What are the contraindications for using modafinil (a wakefulness-promoting agent) in a patient with major depressive disorder (MDD) who has failed multiple antidepressant trials and is being considered for ketamine therapy, with a history of potential suicidal ideation and possible severe cardiovascular conditions, psychosis, mania, or severe anxiety disorders?

Modafinil Contraindications

Modafinil is absolutely contraindicated in patients with known hypersensitivity to modafinil or armodafinil, and should be used with extreme caution—or avoided entirely—in patients with a history of psychosis, depression, mania, or known cardiovascular disease including left ventricular hypertrophy or mitral valve prolapse. 1, 2

Absolute Contraindications

• Known hypersensitivity to modafinil or armodafinil is the only FDA-specified absolute contraindication 1
• This includes patients who have experienced serious rash, Stevens-Johnson Syndrome, angioedema, anaphylaxis, or multi-organ hypersensitivity reactions to either modafinil or armodafinil 1, 2

Critical Cardiovascular Contraindications

• Left ventricular hypertrophy: The FDA explicitly recommends that modafinil not be used in patients with a history of left ventricular hypertrophy 2
• Mitral valve prolapse with prior CNS stimulant complications: Modafinil should not be used in patients with mitral valve prolapse who have experienced mitral valve prolapse syndrome (ischemic ECG changes, chest pain, or arrhythmia) when previously receiving CNS stimulants 2
• Clinical studies documented cardiovascular adverse reactions including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG in patients with these structural cardiac abnormalities 2

Psychiatric Contraindications and High-Risk Populations

For your specific patient scenario with MDD, potential suicidal ideation, and consideration for ketamine therapy:

• History of psychosis, depression, or mania represents a critical warning requiring extreme caution, not an absolute contraindication, but the FDA explicitly states to "use caution" and "consider discontinuing" if psychiatric symptoms develop 1, 2
• Postmarketing reports with armodafinil (the R-enantiomer of modafinil) documented mania, delusions, hallucinations, suicidal ideation, and aggression—some resulting in hospitalization 2
• In pre-approval controlled trials, anxiety, agitation, nervousness, irritability, and depression were reasons for treatment discontinuation more frequently with modafinil compared to placebo 2
• Cases of suicidal ideation were observed in clinical trials 2

Critical consideration for your patient: Many, but not all, patients who developed psychiatric adverse reactions had a prior psychiatric history, and these reactions occurred across a wide dose range (50-450 mg) 2

Practical Clinical Algorithm for Your Patient

Given the context of treatment-resistant MDD with potential suicidal ideation and ketamine consideration:

1. Modafinil should likely be avoided in this patient due to the combination of active major depressive disorder, history of suicidal ideation, and the documented risk of worsening depression and suicidal ideation with modafinil 2

2. If cardiovascular disease is present (severe cardiovascular conditions mentioned in your scenario), perform cardiac evaluation to rule out left ventricular hypertrophy or mitral valve prolapse before any consideration of modafinil 2

3. If modafinil is considered despite psychiatric history, establish intensive monitoring for worsening mood, anxiety, agitation, or emergence of suicidal ideation, with immediate discontinuation if these develop 2

4. Regarding ketamine therapy: The evidence shows ketamine is appropriate for treatment-resistant depression after failure of at least 2 adequate antidepressant trials, but the FDA explicitly states its effectiveness in preventing suicide or reducing suicidal ideation has not been established 3

Additional Safety Warnings

• Severe rash and Stevens-Johnson Syndrome: Discontinue modafinil at the first sign of rash unless clearly not drug-related 1
• Multi-organ hypersensitivity reactions (including one fatality) have occurred, typically within 4-33 days of initiation 2
• Blood pressure elevation: Modafinil causes small but consistent increases in blood pressure (1.2-4.3 mmHg) and heart rate (0.9-3.5 BPM), requiring increased monitoring in patients with cardiovascular disease 2

Common Pitfalls to Avoid

• Do not assume modafinil is safe for augmentation in treatment-resistant depression simply because it has been studied in this population—the psychiatric risks are substantial, particularly in patients with active mood disorders 4, 5
• Do not overlook the cardiovascular screening: Structural cardiac abnormalities represent a specific contraindication that requires evaluation before prescribing 2
• Do not minimize the risk of psychiatric decompensation: The postmarketing data on mania, psychosis, and suicidal ideation should be taken seriously in vulnerable populations 2