What are the potential side effects of combining citalopram (Celexa) or escitalopram (Lexapro) with bupropion?

Combining Citalopram (Celexa) or Escitalopram (Lexapro) with Bupropion: Side Effects

Both combinations of citalopram/bupropion and escitalopram/bupropion are generally well-tolerated with low rates of serious adverse events, though you must monitor for serotonin syndrome, seizure risk, and common side effects like nausea, headache, and sexual dysfunction. 1, 2

Common Side Effects of the Combinations

The most frequently reported adverse effects when combining SSRIs (including citalopram/escitalopram) with bupropion include:

• Gastrointestinal effects: Nausea, vomiting, diarrhea, and constipation are common, with nausea being the most frequent reason for discontinuation 3
• Neurological symptoms: Headache, dizziness, tremor, and insomnia occur regularly 3
• Other common effects: Dry mouth, fatigue, sweating, and agitation 3

In clinical trials of escitalopram combined with bupropion-SR, only 6% of patients discontinued due to side effects, demonstrating good overall tolerability 1. The combination appears to have a lower burden of adverse effects compared to many other antidepressant strategies 2.

Serious Adverse Events to Monitor

Serotonin Syndrome Risk

While bupropion is not primarily serotonergic, there is documented risk of serotonin syndrome when combined with SSRIs like citalopram or escitalopram. 3, 4

Key features to monitor within the first 24-48 hours after starting or dose changes:

• Mental status changes: Confusion, agitation, anxiety 3
• Neuromuscular hyperactivity: Tremors, clonus, hyperreflexia, muscle rigidity 3
• Autonomic hyperactivity: Hypertension, tachycardia, arrhythmias, diaphoresis, shivering 3
• Advanced symptoms: Fever, seizures, unconsciousness (potentially fatal) 3

The mechanism involves bupropion's inhibition of cytochrome P450 2D6, which increases blood levels of SSRIs and can precipitate serotonin syndrome 4. One case report documented a patient on therapeutic doses of bupropion and sertraline who developed serotonin syndrome, with symptoms initially misinterpreted as worsening depression 4.

Seizure Risk

Bupropion carries an increased risk of seizures, particularly at higher doses 3. When combined with SSRIs, monitor for:

• Dose-dependent seizure risk (keep bupropion ≤400 mg/day) 1
• Avoid in patients with seizure disorders or conditions that lower seizure threshold 3

Cardiovascular Effects

Citalopram specifically carries risk of QT prolongation and should not exceed 40 mg/day (20 mg/day in adults >60 years). 3

• Citalopram may cause Torsade de Pointes, ventricular tachycardia, and sudden death at doses >40 mg/day 3
• Avoid in patients with long QT syndrome 3
• Both medications can cause elevated blood pressure and heart rate 3
• Escitalopram has less effect on QT interval than citalopram 3, 5

Bleeding Risk

SSRIs including citalopram and escitalopram increase bleeding risk, especially with concurrent NSAIDs or aspirin 3. Rare events include ecchymosis, epistaxis, petechiae, and hemorrhage 3.

Suicidality

SSRIs are associated with increased risk of nonfatal suicide attempts (odds ratio 1.57-2.25) 3. Monitor closely, especially in patients under 25 years of age during the first 1-2 months of treatment or after dose increases 3.

Drug Interaction Considerations

Escitalopram has the least effect on CYP450 enzymes compared to other SSRIs and therefore has lower propensity for drug interactions, making it preferable to citalopram when combining with bupropion. 3, 5

• Citalopram/escitalopram have minimal CYP450 interactions compared to other SSRIs 3
• Bupropion inhibits CYP2D6, which can increase SSRI levels 4
• Start with low doses and titrate slowly to minimize interaction risks 3

Discontinuation Syndrome

While less common with citalopram than paroxetine, discontinuation syndrome can occur with abrupt cessation 3. Symptoms include:

• Dizziness, fatigue, lethargy, myalgias 3
• Nausea, vomiting, diarrhea 3
• Anxiety, irritability, agitation 3
• Sensory disturbances and paresthesias 3

Clinical Advantages

Despite these risks, the combination offers benefits:

• Sexual dysfunction: Bupropion can reverse SSRI-associated sexual side effects 3, 2
• Enhanced efficacy: Response rates of 62% and remission rates of 50% have been reported with escitalopram/bupropion combination 1
• Better tolerability: Escitalopram is generally better tolerated than other antidepressants with faster onset of action 5

Practical Dosing to Minimize Side Effects

Based on clinical trial data 1:

• Start escitalopram at 10 mg/day
• Add bupropion-SR at 150 mg/day after week 1
• Maximum escitalopram: 20 mg/day (achieved by week 6)
• Maximum bupropion-SR: 400 mg/day (achieved by week 8)
• Titrate slowly in 1-2 week intervals for shorter half-life SSRIs 3