What are the considerations for a patient with Major Depressive Disorder (MDD) taking Zyprexa (Olanzapine) when initiating Wellbutrin (Bupropion)?

Initiating Wellbutrin (Bupropion) in Patients Taking Zyprexa (Olanzapine)

Direct Recommendation

Start bupropion SR at 150 mg once daily in the morning for 3 days, then increase to 150 mg twice daily (maximum 300 mg/day for MDD), with the second dose administered before 3 PM to minimize insomnia risk. 1

Critical Drug Interaction Considerations

No Major Pharmacokinetic Interactions

• Bupropion and olanzapine do not have clinically significant pharmacokinetic interactions, as bupropion is primarily metabolized by CYP2B6 and inhibits CYP2D6, while olanzapine is metabolized through different pathways (primarily CYP1A2 and glucuronidation). 2
• However, both medications can lower the seizure threshold, requiring heightened vigilance when used together, particularly if other risk factors are present (history of head trauma, brain lesions, alcohol use). 1

Seizure Risk Management

• The maximum daily dose must not exceed 450 mg/day to maintain seizure risk at 0.1% (1 in 1,000), though for most MDD patients, 300 mg/day is the target therapeutic dose. 1
• Avoid bupropion entirely if the patient has: active seizure disorder, eating disorders (bulimia/anorexia), or is abruptly discontinuing alcohol, benzodiazepines, or antiepileptic drugs. 1

Specific Titration Protocol

Initial Dosing Strategy

• Begin with 37.5 mg every morning and increase by 37.5 mg every 3 days if the patient is elderly, medically complex, or on multiple psychotropic medications to assess tolerability. 1
• For most patients, start with 150 mg once daily for 3 days, then advance to 150 mg twice daily (total 300 mg/day). 1

Timing Considerations

• Administer the first dose in the morning to leverage bupropion's activating properties, which can improve energy levels and reduce apathy. 1
• Give the second dose before 3 PM to prevent insomnia, a common side effect that may be particularly problematic in patients already taking olanzapine (which typically causes sedation). 1

Monitoring Requirements

Early Assessment (Weeks 1-2)

• Begin monitoring within 1-2 weeks of initiation for worsening depression, suicidal ideation, agitation, irritability, or unusual behavioral changes, as the risk for suicide attempts is greatest during the first 1-2 months of treatment. 3, 1
• Monitor blood pressure and heart rate, especially in the first 12 weeks, as bupropion can cause elevations in both parameters. 1

Efficacy Assessment (Weeks 6-8)

• Allow 6-8 weeks at an adequate dose before determining treatment response; if no adequate response occurs by this timeframe, modify the treatment approach. 3, 1
• Note that bupropion may produce more rapid improvement in energy levels compared to other antidepressants, sometimes within the first few weeks, though full antidepressant effect still requires 6-8 weeks. 1

Clinical Advantages of This Combination

Complementary Mechanisms

• Bupropion works via noradrenergic/dopaminergic pathways, providing a different mechanism than olanzapine's dopamine antagonism, potentially addressing residual depressive symptoms in patients with MDD. 2, 4, 5
• Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs and causes minimal weight gain or even weight loss, which may counterbalance olanzapine's metabolic side effects. 1

Specific Patient Populations That Benefit

• Patients with depression characterized by low energy, apathy, or hypersomnia are ideal candidates for bupropion due to its activating properties. 1
• Patients who also smoke may benefit from bupropion's dual indication for smoking cessation and depression. 1

Critical Safety Precautions

Absolute Contraindications

• Do not use naltrexone-bupropion combination products if the patient is on any opioid therapy, as naltrexone will precipitate severe withdrawal. 1
• Uncontrolled hypertension should preclude bupropion use, particularly given that olanzapine can also affect cardiovascular parameters. 1

Relative Contraindications

• Use extreme caution if the patient has any condition predisposing to seizures beyond those explicitly contraindicated, including history of stroke, brain tumor, or significant head trauma. 1
• Monitor closely for increased agitation, as bupropion is an activating medication and may exacerbate agitation in some patients. 1

Dose Adjustments for Special Populations

Hepatic Impairment

• For moderate to severe hepatic impairment, do not exceed 150 mg daily (one tablet), as bupropion is extensively metabolized by the liver. 1

Renal Impairment

• For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by 50%, as bupropion and its metabolites are cleared renally and may accumulate. 1

Older Adults

• Start with 37.5 mg every morning, increasing by 37.5 mg every 3 days as tolerated, with a maximum of 150 mg twice daily (300 mg total daily dose). 1

Second-Step Strategies if Inadequate Response

Augmentation vs. Switching

• If bupropion monotherapy fails after 6-8 weeks, augment with an SSRI or SNRI rather than switching, as augmentation demonstrates superior efficacy and avoids discontinuation symptoms. 3, 1
• The STAR*D trial showed similar efficacy between various switch strategies (bupropion SR, sertraline, venlafaxine XR) with response rates of 21-28%, suggesting no clear advantage to switching over augmentation. 3
• Augmenting citalopram with bupropion showed significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone augmentation (20.6%, P < 0.001). 3

Common Pitfalls to Avoid

• Do not discontinue treatment prematurely before 6-8 weeks unless significant adverse effects occur, as full antidepressant effect requires adequate time. 1
• Do not exceed 450 mg/day total dose to maintain seizure risk at 0.1%, even if response is suboptimal—instead, consider augmentation strategies. 1
• Do not administer the second dose late in the day, as this significantly increases insomnia risk, which may compound sleep issues in patients with MDD. 1
• Be aware of historical bioequivalence issues with some generic bupropion SR formulations; monitor closely when switching between brand and generic or between SR and XL formulations. 1