SUMMARY

• A real-world retrospective study analyzed physician-reported data from 94 patients with depression, including patients with treatment-resistant depression (TRD) and major depressive disorder with suicidal ideation (MDSI), who received SPRAVATO from July 2022 to February 2023. A majority of prescribers (80%) reported high satisfaction with SPRAVATO to reach patient treatment goals.¹
• A real-world retrospective cohort study analyzed data from 163 adult patients with TRD who received SPRAVATO from March 2019 to June 2022. The study reported a prominent reduction in mean Patient Health Questionnaire-9 (PHQ-9) score in patients treated with a longer duration of SPRAVATO (at least 3 months).²
• A real-world retrospective cohort study analyzed data from 171 patients with TRD with comorbid psychiatric disorders and high exposure to psychiatric medications who received SPRAVATO from July 2019-June 2021. Significant reductions in mean PHQ-9 and Generalized Anxiety Disorder-7 (GAD-7) scores were observed from baseline (PHQ-9, 16.7; GAD-7, 12.0) to last available treatment (PHQ-9, 12.0; GAD-7, 8.7).³
• The REAL-ESK study, a retrospective, observational and multicenter analysis of 116 patients with TRD from Italy who were treated with SPRAVATO, found significant reductions in depressive symptoms at 1-month and 3-month follow-ups compared to baseline. Response and remission rates increased from month 1 (28.4% and 11.2%, respectively) to month 3 (64.2% and 40.6%, respectively). The most common adverse events (AEs) were dissociation, sedation, and transient hypertension.⁴
• A descriptive retrospective multicenter compassionate use study in Spain in 24 patients with TRD found that 60% of patients responded to SPRAVATO nasal spray plus an antidepressant (AD) and 30% remitted.⁵
• The safety profile from a real-world SPRAVATO Temporary Authorization for Use (ATU) program in France in 66 patients with TRD who lacked a therapeutic alternative was consistent with SPRAVATO phase 3 clinical trials.⁶
• The ESKALE study, a retrospective analysis of real-world clinical practice in France, found that there was a greater reduction in the mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score from treatment initiation and a higher number of responders in the cohort of patients who initiated SPRAVATO + AD post launch compared with the cohorts that initiated treatment during and post ATUc.⁷
• An indirect comparison of SUSTAIN-2 and a European Observational TRD cohort (EOTC), where the choice of treatment was at the physician’s discretion (excluding SPRAVATO), found response and remission odds ratios in favor of SPRAVATO + AD treatment at 6 months.^8,9
• Postmarketing safety data from the US Risk Evaluation and Mitigation Strategies (REMS) and SPRAVATO global medical safety database from March 5, 2019, to January 5, 2023, did not identify new safety signals.¹⁰ Sedation and dissociation were the most commonly reported AEs; the majority of sedation and dissociation reports were nonserious and resolved within the postdose monitoring period. Another analysis using the FDA Adverse Event Reporting System (FAERS) was also conducted to identify safety signals.¹¹

REAL WORLD USE

Jha et al (2023)¹ retrospectively analyzed real-world data from 94 patients with depression who were treated with SPRAVATO between July 2022 and February 2023.

Study Design/Methods

Retrospective analysis of data sourced from a large cross-sectional database in the US (the Adelphi Real World Depression Disease Specific Programme XII [DSP™]). Treatment with SPRAVATO was analyzed for its market availability, improvement in disease state and daily functioning (analyzed by the Clinician Global Impression of Improvement [CGI-I]), depression severity (analyzed by the Clinician Global Impression of Severity [CGI-S]), and satisfaction of the physician with the medication.

Results

• A total of 108 eligible physicians (who treated at least 10 patients with depression per week) provided information on 94 patients (mean age, 44.3 years; male, 47%) with depression, including TRD or MDSI, who were treated with SPRAVATO (n=9 for 1-30 days; n=85 for >30days). Of all the patients, ≥30% were receiving SPRAVATO for >2 years.
• The physician-reported CGI-I score showed “much improved” or “very much improved” status in 88%, 60%, 73%, 77%, and 63% of patients after 0-3 months, 3-6 months, 6-12 months, 1-2 years, and >2 years of SPRAVATO treatment, respectively.
• Physicians believed improvement in depressive symptoms occurred in 100% of patients in the 1- to 30-day group vs 98% in the >30-day group (the remaining 2% of patients in the >30-day group neither improved nor worsened in condition severity since initiation.).
• The assessment of CGI-S scores showed that depressive symptoms improved or maintained in 77% and 22% of patients in the 1- to 30-day group vs 65% and 33% of patients in the >30-day group, respectively.
• The CGI-S score showed a mean improvement of 1.2 points in the 1- to 30-day group vs 0.9 in the >30-day group.
• For patients in the >30-day group, better social functioning was reported in 62% of patients; better quality of life, 53% of patients; increased ability to work, 41% of patients; ability to meet their own basic needs, 37% of patients; and improved overall general health, 34% of patients.
• SPRAVATO treatment was “available without restrictions” for 12% of patients; “available with restrictions”, 43% of patients; and “not routinely available”, 45% of patients.
• Most physicians (80%) reported high satisfaction (score, 4 or 5) with the achievement of patient treatment goals with SPRAVATO.
• Similarly, 80% of physicians responded “no” when asked whether patients faced insurance-related delays in receiving SPRAVATO treatment.

Marci et al (2023)² retrospectively analyzed real-world data from 163 adult patients with TRD who were treated with SPRAVATO between March 2019 and June 2022.

Study Design/Methods

A retrospective, longitudinal, observational cohort study utilizing data from the PremiOM™ major depressive disorder (MDD) Dataset in the US. Severity in depressive symptoms, using the PHQ-9 scale, was compared from baseline to >0-3-month and >3-6-month periods after the index date (defined as the day of SPRAVATO initiation). Remission was defined as a follow-up PHQ-9 score of <5.

Results

• A total of 163 patients (mean age, 49.5 years; female, 58.3%) were included in the analysis.
• At baseline, 55.8% of patients had either moderately severe or severe depression (PHQ-9 ≥15; mean PHQ-9 score, 15), which decreased to 34.4% and 20.9% of patients in the >0-3-month and >3-6-month postindex periods, respectively.
• Statistically significant reductions in PHQ-9 scores compared with the baseline were reported in the >0-3-month (2.9 points; 95% confidence interval [CI], 1.7-4.1; P<0.001) and the >3-6-month (4.4 points; 95% CI, 3.2-5.6; P<0.001) postindex periods.
• The average decrease in PHQ-9 score was 3.2 points (95% CI, 2.0-4.5; P<0.001), with an effect size of 0.42, in patients with ≥1 PHQ-9 score in the baseline and the >0-3-month postindex period (n=151).
• The average decrease in PHQ-9 score was 4.4 points (95% CI, 3.2-5.7; P<0.001), with an effect size of 0.60, in patients with ≥1 PHQ-9 score in the baseline and the >3-6-month postindex period (n=136).
• The odds of a patient being in remission were 3.2 (95% CI, 1.5-7.0; P=0.003) and 4.9 (95% CI, 1.9-12.8; P=0.001) times greater in the >0-3-month and the >3-6-month postindex periods, respectively, vs the baseline.
• Longer duration of treatment with SPRAVATO resulted in a more pronounced reduction in PHQ-9 scores, with the largest reduction reported in patients treated with SPRAVATO for at least 3 months.
• Analyses of sensitivity, which did not include estimated PHQ-9 scores, revealed consistent results.

Brendle et al (2022)³retrospectively analyzed data for real-world evidence outcomes from 171 patients with TRD receiving SPRAVATO (July 2019-June 2022) in a private outpatient psychiatric clinic setting.

Study Design

Retrospective observational cohort study utilized data collected from an electronic health record system and medical charts of a REMS-certified psychiatric clinic for SPRAVATO treatment.

Inclusion Criteria: Adults (≥18 years old) with major depressive disorder, recurrent without psychotic features and received SPRAVATO between July 2019-June 2021.

Exclusion Criteria: Patients who had received any other form of ketamine were excluded.

Primary outcomes assessed were PHQ-9 depression scores, GAD-7 anxiety scores and suicidal ideation (SI) score, item 9 on PHQ-9.

Patient Demographics and Characteristics

The mean age of the 171 treated patients was 36 years. Most patients were white (92%), and predominantly female (60.0%), and had comorbid psychiatric diagnoses. Most patients (98%) used other psychiatric medications besides SPRAVATO with a mean of 5.8 (standard deviation [SD], 4.0) medications per patient, out of which there was a mean of 2.3 (SD, 2.3) ADs used per patient.

Results

Depression and Anxiety Outcomes

Based on the PHQ-9 and GAD-7 scores from treatment sessions 1-28, the average PHQ-9, GAD-7 and mean SI scores decreased significantly (P<0.001) from baseline suggesting improvement in severity of depression and anxiety symptoms.

The baseline mean PHQ-9 score was 16.7 (SD, 5.8) and mean GAD-7 score was 12.0 (SD, 5.8). Mean PHQ-9 and GAD-7 scores at last available SPRAVATO treatment were 12.0 (SD, 6.4) and 8.7 (SD, 5.6) showing significant reductions from baseline. There was also a significant decrease in the suicide score from a baseline of 1.09 (SD, 1.06) to 0.79 (SD, 0.94). Refer to Table: PHQ-9 and GAD-7 Scores by Number of SPRAVATO Treatments Received.

Safety

Information from REMS documents were used to account for the number of patients experiencing AEs including sedation, dissociation, and increased blood pressure (BP). Dissociation (73%) occurred more frequently than sedation (22%) with most symptoms presenting within the first 30 minutes of SPRAVATO administration and resolving by 2 hours. Patients were reported to be ready to leave approximately 90 minutes after dosing. Mean BP slightly decreased over time throughout each treatment session. There was 1 serious AE reported in which a patient experienced prolonged dissociation, sedation, nausea, and vomiting with full resolution occurring the same day before leaving the center.

Martinotti et al (2022)⁴ retrospectively analyzed data from 116 patients with TRD treated with SPRAVATO using assessment scores from the MADRS and Hamilton Rating Scale for Depression-21 (HAM-D-21) at baseline (T0), 1-month (T1) and 3-month (T2) follow-ups.

Study Design

This retrospective, observational, multicenter study analyzed patients as part of an “early access programme” in Italy that supplied SPRAVATO to major centers treating TRD across the country.

Inclusion Criteria: Adults (≥18 years old) with TRD:

• No response to ≥2 different Ads.
• Being treated with selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor for which SPRAVATO was considered appropriate.

Exclusion Criteria: Patients with comorbid organic pathologies (untreated arterial hypertension or previous cerebrovascular disorders) that were considered contraindications for SPRAVATO.

Primary outcomes were assessed using MADRS and HAM-D-21 scale scores. Response was defined as 50% reduction from baseline in either score and remission defined as MADRS score of <10 or HAM-D-21 score of <7.

Patient Demographics and Characteristics

The mean age of the 116 treated patients was 50 years and 52.6% of patients were female. Refer to Table: Baseline Demographic and Clinical Characteristics. Psychiatric comorbidities included personality disorders (15%), substance use disorder (6%), and general anxiety disorder (5%), among others.

Results

One-Month and 3-Month Treatment Outcomes

A significant reduction in the MADRS score was observed at T1 (n=106; mean, 22.27±9.81; P<0.0001) and T2 (n=91; mean, 14.69±9.88; P<0.0001) compared to baseline ([T0]; mean, 35±8.53). Furthermore, SPRAVATO had a significant effect (P<0.0001) in reducing suicidal thoughts (MADRS item 10) at T1 (mean, 1±0.55) and T2 (mean, 0.94±0.1) compared to baseline (mean, 2.13±1.58). Compared to T0, there was an increase in clinical response (T1, 28.4%; T2, 64.2%) and remission (T1, 11.2%; T2, 40.6%) with significant improvement in both at T2 vs T1 (P<0.0001). Only 29% (early remitters) of patients in remission at T2 were also in remission at T1. Thirty-eight percent of patients in remission at T2 were non-responders at T1.

Psychiatric Comorbidities and Add-on Therapies

SPRAVATO had similar effectiveness irrespective of psychiatric comorbidities. However, patients on medications other than ADs, such as antipsychotics or mood stabilizers, showed an overall lower response rate to SPRAVATO (T1, P=0.023; T2, P=0.010).

Safety

Dissociation (39.7%), sedation (28.4%), and transient hypertension (10.3%) were the most common side effects, whereas 27.6% of patients reported no side effects. Three patients (2.58%) discontinued because of severe side effects at T1.

Fuertes-Saiz et al (2021)⁵ conducted a retrospective multicenter study in 8 hospitals in Spain where compassionate use of SPRAVATO was approved by the Spanish Medicines and Health Products Agency for use in conjunction with an AD in patients with TRD.

A total of 24 patients were included, of which 66.7% (n=16) were female. The mean age was 53.4 years. Eligible patients had failed to respond to 2 or more “proper AD trials”, 1 augmentation or potentiation strategy and a non-pharmacological treatment such as electroconvulsive therapy (ECT). Approximately 42% (n=10) had already received treatment with ECT.

The HAM-D-17, MADRS and visual analogue scale for depression were measured at baseline and at 3 and 6 months. To compare different depression rating scales, t-scores were calculated and a mixed linear general model for repeated measures was used for mean comparison at different time points.

Results

A statistically significant decrease in the mean depression t-scores (F(1,8)=227.6, P<0.001) was observed when comparing baseline (mean=59.15, standard error [SE]=2.52) to 3-month scores (mean=41.10, SE=3.07, P<0.001) and baseline to 6-month scores (mean=36.99, SE=4.27, P<0.001). Response was achieved in 60% (n=12) and remission in 30% (n=6) of patients. The authors did not define response and remission criteria.

Two patients discontinued treatment due to no therapeutic effect after 6 months of treatment. Feelings of dizziness, dissociative symptoms, irritability, and tiredness were each reported by 4% (n=1) of individuals, with no reported adverse effects in the remainder of patients. The investigators did not report the timing of AE occurrences.

Samalin et al (2022)⁶ presented data from a cohort of patients in France who received SPRAVATO nasal spray via an ATUc program authorized by the French National Agency for Medicines and Health Product Safety (ANSM) to address adult patients with TRD lacking a therapeutic alternative. Note that SPRAVATO has since been approved.

Study Design

Inclusion Criteria: Adults (≥18 years old) with moderate to severe depression and:

• No response to ≥2 different ADs of ≥2 different classes during the current depressive episode
• could not receive ECT due to contraindication, no access, resistance to ECT, or patient refusal.
• Were medically stable based on physical examination, medical history, and vital signs.

Treatment access request forms were completed by treating psychiatrists and sent to the sponsor from September 23, 2019, until March 25, 2020, and in total 66 patients were treated by 36 psychiatrists at 25 centers in France, of whom 54 had documented exposure to SPRAVATO.

Patients received SPRAVATO with an AD according to the Summary of Product Characteristics approved by the ANSM in a hospital setting for both in- and outpatients, and patients were monitored for approximately 2 hours by a healthcare professional following each treatment session.

Patient Demographics and Characteristics

The mean age of the 66 treated patients was 52.5 years and the majority were female (62.1%). The mean MADRS total score was 32.9.

• Since the start of the current depressive episode, all 66 patients were prescribed ≥2 ADs from 2 different classes (mean [SD], 4.2 [2.1]).
  • 54 (81.8%) patients were prescribed ≥1 antipsychotic as part of a potentiation regimen.
  • 21 (31.8%) patients were prescribed repetitive transcranial magnetic stimulation (TMS) sessions.
  • 28 (42.4%) patients were prescribed ECT sessions (median ECT sessions was 17).
  • ECT had been considered at the time of treatment request in all treated patients (N=66) but could not be performed efficiently in 39% as they were resistant. For the others, 53% refused ECT, 3% had no access, and 5% were contraindicated.

Results

Of the 49 patients with a completed treatment initiation form and available data, treatment was initiated in a complete hospitalization setting in 27 (55.1%) patients and in day hospitalization in 22 (44.9%) for treatment administration purposes. SPRAVATO was initiated with AD monotherapy in 16 (28.1%) patients, AD plus augmentation therapy in 9 (15.8%), combination therapy with 2 ADs in 17 (29.8%), and combination therapy plus augmentation in 15 (26.3%). In 47 patients with cumulative data, the median treatment exposure time to SPRAVATO was 30.0 (range, 10-148) days. The mean (SD) duration of monitoring following SPRAVATO administration was 123.3 minutes (25.4), performed mainly by nurses.

MADRS total score reporting was not mandatory but at least 2 scores were reported during the induction period for 46 patients. Of the 46 patients, 25 had scores at the end of induction. Mean MADRS total scores decreased from a baseline score 30.9 to a score of 19.5 by week 4. Of the 46 patients, 22 (47.8%) achieved a response (decrease of ≥50% in the MADRS total score) at least once after treatment initiation (median time to response,18.5 [range, 2-77] days). Of these patients, 17 achieved remission (MADRS total score ≤12) at least once after treatment initiation (median time to remission, 21 [range, 2-46] days). Most patients were using 56 mg of SPRAVATO at the time of response and remission (see Table: Proportion of Patients Receiving 56 mg or 84 mg at the Time of Response, Remission, and Treatment Discontinuation due to Lack of Efficacy). Four weeks following treatment, patients had a 31.6% probability of achieving remission. Using Kaplan-Meier analysis, this increased to 60.3% after 8 weeks.

There were 201 medically confirmed AEs reported in 51 patients (see Table: AEs [Including Serious AEs] Reported in ≥10% of Patients). 187 AEs were non-serious and 14 were considered serious; 8 discontinued due to AEs. All AEs associated with SPRAVATO were transient and self-limiting, and occurred on the day of administration. Overall, 13 patients experienced increased BP or hypertension after administration. Twenty-four patients discontinued after a median time from treatment initiation of 28 days (range, 15-132 days). There were no new safety signals during the ATUc compared with the phase 3 clinical trials, no deaths, and no cases of dependence.

Samalin et al (2021)⁷ presented results from the ESKALE study, a retrospective study of adult (≥18 years old) patients in France with moderate to severe TRD, defined as non-responsive to ≥2 oral ADs.

Study Design

This interim analysis collected data from medical records of patients who had been included in the study from June 26, 2020, to January 11, 2021, and treated with SPRAVATO and an AD between October 29, 2019, and March 1, 2021. Patients were included in 1 of 3 cohorts depending upon treatment initiation date (Figure: Number of Patients Treated With SPRAVATO Overall and per Cohort).

Patient Demographics and Characteristics

The mean age of the 62 treated patients was 49.2 years and the majority were female (67.7%). The median time in years from first diagnosis of depression was 9.3 (range, 3.8-20.9 years). Mean MADRS total score (SD) at baseline was 31.8 (7.3). The mean number of lines of treatment at the time of SPRAVATO initiation ranged from 3.2 to 5.2 across the 3 cohorts.

Patients were on a numerically greater number and variety of drugs compared to previous depressive episodes at the time of SPRAVATO initiation. In the current depressive episode, a higher number of patients had received neurostimulation (ECT, 73.9%; rTMS, 60.8%) in the ATUc (46.2%) and post-ATU (46.2%) cohorts compared to post launch (15%).

Results

Responders were defined as ≥50% decrease in the MADRS total score. There was a greater reduction in the mean MADRS total score from treatment initiation and a higher number of responders in the post launch cohort compared with the other 2 cohorts (see Figure: Change in MADRS From Initiation [A] and Percentage of Responders [B]).

The odds for recording SPRAVATO responders at 1 week was 8-fold higher in patients who had 2 previously well-conducted treatment lines (n=11) in comparison to those with ≥3 (n=22) lines (P=0.027). Those with prior treatment with neurostimulation had a 4.5-fold higher likelihood of a non-satisfactory outcome (P=0.014).

There were 321 AEs in 39 patients. The majority (60%) were mild in severity. The most common AEs were ineffective therapeutic drug (33.9%), dissociative disorder (32%), somnolence (21%), and sedation (16%).

Rive et al (2021)⁸ and Morrens et al (2021)⁹ reported on results of an indirect comparison between 2 studies to compare SPRAVATO efficacy data with specific real-world treatment strategies for TRD.

Study Design

Two studies with similar recruitment conditions were selected:

• The EOTC: A prospective, non-interventional, multicenter study in patients starting a new, routine treatment for TRD, in real-world clinical practice. Data were stratified into 3 groups:
  • Monotherapy (1 AD).
  • Combination therapy (≥2 AD).
  • Augmentation therapy (≥1 augmentation medication plus ≥1 AD).
• SUSTAIN-2: A longterm, open-label study of the safety and efficacy of SPRAVATO nasal spray plus new oral AD, including European patients.

Baseline characteristics were similar between the 2 studies. Subjects who stopped prior to study termination were imputed as non-responders.

Treatment differences were estimated by reweighting observations (inverse probability weighting using propensity scores estimated with 17 covariates) in the EOTC using SUSTAIN-2 as a reference, resulting in an estimate of treatment effects.

Response (≥50% improvement MADRS score) and remission (total MADRS score ≤10) at 6 months were compared. Analysis was based on observed cases.

Results

The overall logistic regressions for response and remission showed a significant odds ratio (OR; both P<0.0001) in favor of SPRAVATO + AD (see Table: Likelihood for Response for SPRAVATO [SUSTAIN-2] vs RWT [EOTC] and Table: Likelihood for Remission for SPRAVATO [SUSTAIN-2] vs RWT [EOTC]). Results were consistent following adjustment for multiple covariates and several sensitivity analyses.

The following were significantly associated with a lower likelihood of achieving response: age ≥55 at major depressive disorder diagnosis; previous treatment failures with augmentation, tricyclic antidepressants (TCAs), or other ADs.

The following were significantly associated with a lower likelihood of achieving remission: higher baseline MADRS (≥31); previous treatment failures with augmentation or TCAs.

Limitations and Bias

Due to the absence of a common comparator in the 2 studies, only an indirect comparison was possible. Increased compliance and motivation to continue treatment in the SUSTAIN2 clinical trial setting may have led to potential bias in favor of SPRAVATO. In addition, higher frequency of visits in SUSTAIN2 compared with the EOTC study may have led to improved outcomes. However, increased visits are also expected in realworld clinical treatment with SPRAVATO.

Postmarketing safety databases

REMS Database

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies from March 5, 2019, to January 5, 2023.¹⁰ Results from this analysis showed that in 34,110 patients who had received at least 1 SPRAVATO treatment session, 21,956 (64.4%) reported sedation, 22,953 (67.3%) reported dissociation, and 4,120 (12.1%) reported increased BP (defined as either an increase of ≥20 mm Hg before administration to ≥180 mm Hg [systolic] after administration and/or ≥15 mm Hg before administration to ≥105 mm Hg [diastolic] after administration, or if values before administration were missing, ≥180 mm Hg [systolic] and/or ≥105 mm Hg [diastolic] were used). In the 815,172 treatment sessions, sedation, dissociation, and increased BP were reported in 36.6%, 42.3%, and 1.0% of treatment sessions. The majority of sedation and dissociation reports were nonserious and resolved within the postdose monitoring period. There were 1,580 serious AEs with increased BP, dizziness, nausea, and vomiting being the most frequently (≥5%) reported; 4.9% of events were non-evaluable, in that key information was missing (eg, lack of information regarding onset of event relative to drug exposure, key patient characteristics, medical and medication history) and a meaningful medical assessment could not be made.

In a separate search of the SPRAVATO global medical safety database, which included AEs reported from the REMS, there were 440,369 cases from the REMS reporting a total of 658,360 AEs within the same time frame. Among those cases, 2,437 (0.4%) were reported as serious. There were 147 fatal cases in 147 unique patients with 160 reported fatal events. Of the 147 cases, 136 cased reported only 1 fatal event which included 67 deaths not otherwise specified, 45 completed suicide, 3 overdose, 2 coronavirus disease 2019 (COVID-19) infection, 2 road traffic accidents, and 1 death each due aortic aneurysm, arteriosclerosis, Candida infection, cerebrovascular accident, diabetes mellitus, drug abuse, electrolyte imbalance, failure to thrive, hepatic cirrhosis, intestinal obstruction, intestinal perforation, multimorbidity, myocardial infarction, neoplasm malignant, post procedural complication, pulmonary embolism, and sepsis. Eleven remaining fatal cases which reported more than 1 fatal event: Cardiac disorder, sepsis, and COVID-19; cardiovascular disorder, multiple organ dysfunction syndrome, and cerebrovascular accident; toxicity to various agents and accidental overdose; hip fracture and gall; hallucination auditory and completed suicide; pneumonia and multiple organ dysfunction syndrome; toxicity to various agents and completed suicide; suspected suicide and alcohol use; overdose and brain injury; organ failure and COVID-19; and substance abuse and accidental overdose. The majority of deaths were assessed by Global Medical Safety as not related to SPRAVATO treatment.¹⁰

FDA Adverse Event Reporting System

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹¹ 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 vs non-cases, then this was considered a disproportionality signal. AEs were classified into 4 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 2,274 SPRAVATO-related AEs in 962 patients with 389 serious AEs, including 22 deaths. The most frequently reported AEs (≥5%) were dissociation (n=212, 9.32%), sedation (n=173, 7.6%), and drug ineffective (n=119, 5.23%). The top 3 AEs in the expected AEs with signal category based on reporting odds ratio (listed in descending order) were dissociation (n=212), sedation (n=173), and feeling drunk (n=20); in the expected AEs without a signal category were vertigo (n=5), vision blurred (n=8), and tremor (n=9); in the disease-related AEs category were self-injurious ideation (n=5), SI (n=64), and depression (n=65); and in the unexpected AEs category were dissociative disorder (n=4), autoscopy (n=6), and drug monitoring procedure not performed (n=4). The frequency of serious AEs was higher in patients receiving SPRAVATO 84 mg compared to patients receiving SPRAVATO 56 mg. Females were also more likely to suffer from serious SPRAVATO-related AEs compared to males. A sensitivity analysis using venlafaxine as a comparator for disease-related AEs identified the following signals: self-injurious ideation, SI, emotional disorder, depression, crying, and depressed mood.¹¹

Limitations of the FAERS includes: the database contains duplicate, incomplete, and/or unverified AEs, making causality difficult to prove; AE reports are voluntary and unsolicited (which generally leads to under-reporting of AEs for most drugs) and, therefore, AE rates cannot be determined; FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).¹² Other considerations include: the increasing AE trends for SPRAVATO over the first year are expected due to the low initial SPRAVATO usage following approval, partly due to REMS requirements for certifying treatment centers; expected AEs such as dissociation and sedation are solicited and reported via the REMS at every SPRAVATO treatment session triggering multiple reports in FAERS; use of venlafaxine as a control for sensitivity analyses may not be appropriate since the TRD population indicated for SPRAVATO likely possess a significantly greater burden of disease.

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 07 November 2023.