Summary

• SPRAVATO nasal spray has not been studied, and is not indicated, for patients with bipolar disorder.
• A retrospective, observational, multicenter study compared the efficacy, safety, and tolerability of SPRAVATO in patients with unipolar treatment-resistant depression (TRD) vs patients with bipolar TRD (B-TRD).¹
  • A significant reduction in the depressive symptoms (change in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) was observed individually in the B-TRD and TRD groups from baseline to the end of the first month of treatment (T1) (BTRD: P<0.0001; TRD: P<0.0001) and from T1 to the end of the third month of treatment (T2) (BTRD: P<0.0001; TRD: P<0.017). No significant difference was observed in response or remission rates between B-TRD and TRD groups.
  • A significant decrease in anxiety symptoms (change in Hamilton Anxiety Scale [HAMA] scores) was observed individually in B-TRD and TRD groups from baseline to T1 (BTRD: P=0.0002; TRD: P=0.003) and from T1 to T2 (BTRD: P=0.003; TRD: P=0.330).
  • Similar adverse events including increase in blood pressure, dissociation, and sedation were reported in BTRD and TRD groups (57.1% vs 77.1%; P=0.075).
• A case report describes the achievement of sustained response in an adult patient with bipolar I disorder (BD-I) after the addition of SPRAVATO to the existing regimen.²
• A case report describes the improvement of depressive symptoms in an adult patient with treatmentresistant bipolar depression prescribed SPRAVATO.³

Clinical data

Martinotti et al (2023)¹ presented the results of a retrospective, observational, multicenter study comparing the efficacy, safety, and tolerability of SPRAVATO in patients with unipolar TRD vs patients with B-TRD.

Study Design/Methods

• The study included patients (aged >18 years) who were experiencing a depressive episode and receiving treatment with selective serotonin reuptake inhibitor or serotonin noradrenaline reuptake inhibitor.
  • B-TRD was defined as failure to respond to ≥2 adequate trials from 2 classes of antidepressants and 2 classes of mood stabilizers (including atypical antipsychotics).
  • TRD was defined as the absence of a clinical response after 2 conventional antidepressant treatments.
  • Patients with comorbidities that are an absolute contraindication of SPRAVATO including untreated arterial hypertension or previous cerebrovascular disorders were excluded.
• Psychometric assessments were performed at baseline, T1, and T2 from the start of treatment; depressive symptoms were assessed using MADRS and the Hamilton Depression Scale (HAM-D-21 items); and severity of anxiety symptoms was assessed using HAMA (HAM-A-21 items).
  • Patients were defined as responders if they showed an overall 50% reduction in the MADRS and HAM-D-21 scores, whereas remission was defined as the MADRS score <10 or HAM-D-21 score <7.

Results

• A total of 70 patients, with a mean age of 53 years, were included in the study, of whom 35 were included each in the B-TRD and TRD groups.
• In the B-TRD vs TRD group, 4 vs 7 patients discontinued treatment with SPRAVATO during the follow-up period.
• The MADRS (P=0.940) and HAM-A (P=0.097) scores did not differ between the B-TRD and TRD groups at baseline. See Table: MADRS and HAM-A Scores in the B-TRD and TRD Groups.
• A significant decrease in the MADRS scores was observed individually in the B-TRD and TRD groups from baseline to T1 (BTRD: P<0.0001; TRD: P<0.0001) and from T1 to T2 (BTRD: P<0.0001; TRD: T1 vs T2, P<0.017).
  • No difference in the MADRS scores was observed between the B-TRD and TRD groups at T1 (P=0.984) and T2 (P=0.986).
• In the B-TRD group, 25.7% and 68.6% of patients responded at T1 and T2, respectively, and 17.1% and 48.6% were remitters at T1 and T2, respectively, whereas in the TRD group, 25.7% and 57.1% of patients responded at T1 and T2, respectively, and 8.6% and 28.6% were remitters at T1 and T2, respectively.
• A significant decrease in the HAM-A scores was observed individually in the B-TRD and TRD groups from baseline to T1 (BTRD: P=0.0002; TRD: P=0.003) and from T1 to T2 (BTRD: P=0.003; TRD: P=0.330).
  • No difference in the HAM-A scores was observed between the B-TRD and TRD groups at T1 (P=0.999) and T2 (P=0.794).
• At T2, the proportion of remitters from anxiety symptoms (HAM-A score <7) was higher in the B-TRD vs TRD group (35% vs 2.9%; P=0.002).

• The B-TRD and TRD groups did not differ in terms of proportion of patients reporting any side effects (57.1% vs 77.1%; P=0.075).
• Adverse events reported in the B-TRD vs TRD group were increased blood pressure (0.0% vs 8.6%), dissociation (31.4% vs 40%), sedation (28.6% vs 45.7%), manic symptoms (2.9% vs 2.9%), anxiety (2.9% vs 0.0%), and dizziness and headache (2.9% vs 2.9%).
• One case of affective switch or maniacal symptom was reported in each group (P=1.000); 1 case of psychomotor agitation was reported in the B-TRD group after SPRAVATO administration, and the treatment was discontinued after 2 weeks.

Case Report

de Filippis et al (2023)² presented a case report of a 39-year-old female patient diagnosed with BD-I and borderline personality disorder who presented to the hospital after a drug ingestion-related suicide attempt. The patient had a long history of alcohol and drug abuse, with prior reports of manic episodes, voluntary and compulsory hospitalizations, drug ingestion-related suicide attempts, and depression. A month after her recent drug ingestion-related suicide attempt, the patient was initiated on SPRAVATO as an adjuvant to the current treatment regimen, including fluoxetine, lithium, lurasidone, and quetiapine. She received a twice-weekly 56 mg SPRAVATO dose for 4 weeks followed by 56 mg once weekly.

After 3 months, a clinical response (50% reduction in the MADRS score) was reported, and at the 12-month follow-up, a clinical remission (MADRS score <10) with improvements in global functioning, sleep cycle, suicidality risk, binge eating, and anxiety symptoms was reported. In the continuation phase, the patient had no clinical relapses or hospitalizations, held a part-time job, and started caring for herself and her daughters.

Skriptshak et al (2021)³ described a case report of a 63-year-old male with a medical history that included BD-I, current episode depression, posttraumatic stress disorder, manic symptoms, and lethargy, with inadequate response to earlier psychotropic therapies, who responded to treatment with SPRAVATO nasal spray.

The patient was diagnosed with bipolar disorder 2 years prior to the initiation of treatment with SPRAVATO. The patient trialed multiple psychotropic medications in the past, including antidepressants with and without active mood stabilizers, and reported partial response to electroconvulsive therapy and transcranial magnetic stimulation. Pharmacogenomic testing did not reveal any significant abnormalities that could account for the patient’s inadequate response to treatment. Laboratory test results were unremarkable, and renal function was stable.

Because of failure to achieve remission with ≥4 antidepressant trials plus 2 augmentation trials, the patient was started on SPRAVATO nasal spray 56 mg twice weekly. Lurasidone
40 mg daily and bupropion 300 mg daily were started prior to and continued throughout the treatment period (1 year). The patient initially responded to treatment until day 7, when depressive symptoms returned. Hence, an increased dose of SPRAVATO 84 mg twice weekly was administered until the end of week 4 (induction phase) and then switched to 84 mg once weekly for the remainder of the treatment period (maintenance phase).

By the end of the induction phase, the self-reported 9-item Patient Health Questionnaire (PHQ-9) scores dropped from 20 (severe depression) at baseline to 0 (absence of depressive symptoms). Although the scores have increased since then, the patient continued to benefit from treatment as evidenced by improved PHQ-9 scores compared with those at baseline, reduced depressive symptoms, and no reported return of manic or hypomanic symptoms. No longterm adverse events were reported. Short-term adverse events included mild blood pressure elevation and subjective reports of dissociation in the first 30 minutes following administration of treatment, which resolved after 1 hour.

Literature Search

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 08 November 2023.