What is the recommended dose of mirtazapine (Remeron) for an adult patient with insomnia, considering their age, medical history, and potential interactions with other medications?

Mirtazapine Dosing for Insomnia

For insomnia, start mirtazapine at 7.5 mg nightly at bedtime, with the option to increase to 15 mg if needed after 1-2 weeks, but do not exceed 30 mg for sleep purposes. 1, 2, 3

Evidence-Based Dosing Strategy

Initial Dose: 7.5 mg

• The optimal starting dose for insomnia is 7.5 mg taken at bedtime, which provides sedation through histamine H1 receptor blockade while minimizing adverse effects 4, 1, 3
• A landmark 2025 randomized controlled trial in older adults (age ≥65) demonstrated that mirtazapine 7.5 mg significantly reduced insomnia severity compared to placebo, with a mean ISI score improvement of -6.5 points versus -2.9 points for placebo (p=0.003) 3
• Another 2025 double-blind RCT showed that low-dose mirtazapine (7.5-15 mg) produced clinically meaningful improvement rates of 52% and recovery rates of 56% at 6 weeks, compared to only 14% for both outcomes with placebo 5

Dose Titration

• If 7.5 mg is insufficient after 1-2 weeks, increase to 15 mg nightly 1, 2, 5
• The FDA label specifies that dose changes should not occur in intervals less than 1-2 weeks to allow adequate evaluation of response 2
• Some patients in clinical trials used a flexible dosing regimen of 7.5-15 mg with optional dose doubling at week 3 if needed 6, 5

Maximum Dose for Insomnia

• Do not exceed 30 mg for insomnia treatment, as higher doses (45 mg) are reserved for depression and may paradoxically reduce sedation due to increased noradrenergic activity 4, 1, 2
• The sedating effects of mirtazapine are most prominent at lower doses (7.5-15 mg) due to preferential histamine H1 antagonism 7

Critical Implementation Requirements

Scheduled Dosing (Not PRN)

• Mirtazapine must be taken nightly on a scheduled basis, NOT as needed (PRN), because it has a 20-40 hour half-life and requires several days to reach steady-state therapeutic levels 1, 7
• The medication cannot provide immediate "on-demand" sedation like short-acting hypnotics such as zolpidem or zaleplon 1

Timing and Administration

• Take mirtazapine preferably in the evening prior to sleep 2
• The elimination half-life of 20-40 hours enables once-daily bedtime dosing 7

Combination with CBT-I

• Always implement Cognitive Behavioral Therapy for Insomnia (CBT-I) alongside mirtazapine, as pharmacotherapy should supplement—not replace—behavioral interventions 1
• CBT-I provides superior long-term outcomes with sustained benefits after medication discontinuation 1

Position in Treatment Algorithm

When to Consider Mirtazapine

• Mirtazapine is positioned as a third-line option for insomnia, after first-line benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) or ramelteon have failed 1
• Mirtazapine is particularly appropriate when comorbid depression or anxiety is present, as it simultaneously addresses both mood disorders and sleep disturbance 4, 1
• The 2002 Alzheimer's Disease Management Guidelines note that mirtazapine is "potent and well tolerated; promotes sleep, appetite, and weight gain" with a dosing range of 7.5-30 mg at bedtime 4

First-Line Alternatives

• For occasional insomnia requiring PRN treatment, consider FDA-approved short-acting options: zaleplon 10 mg (5 mg in elderly) or zolpidem 10 mg (5 mg in elderly) 1
• For scheduled nightly treatment without comorbid depression, first-line options include eszopiclone 2-3 mg, zolpidem 10 mg (5 mg elderly), or ramelteon 8 mg 1

Safety Considerations and Adverse Effects

Common Side Effects

• The most common adverse effects are sedation, increased appetite, and weight gain, which occur more frequently than with placebo 7
• In the 2025 MIRAGE trial, 6 participants in the mirtazapine group versus 1 in placebo discontinued due to adverse events, though no severe adverse events occurred 3
• The 2025 DREAMING trial noted that mirtazapine's use "may be limited by mild but clinically relevant adverse events" 5

Cardiovascular and Anticholinergic Profile

• Mirtazapine has minimal cardiovascular and anticholinergic effects, distinguishing it from tricyclic antidepressants 7
• It essentially lacks serotonergic side effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction common with SSRIs 7

Drug Interactions

• Decrease mirtazapine dose with concomitant strong CYP3A4 inhibitors (ketoconazole, clarithromycin) or cimetidine 2
• Increase mirtazapine dose with concomitant strong CYP3A inducers (carbamazepine, phenytoin, rifampin) 2
• Allow at least 14 days between discontinuing an MAOI and starting mirtazapine, and vice versa 2

Discontinuation

• Gradually taper mirtazapine rather than stopping abruptly to avoid withdrawal symptoms 2
• Adverse reactions may occur upon discontinuation or dose reduction 2

Comparative Safety Data

Versus Quetiapine

• A 2025 retrospective cohort study found that low-dose quetiapine for insomnia in older adults was associated with significantly higher rates of mortality (HR 3.1), dementia (HR 8.1), and falls (HR 2.8) compared to trazodone, and higher dementia rates (HR 7.1) compared to mirtazapine 8
• This evidence strongly supports choosing mirtazapine over quetiapine for insomnia in older adults 8

Versus Trazodone

• Mirtazapine is superior to trazodone for insomnia, as the American Academy of Sleep Medicine explicitly recommends against trazodone due to insufficient efficacy and adverse effects outweighing benefits 1, 9
• The 2025 DREAMING trial showed mirtazapine produced clinically relevant improvement while amitriptyline did not 5

Special Population Considerations

Older Adults

• The 7.5 mg starting dose is particularly appropriate for older adults (≥65 years), as demonstrated in the MIRAGE trial specifically conducted in this population 3
• Mirtazapine is safer than benzodiazepines in elderly patients due to minimal fall risk and cognitive impairment 1

Screening Requirements

• Screen for personal or family history of bipolar disorder, mania, or hypomania before initiating mirtazapine, as with all antidepressants 2

Duration of Effect

Short-Term Efficacy

• Mirtazapine demonstrates significant benefit at 6 weeks, with both the MIRAGE and DREAMING trials showing maximal effect at this timepoint 3, 5
• Sleep disturbances and anxiety symptoms may improve within the first week of treatment 7

Long-Term Considerations

• The DREAMING trial found that from 12 weeks onwards, no statistically significant differences in insomnia severity were observed between mirtazapine and placebo 5
• This suggests mirtazapine may be most effective for short-to-intermediate term use (up to 12 weeks) rather than indefinite treatment 5
• Regular reassessment is essential to determine ongoing need for medication 1