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 studies^{3-5, 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 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 adverse events 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 and 47 deaths were reported due to completed suicides.¹²
• In another analysis of postmarketing safety data (March 2019 to first quarter 2020) using the Food and Drug Administration Adverse Event Reporting System (FAERS), suicidal ideation (n=64), suicidal attempt (n=6), and completed suicide (n=11) were reported as disease-related adverse events.¹³

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.¹⁴

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

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 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 phase^{5, 10}
• In SUSTAIN-2 (open label study): 2 (0.3%) patients in IND phase and 2 (0.4%) patients in the OP/MA phase^{9, 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%) patient^{3, 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

Serious Adverse Events 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.^{16, 17}  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.^{18, 19}

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

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 serious adverse events, 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.²⁰

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹³ 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 serious AEs. Suicidal ideation, suicide attempt, and completed suicides were identified as disease-related adverse events (see Table: Suicide-related Adverse Events).

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.¹³ Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).²¹

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 24 May 2023.