Is an adult patient with a history of opioid dependence, bipolar disorder, ADHD, experiencing nightmares and auditory hallucinations, currently on buprenorphine/naloxone (Suboxone) awaiting extended‑release buprenorphine (Sublocade), aripiprazole, quetiapine, clonidine, atomoxetine, propranolol, prazosin, and tizanidine, eligible for Spravato (esketamine nasal spray)?

Spravato Eligibility in Complex Psychiatric Comorbidity with Opioid Dependence

This patient does NOT automatically qualify for Spravato based on the information provided, and several critical safety assessments and documentation requirements must be completed before proceeding. While the FDA label does not explicitly contraindicate Spravato in patients with opioid dependence history, the drug carries significant abuse potential as a Schedule III controlled substance, and "careful consideration is advised prior to use of individuals with a history of substance use disorder" 1.

Critical Eligibility Requirements That Must Be Verified

Treatment-Resistant Depression Documentation

• The patient must have documented failure of at least 2 adequate antidepressant trials at appropriate doses and durations during the current moderate-to-severe depressive episode 2, 3, 4.
• The current medication regimen (aripiprazole, quetiapine) suggests treatment for bipolar disorder rather than unipolar depression, which fundamentally changes the eligibility assessment 2.
• Spravato is FDA-approved only for treatment-resistant major depressive disorder, NOT for bipolar depression 1, 4.

Diagnostic Clarification Required

• If the patient has bipolar disorder (as suggested by aripiprazole and quetiapine use), Spravato is not indicated and alternative treatments should be pursued 1.
• The presence of auditory hallucinations raises concern for psychotic features; Spravato has not been studied in patients with major depressive disorder with psychotic features and the FDA label specifically studied "nonpsychotic depression" 1, 5.
• Document whether the nightmares and hallucinations represent PTSD symptoms, substance-induced phenomena, or primary psychotic illness, as this affects treatment selection 1.

Substance Use Disorder Considerations

Opioid Dependence on Buprenorphine/Naloxone

• The FDA label explicitly states that "individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO" and recommends careful consideration before use 1.
• Patients on buprenorphine maintenance therapy can theoretically receive Spravato, as there are no documented pharmacokinetic interactions between esketamine and buprenorphine 6, 1.
• However, the abuse potential study showed that esketamine produced significant "Drug Liking," "Hallucinating," "Floating," "Detached," and "Spaced Out" scores in recreational drug users, raising concern about relapse risk in someone with active substance use disorder 1.

Risk Mitigation Strategy

• If proceeding with Spravato in this patient, implement enhanced monitoring for signs of abuse and misuse including craving for esketamine, requests for dose escalation, or behavioral changes suggesting diversion 1.
• The REMS program requirement for supervised administration at certified treatment centers provides some protection against misuse, but does not eliminate risk 1, 7.
• Document that the patient and treatment team understand the Schedule III controlled substance status and the potential for physical and psychological dependence 1.

Medication Interaction and Safety Assessment

Current Medication Regimen Review

• Quetiapine (Seroquel) is sedating and may potentiate esketamine's sedation and dissociative effects, requiring careful monitoring during the 2-hour post-administration observation period 1, 5.
• Clonidine, propranolol, prazosin, and tizanidine all have sedative and hypotensive properties that may be additive with esketamine's cardiovascular effects 1.
• Blood pressure must be monitored before and after each esketamine dose, as the drug causes transient hypertension; the combination with multiple antihypertensive agents creates complex management challenges 1, 5.

Specific Safety Concerns

• The patient's complex polypharmacy (8+ medications) increases risk of drug-drug interactions and adverse effects 8, 1.
• Strattera (atomoxetine) can increase blood pressure and heart rate, potentially compounding esketamine's cardiovascular effects 1.
• Aripiprazole and quetiapine together suggest either treatment-resistant bipolar disorder or inadequate response to monotherapy, which should prompt reconsideration of the primary diagnosis before adding esketamine 8, 2.

Practical Barriers to Treatment Access

Geographic and Logistic Considerations

• Esketamine requires administration at a certified treatment center with 2-hour post-dose observation, which may be challenging for patients with transportation limitations 1, 7.
• Research shows that initiation rates decrease by 50.8% for patients living 20-29 miles from treatment centers, and the patient's ability to attend twice-weekly sessions during induction must be assessed 7.
• Insurance coverage (particularly Medicaid) is associated with lower likelihood of completing the 8-dose induction phase and higher treatment interruption rates 7.

Treatment Commitment Requirements

• The induction phase requires 8 administrations within 45 days (typically twice weekly for 4 weeks), followed by weekly dosing, then maintenance dosing 1, 4, 9.
• Each visit requires 2+ hours including pre-assessment, administration, and post-dose monitoring, representing significant time commitment 1, 7.
• Patients cannot drive or operate machinery for the remainder of the day after each dose 1.

Alternative Treatment Considerations

If Bipolar Disorder is Confirmed

• Optimize mood stabilization with lithium, valproate, or lamotrigine before considering experimental treatments 8.
• Consider electroconvulsive therapy (ECT) for treatment-resistant bipolar depression, which has stronger evidence than esketamine in this population 3.
• Evaluate whether the current antipsychotic regimen (aripiprazole + quetiapine) represents rational polypharmacy or could be simplified 8.

If Unipolar Depression is Confirmed

• Document that at least 2 adequate antidepressant trials have failed (adequate = appropriate dose for appropriate duration, typically 6-8 weeks at therapeutic dose) 2, 3, 5.
• Consider augmentation strategies with proven efficacy (lithium, thyroid hormone, second-generation antipsychotics) before esketamine 2, 3.
• Ensure concurrent evidence-based psychotherapy (cognitive behavioral therapy, interpersonal therapy) is provided, as medication alone is insufficient 2, 3.

Required Documentation Before Approval

Clinical Documentation Needed

1. Confirmed DSM-5 diagnosis of major depressive disorder without psychotic features (not bipolar disorder, not schizoaffective disorder) 1, 5.
2. Documentation of at least 2 failed adequate antidepressant trials with specific medications, doses, durations, and reasons for discontinuation 2, 3, 4.
3. Baseline depression severity score using validated instrument (MADRS, PHQ-9, HAM-D) showing moderate-to-severe depression 2, 5.
4. Substance use assessment documenting current stability on buprenorphine maintenance and absence of active substance use 1.
5. Cardiovascular assessment including baseline blood pressure and evaluation of risk given multiple antihypertensive medications 1.

Safety Assessments Required

• Baseline liver function tests (esketamine can cause hepatotoxicity, though rare at therapeutic doses) 1.
• Pregnancy test for females of reproductive potential (esketamine may cause fetal harm based on animal studies) 1.
• Assessment of suicidal ideation and plan, noting that esketamine's effectiveness in preventing suicide has NOT been established by FDA 3, 1.
• Evaluation of patient's ability to comply with REMS requirements including transportation to certified center and 2-hour observation 1, 7.

Common Pitfalls to Avoid

• Do not approve Spravato for bipolar depression – it is not FDA-approved for this indication and may destabilize mood 1, 4.
• Do not approve without documented failure of adequate antidepressant trials – esketamine is explicitly NOT first-line treatment 3, 4, 5.
• Do not overlook the substance use disorder history – the Schedule III status and abuse potential require enhanced monitoring in this population 1.
• Do not assume the patient can access treatment – verify proximity to certified treatment center and insurance coverage before approval 7.
• Do not approve if psychotic features are present – esketamine has not been studied in psychotic depression and may worsen symptoms 1, 5.