Use of SPRAVATO in Patients With Bipolar Disorder

Summary

• SPRAVATO nasal spray has not been studied, and is not indicated, for patients with bipolar disorder.
• A secondary analysis of REAL-ESK evaluated the effect of SPRAVATO on anhedonia symptoms in 253 patients with treatment-resistant depression (TRD), including 54 patients with bipolar-TRD (B-TRD).¹
  • There was a significant decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonic subscale values at 1 month (P<0.0001) and 3 months (P<0.0001) in patients with B-TRD who initiated SPRAVATO.
  • Anti-anhedonic response was observed in 17.3% and 51.9% of patients at 1 month and 3 months after SPRAVATO initiation.
  • The incidence of AEs did not differ between groups (B-TRD, 64.8%; TRD, 72.4%); manic symptoms were reported in 5.6% and 2.0% of these patients, respectively, with no significant difference between the groups (P=1.000).
• A real-world study in 45 adults with refractory bipolar depression evaluated the efficacy and safety of intravenous (IV) ketamine (n=23) and SPRAVATO (n=22).² 
  • Significant improvements in depressive symptoms were observed over the acute treatment phase (2-4 weeks) (based on MADRS and Quick Inventory of Depressive Symptomatology-self report [QIDS-SR] scores).
  • No reports of mania or hypomania were reported during induction. However, 16 episodes of mania/hypomania (ketamine, n=6; SPRAVATO, n=10) were reported in 13 patients (ketamine, n=5; SPRAVATO, n=8) during the maintenance phase, with the majority of episodes rated as mild or moderate and did not require hospitalization. Mean time between the first treatment and the initial hypomanic/manic event was 297 days (median, 266 days).
    • The authors noted that manic or hypomanic symptoms could have been associated with treatment modifications to either the study drug treatment schedule or changes related to adjunctive therapies. Two of the 10 events with SPRAVATO occurred in patients who were initially diagnosed with unipolar depression and then subsequently diagnosed with bipolar depression.
• A retrospective, observational, multicenter study compared the efficacy, safety, and tolerability of SPRAVATO in patients with unipolar TRD vs patients with B-TRD.³
  • A significant reduction in the depressive symptoms (change in 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 AEs including increase in blood pressure, dissociation, and sedation were reported in BTRD and TRD groups (57.1% vs 77.1%; P=0.075).
• Four case reports describing adult patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who received SPRAVATO are described below.^4-7 

Clinical data

d’Andrea et al (2025)¹ conducted a secondary analysis of the REAL-ESK study (a multicenter, observational, real-world investigation conducted across Italian clinical settings) to evaluate the effects of repeated SPRAVATO administration on anhedonia in 253 patients with TRD, including 54 with B-TRD and 199 with unipolar TRD.

Study Design/Methods

• All patients received SPRAVATO adjunctive to ongoing selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) therapy.
• Anhedonia was assessed using a validated 5-item subscale of MADRS (visible sadness, expressed sadness, problems with concentration, fatigue, and inability to experience pleasure) at baseline (T0), 1 month (T1), and 3 months (T2).
• Response was defined as ≥50% reduction in the MADRS anhedonia subscale score from baseline.
• SPRAVATO was administered at a dose of 28 mg, 56 mg, or 84 mg.
• Psychometric assessments and AE monitoring were conducted throughout the study period.

Results

• At baseline, 68.5% of patients with B-TRD and 67.3% of patients with TRD had clinically significant anhedonia (MADRS subscale score ≥18).
• In the B-TRD group, 14 patients had BD-I and 40 patients had bipolar II disorder.
• In the B-TRD group, the mean MADRS anhedonia score significantly decreased from baseline (20.1) to T1 (14.9; P<0.0001; Cohen’s d=0.928) and from baseline to T2 (10.0; P<0.0001; d=1.810). Similarly, in the TRD group, the mean MADRS anhedonia score decreased from baseline (20.2) to T1 (14.5; P<0.0001; d=1.039) and from baseline to T2 (11.3; P<0.0001; d=1.612).
• The response rate was 17.3% at T1 and 51.9% at T2 in the B-TRD group and 22.3% at T1 and 38.0% at T2 in the TRD group.
• The dropout rates in the TRD and B-TRD groups were 14.0% (28/199) and 13.0% (7/54), respectively.
• AEs were reported in 64.8% of patients with B-TRD and 72.4% of patients with TRD. The most common events in both groups included dissociation (B-TRD, 33.3%; TRD, 41.7%), sedation (B-TRD, 22.2%; TRD, 23.1%), and manic symptoms (B-TRD, 5.6%; TRD, 2.0%), dizziness/headache (B-TRD, 5.6%; TRD, 4.5%), increased blood pressure (B-TRD, 1.9%; TRD, 8.6%), and anxiety (B-TRD, 1.9%; TRD, 3.5%).
• The incidence of overall AEs and manic symptoms did not differ significantly between the B-TRD and TRD groups.

Santucci et al (2024)² conducted a real-world, retrospective study using electronic record and chart review data in 45 patients with refractory bipolar depression to evaluate the efficacy and safety of treatment with IV ketamine (n=23) or SPRAVATO (n=22).

Study Design/Methods

• The treatment comprised a 4-week initial acute phase with twice weekly doses for up to 4 weeks. In patients who achieved meaningful improvement, treatment was continued for another 4 weeks with weekly doses, followed by tapering to less frequent doses to maintain response or remission (generally every 2-4 weeks).
• The total follow-up period was 518 patient-months.
• Depressive symptoms were measured by the MADRS and QIDS-SR scales in 38 patients.

Results

• The mean (standard deviation [SD]) age of the overall group was 37.5 (14.5) years; 93% of the patients were White, and 64% were female. The mean (SD) age of the patients who received SPRAVATO was 38.9 (14.7) years, and 73.9% were female.
• Concomitant medications during the acute phase in the overall cohort included antipsychotics, lithium, mood stabilizers, or anticonvulsants (88.9%), and antidepressants (51.1%). Additionally, 51.1% of patients had ≥1 psychiatric comorbidity, and 53.3% ≥1 medical comorbidity.
• The median treatment duration with IV ketamine and SPRAVATO were 1.9 and 4.0 months, respectively.
• Overall, 39% of patients achieved clinical response (≥50% improvement on MADRS), and 13.2% achieved remission (MADRS ≤10) during the acute phase. During the acute treatment phase with SPRAVATO, significant improvements were noted in the mean MADRS score (coefficient, -7.55 per 4 treatments; 95% confidence interval [CI], -9.57 to -5.54; P<0.001) and the mean QIDS-SR score (coefficient, -4.12 per 4 treatments; 95% CI, -5.20 to -3.03; P<0.001).
• There were 16 hypomania or mania events reported in 13 patients, all of which occurred during the maintenance phase. Mean time between the first treatment and the initial hypomanic/manic event was 297 days (median, 266 days). Ten of these events were related to SPRAVATO during a follow-up period of 247 patient-months. Among these cases, 2 patients had an initial diagnosis of unipolar depression, and this was their first episode that led to their bipolar diagnosis.
  • Notably, 87.5% of these events occurred in patients on mood stabilizers, antipsychotics, or lithium; 50% were classified as mild and resolved without intervention; and 43.8% were moderate, resolving with medication adjustments without the need for hospitalization. Only one severe manic episode was reported in a patient who received IV ketamine.
  • The authors noted that manic or hypomanic symptoms could have been attributed to treatment modifications to either the study drug treatment schedule or changes related to adjunctive therapies.

Martinotti et al (2023)³ 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 SSRI or SNRI.
  • 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).
• AEs 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.
  • The authors acknowledged the potential bias in assessing overall SPRAVATO-related affective switches in patients with bipolar depression due to the concomitant use of mood stabilizers.

Case Report

Farahmandpour et al (2026)⁴ presented a case report of a 43-year-old male with recurrent depression and BD-II features. After undergoing 8 antidepressant and mood-stabilizing trials over 2 decades with only partial or short-term response, the patient started a 4-week course of twice weekly SPRAVATO nasal spray. The patient had a baseline MADRS score of 36 and Clinical Global Impression-Severity (CGI-S) score of 6 at the time of referral.

In early sessions, he experienced mild to moderate nausea, dizziness, and dissociation that resolved within 1 hour and attenuated over time. At the end of 4 weeks, his MADRS score decreased to 14 and his CGI-Improvement (CGI-I) score was 2. After discontinuing SPRAVATO, he remained in remission for about 6 months before experiencing a relapse. Following his relapse, he started dextromethorphan/bupropion 45/105 mg twice daily, and his symptoms improved with MADRS declining to 10 and CGI-I to 1. Over the following year, the patient maintained stable mood, employment, and social functioning without needing additional pharmacotherapy.

Lin et al. (2025)⁵ described a case report of a 62-year-old male with treatment-resistant BD-II and hypertension. The patient had a poor response to multiple psychotropic medications and reported partial response to electroconvulsive therapy (ECT) combined with IV ketamine and repetitive transcranial magnetic stimulation (rTMS).

He started SPRAVATO nasal spray during his fourth major depressive episode. During the induction phase, he received twice weekly SPRAVATO for 4 weeks, combined with venlafaxine, mirtazapine, lithium, and quetiapine. His PHQ-9 score decreased from 25 to 15 at the end of induction. He continued maintenance treatment with weekly or biweekly SPRAVATO. After another 4 months, his PHQ-9 decreased to 7, and he transitioned to monthly SPRAVATO dosing. During the monthly dosing period, he experienced buying spree although no other manic symptoms were reported. By month 9, his PHQ-9 further decreased to 5. His dosing frequency was further adjusted to once every 2 months while his lithium dosage increased from 300 mg every other day to 300 mg daily. However, several months later, he relapsed with PHQ-9 increasing to 23. A second induction phase was initiated for a month, resulting in symptom improvement and a PHQ-9 score reduction to 12. After 6 months of maintenance treatment, his PHQ-9 decreased to 6.

Throughout the treatment, he experienced side effects including dissociation, dizziness, and transient hypertension. He remained on nebivolol and valsartan for blood pressure control but received nifedipine in 3 instances when his systolic blood pressure exceeded 160 mm Hg.

de Filippis et al (2023)⁶ 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)⁷ 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. The patient was diagnosed with bipolar disorder 2 years prior to the initiation of treatment with SPRAVATO. Having had inadequate/partial response to multiple psychotropic medications, including antidepressants with and without active mood stabilizers, and to electroconvulsive therapy and transcranial magnetic stimulation, 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). After the first week, due to symptom worsening, the dose of SPRAVATO was increased to 84 mg twice weekly until the end of week 4 (induction phase) and then switched to once weekly for the remainder of the treatment period (maintenance phase).

By the end of the induction phase, 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 AEs were reported. Short-term AEs 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 5 August 2026.