What are the contraindications and significant medication interactions to consider when starting a patient on Selective Serotonin Reuptake Inhibitors (SSRIs)?

SSRI Contraindications and Significant Drug Interactions

Absolute Contraindications

SSRIs are absolutely contraindicated with MAOIs due to life-threatening serotonin syndrome risk. 1, 2

• Do not combine SSRIs with MAOIs (including linezolid and intravenous methylene blue at doses of 1-8 mg/kg) 2
• Required washout period: Discontinue SSRI before starting MAOI; specific timing depends on the SSRI's half-life 2
• Citalopram contraindication: Avoid in patients with congenital long QT syndrome and do not exceed 40 mg/day due to risk of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death 1

High-Risk Drug Interactions Requiring Extreme Caution

Serotonin Syndrome Risk (Potentially Fatal)

The combination of SSRIs with other serotonergic agents creates additive risk for serotonin syndrome, which has an 11% mortality rate in severe cases. 3

Serotonergic drugs to avoid or use with extreme caution: 1, 2

• Other antidepressants: SNRIs, TCAs, MAOIs, atypical antidepressants
• Opioids: Tramadol, meperidine, methadone, fentanyl 1, 2
• Stimulants: Amphetamines (including Vyvanse), possibly methylphenidate 1, 3
• Triptans: Sumatriptan and other migraine medications 2
• Other medications: Dextromethorphan, buspirone, lithium, tryptophan 1, 2
• Over-the-counter/supplements: St. John's Wort, L-tryptophan, diet pills 1
• Illicit drugs: MDMA (ecstasy), methamphetamine, cocaine, LSD 1

Serotonin syndrome presents with: 3, 2

• Mental status changes (confusion, agitation, delirium, coma)
• Autonomic instability (hyperthermia, tachycardia, labile blood pressure, diaphoresis)
• Neuromuscular hyperactivity (myoclonus, clonus, hyperreflexia, rigidity) occurring in 57% of cases 3
• Symptoms typically develop within 24-48 hours of combining medications or dose changes 3

Cytochrome P450 Interactions

Different SSRIs have markedly different interaction profiles through CYP450 inhibition: 1, 2

• Fluvoxamine: Most extensive interactions—inhibits CYP1A2, CYP2C19, CYP2C9, CYP3A4, and CYP2D6 1
• Fluoxetine, paroxetine, sertraline: Inhibit CYP2D6, affecting drugs with narrow therapeutic indices (TCAs, Type 1C antiarrhythmics like propafenone and flecainide) 1, 2
• Citalopram/escitalopram: Least CYP450 inhibition, lowest propensity for drug interactions 1

High-risk CYP2D6 substrates requiring dose reduction when combined with SSRIs: 2

• Tricyclic antidepressants (monitor plasma levels)
• Type 1C antiarrhythmics (propafenone, flecainide)

Bleeding Risk

SSRIs increase bleeding risk, particularly when combined with anticoagulants or NSAIDs. 2

• Warfarin: Requires careful monitoring when initiating or discontinuing SSRIs 2
• NSAIDs and aspirin: Concurrent use potentiates upper GI bleeding risk 2
• Mechanism: Serotonin depletion from platelets impairs hemostasis 2

QT Prolongation

Citalopram specifically interacts with other QT-prolonging drugs, increasing arrhythmia risk. 1

Special Population Considerations

Elderly Patients

Preferred SSRIs for elderly patients: citalopram, escitalopram, sertraline, or consider mirtazapine, venlafaxine, bupropion. 1

• Avoid paroxetine and fluoxetine in older adults due to higher adverse effect rates 1
• Elderly patients have higher risk of serotonin syndrome due to altered drug metabolism 3
• Increased risk of hyponatremia 4

Pregnancy

Paroxetine is FDA pregnancy category D due to cardiac malformation concerns. 1

• SSRI use after 20 weeks gestation may increase risk of persistent pulmonary hypertension of the newborn (PPHN), with number needed to harm of 286-351 1
• Consider risks of untreated depression versus medication exposure 1

Children and Adolescents

Paroxetine has been associated with increased suicidal thinking compared to other SSRIs in this population. 1

• Start with subtherapeutic "test" dose due to initial anxiety/agitation risk 1
• Parental oversight of medication regimens is paramount 1

When to Start SSRIs

Initiation Strategy

Start with a subtherapeutic "test" dose because initial adverse effects can include anxiety and agitation. 1

Dose titration schedule: 1

• Shorter half-life SSRIs (sertraline, citalopram, paroxetine): Increase at 1-2 week intervals
• Longer half-life SSRIs (fluoxetine): Increase at 3-4 week intervals
• Use smallest available increments to optimize benefit-to-harm ratio

Pre-Treatment Screening

Screen all patients with depressive symptoms for bipolar disorder before initiating SSRI therapy. 2

• Obtain detailed psychiatric history including family history of suicide, bipolar disorder, and depression 2
• SSRIs may precipitate mixed/manic episodes in undiagnosed bipolar disorder 2
• Note: SSRIs are not approved for bipolar depression 2

Monitoring Requirements

Monitor closely for emergent suicidality and behavioral changes, especially in the first 24-48 hours after initiation or dose changes. 3, 2

Warning signs requiring immediate attention: 2

• Anxiety, agitation, panic attacks
• Insomnia, irritability, hostility, aggressiveness
• Impulsivity, akathisia (psychomotor restlessness)
• Hypomania, mania
• Worsening depression or emerging suicidality

Critical Pitfalls to Avoid

Never combine SSRIs with MAOIs or start within inadequate washout periods—this is the most dangerous interaction. 2

Do not assume all SSRIs have the same interaction profile—fluvoxamine has the most extensive CYP450 interactions while citalopram/escitalopram have the least 1

When combining SSRIs with other serotonergic agents is clinically necessary: 1

• Start the second agent at low dose
• Increase slowly
• Monitor intensively for serotonin syndrome symptoms in first 24-48 hours after any dose change

Recognize discontinuation syndrome risk, particularly with paroxetine, fluvoxamine, and sertraline—taper over 10-14 days rather than abrupt cessation 1

Screen for angle-closure glaucoma risk—SSRIs cause pupillary dilation that may trigger angle-closure attack in susceptible patients 2