Clinical Studies

Cardiovascular- or Cerebrovascular-Related Exclusion Criteria From SPRAVATO Phase 3 Studies

Treatment-Resistant Depression^2,6

• Cerebrovascular disease with a medical history of stroke or transient ischemic attack
• Untreated glaucoma, current penetrating or perforating eye injury, brain injury, hypertensive encephalopathy, intrathecal therapy with ventricular shunts, or any other condition associated with increased intracranial pressure or increased intraocular pressure or planned eye surgery
• Active aneurysmal vascular disease (including intracranial, thoracic or abdominal aorta, or peripheral arterial vessels)
• Coronary artery disease with myocardial infarction (MI), unstable angina, or revascularization procedure (eg, coronary angioplasty or bypass graft surgery), within 12 months before the start of the screening/prospective observational phase
  • Patients who have had a revascularization performed ˃12 months prior to screening and were clinically stable and symptom-free, per investigator’s clinical judgment, were included.
• Hemodynamically significant valvular heart disease such as mitral regurgitation, aortic stenosis, or aortic regurgitation
• New York Heart Association Class III-IV heart failure of any etiology
• Medical history of uncontrolled hypertension despite diet, exercise, or antihypertensive medications, defined as:
  • Supine systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg during screening/prospective observational phase in patients <65 years old
  • Supine SBP >150 mmHg or DBP >90 mmHg during screening/prospective observational phase in patients ≥65 years old
• Patients could have current antihypertensive medication(s) adjusted during the screening/prospective observational phase and be re-evaluated to assess BP control.
  • The patient had to be on a stable regimen for at least 2 weeks before day 1 of SPRAVATO treatment.
• Patients with a current or past history of significant pulmonary insufficiency/condition or with an arterial blood oxygen saturation of <93%
• Patients with clinically significant ECG abnormalities
  • On day 1 (predose), a QT interval corrected according to Fridericia's formula (QTcF): ≥450 msec based on the site-evaluated ECG; if the QTcF is prolonged on the initial ECG, the average QTcF of three ECGs, recorded 4 minutes apart, must not be ≥450 msec
    • Note: this was prior to conduct of the thorough QT study which indicated that concurrent use of SPRAVATO did not have a significant effect on QT interval
  • Evidence of 2nd and 3rd degree AV block, complete left bundle branch block, or complete right bundle branch block
  • Features of new ischemia
  • Arrhythmia (except premature atrial contractions and premature ventricular contractions)
• Patients with a history of additional risk factors for Torsades des Pointes (eg, heart failure, hypokalemia, family history of Long QT Syndrome)

Major Depressive Disorder and Active Suicidal Ideation and Intent^7,8

• Clinically significant cardiac disease, which included unstable coronary artery disease, congestive heart failure, tachyarrhythmias, and recent myocardial infarction
• Uncontrolled hypertension or history of hypertensive crisis
  • This includes conditions in which elevated BP could pose a serious risk, including unstable heart failure, severe cardiovascular disease, recent cerebral injury, increased intracranial pressure, intracranial mass lesion, intracranial bleeding or acute stroke, untreated glaucoma, perforating eye injury

Case Study

Romani et al (2023)⁹ reported an 84-year-old female patient with dementia and behavioral disorder and a history of cerebrovascular cognitive impairment, who presented with an exacerbation of anxiety-depressive and behavioral disorders, and extrapyramidal symptoms with a resting tremor. The patient’s prior medications included mirtazapine and clomipramine; the latter was switched to venlafaxine due to extrapyramidal symptoms, but the resting tremor persisted. A cerebral MRI revealed age-related homogeneous cortico-subcortical atrophy and a stage Fazekas 3 vascular leukopathy. In addition to treatment with venlafaxine (75 mg), the patient was initiated on 28 mg SPRAVATO given twice weekly for 4 weeks and once weekly as a maintenance dose. After 3 months of treatment, the patient demonstrated a significant reduction in anxiety-depressive symptoms and improvement in social interaction. Due to good neurocognitive and cardiovascular tolerance, a higher maintenance dose of 56 mg SPRAVATO was given at the fourth administration. At the time of the report, the treatment was ongoing and administered regularly.

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 14 February 2025.