What are the clinical pearls for prescribing Selective Serotonin Reuptake Inhibitors (SSRIs) to patients, including those with a history of bipolar disorder?

SSRI Clinical Pearls

Start SSRIs at therapeutic doses in most adults—dose titration is generally unnecessary and delays response, though lower starting doses may reduce initial side effects in anxiety disorders. 1, 2

Dosing Strategy

• Most SSRIs have flat dose-response curves—higher doses do not typically improve efficacy for depression 3
• Initial therapeutic doses are often effective: paroxetine 20mg, sertraline 50mg, fluoxetine 20mg, citalopram 20mg 1, 2
• For anxiety disorders, start at lower doses (e.g., sertraline 25mg, paroxetine 10mg) and titrate slowly over 1-2 weeks to minimize activation/agitation 1
• Allow 8 weeks at maximum tolerated dose before declaring treatment failure 1
• Dose increases beyond standard ranges rarely improve outcomes and increase side effects 3

Critical Safety Concerns

Bipolar Disorder - Absolute Contraindication

SSRIs should be avoided in patients with bipolar disorder due to significant risk of inducing mania 1

• Risk of mood switching: 24-27% in bipolar patients treated with SSRIs 4
• Hyperthymic temperament increases switch risk further 4
• If mood stabilization needed, use lithium or anticonvulsants plus CBT instead 1

Serotonin Syndrome

Avoid combining SSRIs with other serotonergic agents, especially MAOIs (absolute contraindication) 1

Critical combinations to avoid:

• MAOIs (phenelzine, isocarboxazid, linezolid)—wait 2 weeks after MAOI discontinuation 1
• Tramadol, meperidine, methadone, fentanyl 1
• Dextromethorphan, St. John's wort, tryptophan 1
• Amphetamines, cocaine, MDMA 1

Symptoms appear within 24-48 hours: clonus, tremor, hyperreflexia, agitation, diaphoresis, fever; severe cases include seizures and rhabdomyolysis 1

When combining non-MAOI serotonergic drugs, start low, titrate slowly, and monitor closely in first 24-48 hours after dose changes 1

Drug-Specific Considerations

Paroxetine

• Strongest ejaculation delay (8.8-fold increase)—useful for premature ejaculation 1
• Highest discontinuation syndrome risk 1
• Associated with increased suicidal thinking compared to other SSRIs 1

Citalopram/Escitalopram

• Maximum dose 40mg/day due to QT prolongation risk (Torsades de Pointes, sudden death) 1
• Avoid in long QT syndrome 1
• Least drug interactions via CYP450 system 1

Fluvoxamine

• Most drug-drug interactions: inhibits CYP1A2, 2C19, 2C9, 3A4, 2D6 1
• Higher discontinuation syndrome risk 1

Sertraline

• Moderate discontinuation syndrome risk 1
• Common side effects: diarrhea (18-21%), nausea (26%), ejaculatory dysfunction (14-17%) 5

Fluoxetine

• Longest half-life—titrate every 3-4 weeks (vs 1-2 weeks for others) 1
• Lowest discontinuation syndrome risk due to long half-life 1

Common Adverse Effects

Sexual dysfunction is the most common dose-limiting side effect 5

• Ejaculatory delay/failure: 14-17% (vs <1% placebo) 5
• Decreased libido: 6-11% 5
• Occurs in both sexes; counsel patients proactively 5

Other frequent effects (>10%):

• Nausea (26%), diarrhea (18-21%), dry mouth (14%) 5
• Insomnia (16-25%), somnolence (13%) 5
• Sweating (7-8%) 5

Discontinuation Syndrome

Never abruptly stop SSRIs—taper gradually to prevent withdrawal 1

Symptoms: dizziness, fatigue, myalgias, headache, nausea, insomnia, paresthesias, anxiety, irritability 1

Highest risk: paroxetine > fluvoxamine > sertraline > citalopram > fluoxetine 1

Special Populations

Adolescents

• Small increased risk of suicidal ideation in patients <18 years 1
• Monitor closely, especially in first weeks of treatment 1
• Risk not elevated in non-depressed adults treated for other conditions 1

Bleeding Risk

• SSRIs increase bleeding risk, especially with NSAIDs or aspirin 1
• Monitor patients on warfarin closely when initiating/discontinuing SSRIs 5
• Rare events: ecchymosis, epistaxis, petechiae, hemorrhage 1

Drug Interactions via CYP450

SSRIs inhibit CYP2D6—reduce doses of co-administered drugs metabolized by this pathway 5

Affected drugs requiring dose reduction:

• Tricyclic antidepressants 5
• Type 1C antiarrhythmics (propafenone, flecainide) 5
• Monitor TCA levels if co-prescribed 1

When SSRIs Don't Work

For IBS, SSRIs are NOT recommended—evidence shows no significant benefit 1

For depression/anxiety with inadequate response:

• Ensure adequate trial: 8 weeks at maximum tolerated dose 1
• Consider augmentation rather than dose escalation 1
• Switch to different SSRI or SNRI if no response 1