Can Remeron and Clonazepam Be Combined?
Yes, mirtazapine (Remeron) can be safely combined with clonazepam, and this combination is commonly used in clinical practice, particularly when treating depression with comorbid anxiety or insomnia. The FDA label for mirtazapine does not list benzodiazepines as contraindicated, and research supports clonazepam as a therapeutic adjunct in depression management 1, 2.
Starting Dose Regimen for Adults
Start mirtazapine at 15 mg once daily at bedtime 1. This is the FDA-approved starting dose for adults without severe hepatic or renal disease. If clonazepam is being added as an adjunct:
- Clonazepam dosing: Use 0.5-1 mg initially, with therapeutic range of 2.5-6.0 mg/day when used as an antidepressant adjunct 2
- Timing: Administer mirtazapine preferably in the evening prior to sleep 1
- Dose adjustments: Do not increase mirtazapine more frequently than every 1-2 weeks; maximum dose is 45 mg/day 1
Clinical Rationale for This Combination
The combination leverages complementary mechanisms:
- Mirtazapine enhances noradrenergic and serotonergic neurotransmission while blocking 5-HT2 and 5-HT3 receptors, providing antidepressant effects with beneficial anxiolytic and sedative properties 3, 4
- Clonazepam accelerates antidepressant response and is particularly effective for treatment-resistant depression when combined with SSRIs or other antidepressants 2
Research indicates clonazepam should produce observable response within 2-4 weeks if effective, and is significantly more effective for unipolar than bipolar depression 2.
Important Safety Considerations
Screen for bipolar disorder before initiating - this is an FDA requirement for all antidepressants including mirtazapine 1. Look specifically for personal or family history of mania or hypomania.
Monitor for additive sedation - both medications cause CNS depression. The combination may impair cognitive and motor performance more than either agent alone 5. Warn patients about:
- Driving or operating machinery
- Alcohol use (avoid completely)
- Risk of falls, especially in elderly patients
Common adverse effects to anticipate:
- Somnolence and sedation (paradoxically may decrease at higher mirtazapine doses >15 mg) 6
- Increased appetite and weight gain (occurs in ~10% with mirtazapine) 7, 4
- Dry mouth 7
Specific Monitoring Requirements
While mirtazapine is generally well-tolerated, be aware of rare but serious concerns:
- Hepatic monitoring: Consider baseline and periodic liver function tests, as asymptomatic hepatotoxicity can occur even at low doses 8
- Hematologic monitoring: Rare cases of reversible neutropenia have been reported 6
- Metabolic effects: Monitor weight, glucose, and lipids, as mirtazapine can cause modest cholesterol elevations (3-4%) 5
Drug Interaction Considerations
The FDA label specifies dose adjustments may be needed with 1:
- Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) - may need to decrease mirtazapine dose
- Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin) - may need to increase mirtazapine dose
- Cimetidine - may need to decrease mirtazapine dose
Clonazepam does not significantly interact with mirtazapine's metabolism 3.
Discontinuation Strategy
Taper both medications gradually rather than stopping abruptly 1. This minimizes withdrawal symptoms and prevents rebound anxiety or insomnia. The FDA specifically warns that adverse reactions may occur upon discontinuation or dose reduction of mirtazapine 1.
Clinical Advantages of This Combination
This pairing is particularly useful when depression presents with:
- Prominent anxiety symptoms
- Severe insomnia
- Treatment-resistant features
- Need for rapid symptom relief
Mirtazapine has demonstrated early onset of action (significant improvement within 1 week in some studies) 6, and clonazepam may further accelerate response 2. Unlike SSRIs, mirtazapine causes no sexual dysfunction 3, which improves adherence.