Spravato is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist.¹ Spravato is indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.¹

Major depressive disorder (MDD) is a common psychiatric condition, with an estimated 16 million adults or 7% of adults in the United States experiencing at least one major depressive episode each year.² Symptoms of depression can include persistent sadness, feelings of hopelessness, loss of interest in usual activities, decreased energy, difficulty concentrating or sleeping, change in appetite and thoughts of hurting oneself. Depression can increase the risk of suicide and result in long-term suffering. It impacts all aspects of life including social relationships and the ability to work, and is the second leading cause of disability in the United States.³ Treatment, including medication and psychotherapy, leads to improvement in many individuals, but multiple iterations in the therapeutic regimen may be required to achieve an adequate outcome. Treatment-resistant depression (TRD) refers to a major depressive episode with an inadequate response to therapy of adequate dosing and duration.^4,5 The failure of at least two trials of antidepressant monotherapies in the current episode is considered to indicate TRD,⁶ but the number of trials has not been standardized.⁷ Overall, approximately one in three patients with depression are considered ‘treatment resistant’.⁸   

Spravato was approved on a short-term and a long-term study.  The short-term study was a randomized, placebo-controlled, double-blind, multicenter, 4-week study in patients aged 18 to <65 years old.  Patients met the DSM-5 criteria for major depressive order, and in the current depressive episode, had not responded adequately to at least two different antidepressants of adequate dose and duration.  Patients were randomized to either twice weekly doses of Spravato (flexible at 56 or 84 mg) or placebo.  Both groups were given concomitant treatment with a newly-initiated oral antidepressant.  The primary efficacy measure was the change in baseline in the Montgomery-Asberg Depression Rating Scale (MADRS).  The MADRS is scored from 0 to 60, with the higher MADRS scores indicating more severe depression.  Scoring is usually broken down with 0 and 6 indicating no depression, 7-19 mild depression, 20-34 moderate depression, and over 34 severe depression.⁹ The Spravato arm had a mean baseline score of 37.0, while the control arm had a score of 37.3.  The Spravato plus antidepressant arm demonstrated statistically superiority in the primary efficacy measure over the placebo plus antidepressant arm.  Spravato caused a decrease in score of 19.8, versus a decrease of 15.8 for placebo.

The long-term study was a randomized, double-blind, parallel group, multicenter maintenance of effect study in adults 18 to <65 years of age who were known responders to Spravato.  After at least 16 weeks of treatment with Spravato and an oral antidepressant, stable patients were randomized to continue the Spravato and antidepressant or to be switched to a placebo spray and antidepressant.  The primary endpoint was time to relapse, where relapse was defined as a MADRS score of ≥ 22 for 2 consecutive weeks or hospitalization for depression.  Patients who continued Spravato with an antidepressant experienced a statistically significantly longer time of relapse than did placebo patients.¹   

Safety Issues¹ - Spravato causes increases in systolic and/or diastolic blood pressure (BP) at all recommended doses. Increases in BP peak approximately 40 minutes after Spravato administration and last approximately 4 hours. Approximately 8% to 17% of Spravato-treated patients and 1% to 3% of placebo-treated patients experienced an increase of more than 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment. A substantial increase in blood pressure could occur after any dose administered even if smaller blood pressure effects were observed with previous administrations. Assess BP prior to administration of SPRAVATO. In patients whose BP is elevated prior to Spravato administration (as a general guide: >140/90 mmHg) a decision to delay Spravato therapy should take into account the balance of benefit and risk in individual patients.