Is the sedative effect of mirtazapine as pronounced when increasing from 7.5mg to 15mg as it is from 0 to 7.5mg?

Sedative Effect of Mirtazapine: Dose-Response Relationship

No, the sedative effect is NOT as pronounced when increasing from 7.5mg to 15mg as it is from 0 to 7.5mg—in fact, sedation paradoxically decreases at higher doses of mirtazapine due to its unique pharmacology.

Inverse Dose-Sedation Relationship

Mirtazapine exhibits a paradoxical inverse relationship between dose and sedation, where lower doses cause MORE sedation than higher doses. 1, 2

• At very low doses (7.5mg), mirtazapine's antihistamine (H1 receptor antagonism) effects predominate, causing pronounced sedation 3
• As the dose increases to 15mg and beyond, the noradrenergic effects (α2-adrenergic receptor antagonism) become more prominent, which actually counteracts the sedative effects 1, 2
• Clinical data indicates that sedation is reported in substantially fewer patients when mirtazapine is used at appropriate dosages (≥15mg) compared to subtherapeutic dosages 2

Clinical Implications

The initial jump from 0 to 7.5mg produces the MOST sedation you will experience with mirtazapine—subsequent dose increases to 15mg typically result in LESS sedation, not more. 2, 3

• The recommended starting dosage is 15mg once daily at bedtime specifically to minimize the sedation problem that occurs at lower doses 1, 4
• Patients who start at 7.5mg often report significant drowsiness, but this typically improves (not worsens) when titrated to 15mg 2
• The therapeutic dosage range is 15-45mg daily, with sedation becoming less problematic at higher doses within this range 1, 4

Mechanism Explanation

The unique pharmacological profile explains this counterintuitive pattern:

• At 7.5mg: Potent H1 histamine receptor blockade dominates → maximal sedation 3
• At 15mg and above: Enhanced noradrenergic neurotransmission via α2-receptor antagonism becomes more prominent → increased alertness that counterbalances H1 effects 1, 2
• The elimination half-life of 20-40 hours allows once-daily bedtime dosing at any dose level 1, 4

Practical Guidance

If you are experiencing excessive sedation at 7.5mg, increasing to 15mg will likely REDUCE rather than increase this side effect. 2

• Most patients tolerate 15mg better than 7.5mg from a sedation standpoint 2
• Sleep disturbances and anxiety may improve within the first week at 15mg, while full antidepressant effects take 2-4 weeks 1
• If sedation persists at 15mg, further increases to 30mg or 45mg typically provide even less sedation 4, 5