the 2437 SAEs, suicidal ideation was reported in 10.2% (N=249) of cases. There were 47 (0.14%) completed suicides among the 34,110 patients treated. For comparison, the rate of completed suicide was estimated to be 0.95% in a similar real-world epidemiological study of patients with TRD (n=15,013) who were treated for an average of 4.2 years.²⁴

Safety data of interest were gathered from REMS patient enrollment and monitoring forms completed by certified US healthcare settings and pharmacies from 5 March 2019 to 5 January 2024. Of the 58,483 patients who received at least 1 SPRAVATO treatment session, 44,908 patients (76.8%) reported ≥1 AE of special interest. Of the 2096 AEs reported to be serious (ie, led to death, disability or permanent damage, hospitalization, a life-threatening event, or any event that may jeopardize the patient or require intervention to prevent the above outcomes), 76 (3.6%) were due to suicidal ideation.¹³

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.²⁵ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval. If the proportion of AEs of interest was greater in cases versus non-cases, then this was considered a disproportionality signal. AEs were classified into four categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

There was a total of 2274 SPRAVATO-related AEs in 962 patients with 389 SAEs. Suicidal ideation, suicide attempt, and completed suicides were identified as disease-related AEs (see Table: Suicide-related Adverse Events).

Suicide-related Adverse Events²⁵

Adverse Event	n	Reporting Odds Ratio (95% CI)	Bayesian Information Component (95% CI)
Suicidal ideation	64	24.03 (18.72 to 30.84)	4.31 (3.9 to 4.61)
Suicidal attempt	6	3.75 (1.68 to 8.35)	1.63 (0.21 to 2.54)
Completed suicide	11	5.75 (3.18 to 10.41)	2.25 (1.23 to 2.94)
Abbreviations: CI, confidence interval.

The authors noted that the results must be interpreted with caution, partly due to the FAERS database having limitations, including the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate an incidence rate due to a lack of a denominator.²⁵ Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).²⁶

Another analysis conducted using the FAERS database for 5061 SPRAVATO-related AEs from the first quarter of 2019 to the first quarter of 2023 reported the occurrence of suicidal ideation and suicide attempts (see Table: Suicide-related Adverse Events).¹⁴

Suicide-related Adverse Events¹⁴

Adverse Event	n	Reporting Odds Ratio (95% CI)	Proportional Reporting Ratio (95% CI)	Bayesian Information Component (IC025)	Empirical Bayes Geometric Mean (EBGM05)
Suicidal ideation	456	38.54 (35.06 to 42.37)	37.00 (33.79 to 40.52)	5.07 (4.93)	36.25 (32.97)
Suicidal attempt	140	15.67 (13.26 to 18.53)	15.49 (13.13 to 18.27)	3.80 (3.56)	15.36 (12.99)
Abbreviations: CI, confidence interval; EBGM, Empiric Bayes Geometric Mean; EBGM05, the lower limit of the 90% confidence interval for the Empiric Bayes Geometric Mean; IC, information component; IC025, the lower limit of the 95% confidence interval for the information component.

Liu et al (2024),¹⁵ using data from the FAERS database, conducted an analysis of 14,606 SPRAVATO-related AEs reported in 6887 patients between the first quarter of 2019 and the fourth quarter of 2023. Suicidal ideation was among the 5 most frequently reported AEs in the database at the preferred terms (PT) level (cases, 720; ROR, 52.93; proportional reporting ratio [PRR], 47.50; and empirical Bayesian geometric mean [EBGM], 46.18). At the PT level, the signal intensity for suicide attempt included 205 cases (ROR, 18.55; PRR, 18.03; and EBGM, 17.84) for self-injurious ideation, 16 cases (ROR, 22.51; PRR, 22.46; and EBGM, 22.17), for suicidal depression, 9 cases (ROR, 11.53; PRR, 11.52; and EBGM, 11.45), and for suicide threat, 3 cases (ROR, 28.22; PRR, 28.21; and EBGM, 27.75).

Limitations of the FAERS database include an inability to infer causality, barriers to reporting, limitations in the quality of information received, and an inability to calculate the incidence rates of the events.²⁷

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 3 April 2025.

References

Show

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