What are the common and serious side effects of mirtazapine, its usual dosing schedule, and the recommended monitoring and management strategies?

Mirtazapine Side Effects

Mirtazapine causes sedation/somnolence (23% vs 14% placebo), increased appetite (11% vs 2% placebo), weight gain (10% vs 1% placebo), and dry mouth (25% vs 16% placebo) as its most common side effects, with these effects being more pronounced than most other antidepressants. 1, 2

Common Side Effects

Sedation and Sleep Effects

• Somnolence is the most frequently reported side effect, occurring in approximately 23% of patients compared to 14% with placebo 1
• Sedation appears paradoxically less frequent at higher dosages, as the antihistaminic (H1) activity is more prominent at low doses 3
• The sedative effects can be therapeutically beneficial when given at bedtime for patients with insomnia 1, 4
• An elimination half-life of 20-40 hours enables once-daily bedtime dosing 4

Appetite and Weight Changes

• Increased appetite occurs in approximately 11% of patients versus 2% with placebo 1
• Weight gain occurs in approximately 10% of patients versus 1% with placebo, with mirtazapine causing higher weight gain than sertraline, trazodone, or venlafaxine 1
• These effects may be attributed to antihistaminic (H1) activity at low doses 3
• Weight gain can be therapeutically beneficial in patients with anorexia, weight loss, or elderly patients with dementia and depression 1

Anticholinergic Effects

• Dry mouth occurs in approximately 25% of patients versus 16% with placebo 1, 5
• Constipation is a frequently reported gastrointestinal side effect 1
• Mirtazapine has minimal anticholinergic effects compared to tricyclic antidepressants 4, 3

Other Common Effects

• Dizziness is commonly reported 2, 6
• Mirtazapine essentially lacks gastrointestinal symptoms, insomnia, and sexual dysfunction common with SSRIs 1, 4

Serious Side Effects

Hematologic Effects

• Low white blood cell count can occur; patients should immediately report fever, sore throat, flu-like symptoms, chills, mouth and nose sores, or infections 2
• Two cases of reversible severe symptomatic neutropenia were reported in clinical trials, though no additional cases have been reported since market introduction 7

Serotonin Syndrome

• A potentially life-threatening condition that requires immediate discontinuation and emergency care 2
• Signs include agitation, confusion, fast heart beat, dizziness, flushing, tremors, stiff muscles, muscle twitching, seizures, hallucinations, coma, blood pressure changes, sweating, hyperthermia, loss of coordination, nausea, vomiting, and diarrhea 2

Cardiovascular and Metabolic Effects

• Heart rhythm problems can occur 2
• Increased fat levels (cholesterol and triglycerides) in blood 2, 8
• Mirtazapine has minimal cardiovascular effects and has been shown to be safe in patients with cardiovascular disease 1, 4
• No significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose 3

Neuropsychiatric Effects

• Mania or hypomania in people with a history of bipolar disorder, with symptoms including greatly increased energy, racing thoughts, unusually grand ideas, talking more or faster than usual, severe trouble sleeping, reckless behavior, and excessive happiness or irritability 2
• Seizures (convulsions) 2
• Angle-closure glaucoma: eye pain, changes in vision, or swelling/redness in or around the eye 2

Electrolyte Disturbances

• Low sodium levels (hyponatremia) may be serious and potentially fatal, with elderly people at greater risk 2
• Signs include headache, memory changes, weakness and unsteadiness leading to falls, difficulty concentrating, and confusion 2
• Severe cases may include hallucinations, seizures, respiratory arrest, fainting, coma, and death 2

Dermatologic Effects

• Severe skin reaction may include rash, fever, swollen glands, and other organ involvement (liver, kidney, lung, heart), which may sometimes be fatal 2

Hepatic Effects

• Changes in liver function tests may occur 2
• Transient elevations in liver function tests have been reported 8

Dosing Schedule

Standard Dosing

• The recommended starting dose is 15 mg once daily, administered orally, preferably in the evening prior to sleep 2
• If inadequate response to 15 mg, increase dose up to a maximum of 45 mg per day 2
• Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response 2

Special Populations

• For elderly, debilitated, or frail patients, consider starting at 7.5 mg at bedtime 5
• Clearance may be reduced by hepatic or renal impairment 7

Dose Adjustments for Drug Interactions

• Increase dosage with concomitant strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin); decrease if inducer discontinued 2
• Decrease dosage with concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin); increase if inhibitor discontinued 2
• Decrease dosage with concomitant cimetidine; increase if cimetidine discontinued 2

Monitoring and Management Strategies

Timeline for Assessment

• Begin assessing patient status, therapeutic response, and adverse effects within 1-2 weeks of treatment initiation 5
• If inadequate response within 6-8 weeks, treatment modification is strongly recommended 5
• Onset of clinical effect typically occurs in 2-4 weeks, though sleep disturbances and anxiety symptoms may improve in the first week 4

Treatment Duration

• Continue treatment for 4-9 months after satisfactory response in patients with first episode of major depressive disorder 5
• For patients with 2 or more episodes of depression, even longer duration may be beneficial 5

Discontinuation Management

• Gradually reduce the dosage rather than stopping abruptly whenever possible 2
• Discontinuation syndrome symptoms may include dizziness, irritability, agitation, anxiety, sweating, seizures, tinnitus, nausea, vomiting, sleep problems, tiredness, confusion, electric shock sensation (paresthesia), tremor, headache, abnormal dreams, mood changes, and hypomania 2

Special Monitoring Considerations

• Screen for personal or family history of bipolar disorder, mania, or hypomania prior to initiating treatment 2
• Monitor for signs of low white blood cell count throughout treatment 2
• Elderly patients require particular monitoring for sedation, orthostatic hypotension, and hyponatremia 1
• Monitor weight and appetite changes, which may require intervention or can be therapeutically beneficial depending on patient presentation 1
• Assess for eye symptoms if angle-closure glaucoma risk factors present 2

Drug Interactions

• At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of mirtazapine, and vice versa 2
• Mirtazapine is unlikely to inhibit metabolism of coadministered drugs metabolized by CYP1A2, CYP2D6, or CYP3A4 7
• Strong inhibitors of CYP2D6 would have no effect on racemic mirtazapine concentration 7

Administration Considerations

• Administration on an empty stomach is advised to maximize effectiveness 9
• Not recommended during pregnancy or nursing 9
• Caution advised if signs/symptoms of depression, compromised respiratory function (asthma, COPD, sleep apnea), or hepatic heart failure are present 9
• Additive effect on psychomotor performance with concomitant CNS depressants and/or alcohol use 9