Mirtazapine (Remeron)

Mirtazapine is an antidepressant medication used primarily to treat major depressive disorder and other depressive illness in adults. It has a distinctive mechanism that differs substantially from SSRIs such as fluoxetine or escitalopram and SNRIs such as duloxetine.

Mirtazapine does not primarily block the serotonin transporter (SERT) or norepinephrine transporter (NET). Instead, it changes serotonin and norepinephrine signaling mainly by blocking:

• Alpha-2 adrenergic receptors
• 5-HT2 serotonin receptors
• 5-HT3 serotonin receptors
• Histamine H1 receptors Its strong H1 receptor blockade helps explain why mirtazapine frequently causes sleepiness and increased appetite.

Health Canada currently lists Remeron and Remeron RD as marketed, along with several generic mirtazapine products.

What You Need to Know About Mirtazapine

Mirtazapine is sometimes described pharmacologically as a:

Noradrenergic and Specific Serotonergic Antidepressant — NaSSA

Rather than simply increasing serotonin everywhere, mirtazapine modifies several receptor systems simultaneously.

A simplified mechanism is:

1. Mirtazapine
2. Blocks presynaptic α2 adrenergic receptors
3. Norepinephrine + serotonin signaling increases

while simultaneously:

1. 5-HT2 + 5-HT3 receptors are blocked
2. Serotonin signaling is redirected through other pathways

and:

1. H1 histamine receptors are blocked
2. Sedation + increased appetite may occur
3. Depressive symptoms may improve

The exact mechanism responsible for mirtazapine’s antidepressant effect is not fully established, but α2 antagonism with enhanced noradrenergic and serotonergic activity is considered central to its pharmacology.

What Is Mirtazapine Used For?

In Canada, Remeron is indicated for the symptomatic relief of depressive illness. Its efficacy in maintaining a response in major depressive disorder has also been demonstrated during longer-term treatment. It is not indicated in Canada for patients under 18 years of age.

Mirtazapine may help improve symptoms such as:

• Persistent low mood
• Loss of interest or pleasure
• Anxiety associated with depression
• Difficulty sleeping
• Reduced appetite
• Low energy
• Difficulty concentrating
• Negative or repetitive thinking Although mirtazapine is often prescribed when depression occurs together with insomnia or poor appetite, those features do not mean that mirtazapine is specifically approved as a sleeping medication or appetite stimulant.

Is Mirtazapine an SSRI?

No.

SSRIs such as:

• Escitalopram
• Fluoxetine
• Sertraline
• Fluvoxamine primarily work by blocking:

SERT — Serotonin Transporter

Mirtazapine does not primarily work this way.

Instead:

SSRI

1. SERT blockade
2. Serotonin reuptake decreases

while:

Mirtazapine α2 receptor blockade

• Norepinephrine and serotonin release increases

5-HT2 and 5-HT3 receptors are blocked

This produces a distinctly different pharmacological profile.

Is Mirtazapine an SNRI?

No.

An SNRI such as duloxetine or venlafaxine directly inhibits:

SERT + NET

Mirtazapine does not significantly inhibit either transporter as its principal mechanism.

Instead, it increases noradrenergic and serotonergic transmission primarily through:

Presynaptic α2 receptor antagonism

How Does Mirtazapine Work?

Mirtazapine blocks inhibitory:

Alpha-2 adrenergic autoreceptors

and:

Alpha-2 adrenergic heteroreceptors

These receptors normally function partly as a feedback brake on neurotransmitter release.

When mirtazapine blocks them:

1. α2 inhibitory receptors blocked
2. Feedback inhibition decreases

• Norepinephrine release increases
• Serotonergic activity increases Mirtazapine simultaneously blocks:

5-HT2

and:

5-HT3

serotonin receptors.

It has little significant affinity for 5-HT1A and 5-HT1B receptors.

Why Is Mirtazapine Different from Most Antidepressants?

Mirtazapine’s receptor profile is unusual because it simultaneously affects:

Norepinephrine

through α2 receptor blockade

Serotonin

through increased release and selective receptor blockade

Histamine

through strong H1 receptor blockade

This means its therapeutic and adverse-effect profile differs considerably from conventional serotonin reuptake inhibitors.

It is particularly associated with:

Sedation

and:

Increased appetite

rather than the nausea and sexual side effects often associated with strong SERT inhibition.

Sexual side effects can still occur with mirtazapine; they are simply not absent.

Why Does Mirtazapine Make You Sleepy?

One of mirtazapine’s strongest pharmacological actions is blockade of:

Histamine H1 Receptors

Histamine in the brain promotes:

• Wakefulness
• Alertness
• Arousal When H1 receptors are blocked:

1. Mirtazapine
2. H1 receptor blockade
3. Histamine-mediated wakefulness decreases
4. Sleepiness and sedation

This effect is substantial.

In controlled trials, somnolence was reported in approximately:

54% of mirtazapine-treated patients

compared with:

18% receiving placebo.

For this reason, mirtazapine is generally taken:

In the evening before sleep.

Is Mirtazapine a Sleeping Pill?

No.

Mirtazapine is an: Antidepressant not a conventional hypnotic or sleeping medication.

However, its strong H1 antihistamine activity can produce significant sedation.

Clinicians therefore sometimes use mirtazapine when depression occurs together with:

• Insomnia
• Frequent nighttime awakening
• Poor appetite
• Weight loss Using mirtazapine solely for insomnia would generally be an off-label clinical use.

Is a Lower Dose of Mirtazapine More Sedating?

It is often stated that:

7.5 or 15 mg is more sedating than 30 or 45 mg

because H1 blockade is prominent at lower doses while greater noradrenergic activity may emerge as the dose rises.

There is a pharmacological rationale for this idea, but the clinical dose-sedation relationship is not sufficiently consistent to treat it as a rule.

Mirtazapine can cause substantial sedation at:

• 15 mg
• 30 mg
• 45 mg Therefore a patient’s dose should not be increased simply to reduce sedation without clinical supervision.

The safest description is:

Sedation is often prominent at lower therapeutic doses, but individual responses vary and higher doses are not reliably non-sedating.

Why Does Mirtazapine Increase Appetite?

Histamine and serotonin both participate in regulation of:

• Hunger
• Satiety
• Food reward
• Body weight Mirtazapine blocks:

H1 receptors

and:

5-HT2 receptors

including effects within receptor systems involved in appetite regulation.

The result can be:

1. H1 + serotonergic receptor blockade
2. Appetite increases
3. Food intake may increase
4. Weight gain may occur

In controlled studies:

• Increased appetite occurred in about 17%
• Reported weight gain occurred in about 12%
• Weight gain of at least 7% of body weight occurred in approximately 7.5% of mirtazapine-treated patients.

Does Mirtazapine Cause Weight Gain?

Yes, it can.

Weight gain is one of the more characteristic adverse effects of mirtazapine.

Potential contributors include:

• Increased appetite
• H1 receptor blockade
• Changes in satiety signaling
• Increased caloric intake
• Sedation and reduced activity in some patients Not everyone gains weight, but weight should be monitored during longer-term treatment.

Can Mirtazapine Affect Cholesterol and Triglycerides?

Yes.

In controlled studies, increases in:

Cholesterol

and:

Triglycerides

were observed in some mirtazapine-treated patients.

Some of these changes may be related to increased appetite and food intake.

For patients with:

• Obesity
• Diabetes
• High cholesterol
• High triglycerides
• Cardiovascular risk periodic metabolic monitoring may be appropriate.

What Are the Common Side Effects of Mirtazapine?

Common side effects include:

• Sleepiness or sedation
• Increased appetite
• Weight gain
• Dry mouth
• Constipation
• Dizziness
• Fatigue or weakness
• Abnormal dreams
• Occasionally confusion or cognitive slowing
• Peripheral edema in some patients In short-term controlled trials, prominent adverse effects included somnolence, increased appetite, weight gain and dizziness. Dry mouth and constipation were also common.

Why Does Mirtazapine Cause Dry Mouth and Constipation?

Mirtazapine has some:

Muscarinic receptor antagonism

although its anticholinergic activity is weaker than that of many tricyclic antidepressants.

This can contribute to:

• Dry mouth
• Constipation
• Occasionally urinary difficulty
• Blurred vision in susceptible patients Its H1 antihistamine activity may contribute as well.

Can Mirtazapine Cause Dizziness or Low Blood Pressure?

Yes.

Mirtazapine has some antagonistic activity at:

Peripheral α1 adrenergic receptors

Alpha-1 receptors help maintain vascular tone and blood pressure.

Therefore:

1. Mirtazapine
2. α1 receptor blockade
3. Blood vessels may dilate
4. Blood pressure may fall when standing

Possible symptoms include:

• Dizziness
• Lightheadedness
• Weakness
• Faintness This is called:

Orthostatic Hypotension

Mirtazapine’s α1 antagonism is recognized as a possible explanation for orthostatic hypotension.

Can Mirtazapine Cause Sexual Side Effects?

Yes, although sexual dysfunction is generally less prominent in mirtazapine’s clinical profile than with strong serotonin-reuptake inhibitors.

Possible effects can include:

• Reduced libido
• Sexual dysfunction
• Changes in arousal or orgasm Mirtazapine’s blockade of 5-HT2 receptors may reduce some of the serotonin-mediated sexual effects associated with SERT inhibition, but this does not guarantee freedom from sexual side effects.

Can Mirtazapine Help Anxiety?

Mirtazapine may reduce anxiety symptoms when they occur as part of depression, and it is used off-label in some anxiety disorders.

Potentially relevant mechanisms include:

• 5-HT2 blockade
• 5-HT3 blockade

Changes in serotonergic signaling

and:

Sedation through H1 blockade

However, its principal Canadian approved indication remains:

Depressive illness

rather than a specific anxiety disorder.

Can Mirtazapine Cause Serotonin Syndrome?

Rarely, yes.

Although mirtazapine does not inhibit SERT like an SSRI, it does modify serotonergic neurotransmission.

Serotonin syndrome is more concerning when mirtazapine is combined with other serotonergic medications.

Possible interacting drugs include:

• SSRIs

• SNRIs

• Tricyclic antidepressants

• Tramadol

• Lithium

• Buspirone

• Triptans

• St. John’s Wort

• Other serotonergic medications Symptoms can include:

• Agitation

• Confusion

• Sweating

• Fever

• Rapid heart rate

• Tremor

• Muscle twitching

• Hyperreflexia

• Diarrhea Canadian and U.S. prescribing information both recognize serotonin toxicity as a potentially serious adverse effect, particularly with serotonergic combinations.

Mirtazapine and MAO Inhibitors

Mirtazapine should not be combined with:

Monoamine Oxidase Inhibitors — MAOIs

because of the risk of serious serotonin-related reactions.

The Canadian Remeron monograph specifies a minimum:

2-week interval after stopping an MAOI before starting mirtazapine

and similarly recommends that an MAOI not be started until at least:

2 weeks after stopping mirtazapine.

This includes MAOI activity from medications such as:

• Phenelzine
• Tranylcypromine
• Linezolid
• Intravenous methylene blue in relevant circumstances

Can Mirtazapine Cause Low Sodium?

Rarely, yes.

Antidepressants including mirtazapine can cause:

Hyponatremia

sometimes associated with:

SIADH

Risk may be greater in:

• Older adults

• People taking diuretics

• People who are dehydrated or volume-depleted Possible symptoms include:

• Headache

• Confusion

• Weakness

• Difficulty concentrating

• Unsteadiness Severe cases can cause:

• Seizures

• Loss of consciousness

• Serious neurological complications.

Mirtazapine and Agranulocytosis

Mirtazapine can very rarely cause:

Agranulocytosis

This is a severe reduction in infection-fighting white blood cells.

In premarketing trials, agranulocytosis occurred in a very small number of patients, and very rare post-marketing cases have also been reported.

Warning symptoms can include:

• Fever
• Chills
• Sore throat
• Mouth ulcers
• Other signs of infection A patient taking mirtazapine who develops significant unexplained infection symptoms should contact a healthcare professional promptly.

A blood count may be required.

Does Mirtazapine Require Routine Blood Counts?

Unlike clozapine, mirtazapine does not generally require routine scheduled white-blood-cell monitoring in every patient.

However, a CBC or white-blood-cell assessment may be appropriate if a patient develops:

• Fever
• Persistent sore throat
• Mouth ulcers
• Recurrent infections
• Other symptoms suggesting neutropenia or agranulocytosis

Can Mirtazapine Affect the Heart?

Mirtazapine generally has a relatively modest effect on cardiac repolarization at therapeutic doses, but:

QT prolongation and torsades de pointes have been reported

particularly:

• During overdose

• In people with other QT-risk factors

• When combined with other QT-prolonging medications. Additional caution may therefore be appropriate for patients with:

• Congenital long-QT syndrome

• Significant cardiac disease

• Low potassium or magnesium

• Multiple QT-prolonging medications

Can Mirtazapine Trigger Mania?

Rarely.

Like other antidepressants, mirtazapine can potentially precipitate:

Mania

or:

Hypomania

in susceptible individuals, particularly those with bipolar disorder.

In the clinical database cited in the Canadian monograph, mania/hypomania occurred in approximately 0.2% of mirtazapine-treated patients.

Patients should generally be assessed for a history suggestive of bipolar disorder before starting antidepressant therapy.

Can Mirtazapine Cause Suicidal Thoughts?

Depression itself carries a risk of:

• Suicidal thoughts

• Self-harm

• Behavioural deterioration Antidepressant treatment also requires monitoring for new or worsening:

• Suicidal thinking

• Agitation

• Restlessness

• Behavioural changes particularly:

• Early in treatment

• After dose changes

• In younger patients The Canadian monograph emphasizes careful monitoring for behavioural and emotional changes and suicidal ideation during antidepressant treatment.

Drug Interactions

Several medication interactions are clinically important.

Alcohol

Mirtazapine can impair:

• Alertness
• Coordination
• Reaction time Alcohol can add to these effects.

Canadian prescribing information specifically states that the impairment caused by alcohol and mirtazapine is additive and advises avoiding alcohol during treatment.

Benzodiazepines and Other Sedatives

Sedating medications can produce additive effects with mirtazapine.

Examples include:

• Diazepam
• Lorazepam
• Clonazepam
• Sleep medications
• Opioids
• Sedating antihistamines
• Some antipsychotics The Canadian monograph specifically demonstrated additive motor impairment with diazepam.

The combination may increase:

• Sleepiness
• Dizziness
• Falls
• Cognitive impairment
• Driving impairment

Strong CYP3A4 Inhibitors

Mirtazapine is metabolized partly through:

CYP3A4

Strong CYP3A4 inhibitors can increase mirtazapine exposure.

Examples can include:

• Ketoconazole
• Itraconazole
• Clarithromycin
• Some antiviral medications In a pharmacokinetic study, ketoconazole increased mirtazapine:

Peak concentration by approximately 40%

and:

Overall exposure by approximately 50%.

Higher exposure may increase:

• Sedation
• Dizziness
• Other adverse effects

Carbamazepine

Carbamazepine induces hepatic drug-metabolizing enzymes, including CYP3A pathways.

Therefore:

1. Carbamazepine
2. Mirtazapine metabolism increases
3. Mirtazapine concentration decreases

In one study, carbamazepine increased mirtazapine clearance enough to produce approximately a:

Two-fold decrease in plasma mirtazapine concentrations.

This may reduce antidepressant effectiveness.

Phenytoin

Phenytoin can produce a similar enzyme-inducing effect.

Canadian pharmacokinetic data found approximately a:

Two-fold reduction in mirtazapine plasma concentration

during concomitant phenytoin treatment.

Cimetidine

Cimetidine can inhibit mirtazapine metabolism.

In a controlled study:

Mirtazapine exposure increased by approximately 60%.

Dose reassessment may therefore be appropriate when cimetidine is started or stopped.

Warfarin

Mirtazapine produced a small increase in: INR in a controlled warfarin interaction study.

Canadian labeling recommends monitoring INR when the medications are used together.

Other Serotonergic Medications

Caution is appropriate when mirtazapine is combined with medications that significantly affect serotonin.

Examples include:

• SSRIs
• SNRIs
• Tramadol
• Lithium
• Triptans
• St. John’s Wort These combinations may be clinically appropriate, but monitoring for serotonin toxicity is important.

QT-Prolonging Medications

Combining mirtazapine with other medications that prolong the QT interval can increase overall cardiac risk.

Examples can include certain:

• Antipsychotics
• Antibiotics
• Antiarrhythmics
• Other psychiatric medications The total risk should be assessed rather than evaluating mirtazapine in isolation.

Mirtazapine Dosage

Mirtazapine dosing is individualized according to:

• Depression severity
• Clinical response
• Sedation
• Appetite and weight changes
• Age
• Kidney function
• Liver function
• Other medications The current Canadian Remeron monograph recommends an initial adult dose of:

15 mg once daily

preferably:

In the evening before sleep

The usual therapeutic range is:

15–45 mg/day

with a maximum of:

45 mg/day.

Because mirtazapine has a relatively long half-life, Canadian labeling recommends that dose changes generally occur at intervals of:

At least one week.

Why Is Mirtazapine Usually Taken at Night?

The main reason is:

H1 histamine receptor blockade

which can cause substantial sleepiness.

Therefore:

1. Mirtazapine
2. H1 blockade
3. Wakefulness signaling decreases
4. Sedation

Taking the medication in the evening can reduce the impact of daytime sleepiness.

However, individual responses vary.

Can Mirtazapine Be Taken with Food?

Yes.

Food has relatively little effect on the rate or extent of mirtazapine absorption.

Mirtazapine can therefore generally be taken:

With or without food.

Consistency in daily dosing is still useful.

How Long Does Mirtazapine Stay in the Body?

Mirtazapine has an elimination half-life of approximately:

20–40 hours

and reaches steady-state concentrations in approximately:

5 days.

Its relatively long half-life supports:

Once-daily dosing

for most patients.

Does Mirtazapine Need to Be Tapered?

Generally:

Yes.

Abrupt discontinuation can produce symptoms such as:

• Dizziness
• Anxiety
• Agitation
• Abnormal dreams
• Nausea
• Vomiting
• Sweating
• Headache
• Tremor
• Fatigue
• Sensory disturbances Canadian labeling recommends a:

Gradual reduction over several weeks whenever possible

rather than abrupt cessation.

There is no single taper schedule appropriate for every person.

The taper should consider:

• Current dose
• Treatment duration
• Previous withdrawal symptoms
• Depression history
• Other medications

Is Mirtazapine Addictive?

Mirtazapine is not considered an addictive medication in the way that substances such as opioids or benzodiazepines can be.

However, the nervous system can:

Physiologically adapt to regular mirtazapine treatment

which explains why discontinuation symptoms can occur if it is stopped abruptly.

Physical adaptation is not the same as addiction.

Frequently Asked Questions About Mirtazapine

Is Mirtazapine the Same as Remeron?

Yes.

Remeron is the best-known brand name for mirtazapine.

Health Canada currently lists Remeron 30 mg as marketed and also lists marketed Remeron RD orally disintegrating mirtazapine products, along with several generics.

What Is Mirtazapine Used For?

Its principal Canadian indication is:

Depressive illness

including major depressive disorder.

Does Mirtazapine Help Sleep?

It can cause substantial sleepiness because it strongly blocks:

Histamine H1 receptors

This is why it is usually taken at night.

However, mirtazapine is an antidepressant, not primarily an approved sleep medication.

Does Mirtazapine Increase Appetite?

Yes, commonly.

In controlled studies, increased appetite occurred in approximately 17% of treated patients compared with 2% receiving placebo.

Does Mirtazapine Cause Weight Gain?

It can.

Weight gain was reported in approximately 12% of mirtazapine-treated patients compared with 2% receiving placebo in short-term controlled trials.

Does Mirtazapine Increase Serotonin?

Indirectly.

Mirtazapine does not principally block SERT.

Instead:

1. α2 receptor blockade
2. Serotonergic activity increases

while:

5-HT2 + 5-HT3 receptors are blocked

This produces a more selective serotonergic effect than simply increasing signaling at every serotonin receptor.

Does Mirtazapine Increase Norepinephrine?

It can increase central noradrenergic signaling by blocking presynaptic:

α2 inhibitory autoreceptors

These receptors normally suppress norepinephrine release.

Blocking the feedback brake can therefore enhance norepinephrine signaling.

Does Mirtazapine Increase Dopamine?

Mirtazapine is not primarily a dopamine reuptake inhibitor or dopamine receptor agonist.

However, serotonin and norepinephrine systems interact with dopamine pathways, so dopamine signaling may change indirectly in some brain regions.

Its principal established pharmacology remains:

α2 + 5-HT2 + 5-HT3 + H1 receptor antagonism

rather than direct dopamine targeting.

Does Mirtazapine Cause Less Nausea Than SSRIs?

Mirtazapine blocks:

5-HT3 receptors

The 5-HT3 receptor is strongly involved in:

• Nausea
• Vomiting
• Gastrointestinal signaling This receptor blockade provides a plausible reason mirtazapine has a different gastrointestinal profile from drugs that broadly enhance serotonergic signaling.

However, mirtazapine can still cause nausea.

Can Mirtazapine Be Used with an SSRI or SNRI?

Sometimes.

Psychiatrists may combine mirtazapine with another antidepressant in selected patients.

However, combinations can increase:

• Sedation
• Drug interactions
• Serotonergic effects and require clinical supervision.

Can Mirtazapine Be Taken with Alcohol?

Canadian product information recommends avoiding alcohol because mirtazapine and alcohol produce additive impairment of mental and motor function.

Can Mirtazapine Cause Withdrawal?

Yes.

Stopping abruptly can produce:

• Dizziness
• Anxiety
• Abnormal dreams
• Tremor
• Nausea
• Sweating
• Sensory disturbances Gradual reduction over several weeks is recommended whenever possible.

Does Mirtazapine Affect CYP2D6?

CYP2D6 helps metabolize mirtazapine, but mirtazapine is not dependent on CYP2D6 alone.

CYP3A4 and CYP1A2 also contribute.

The DPWG does not recommend a mirtazapine dose adjustment based on CYP2D6 phenotype.

Does CYP2D6 Poor Metabolizer Status Require a Lower Mirtazapine Dose?

Not routinely.

Although CYP2D6 Poor Metabolizers can have somewhat increased mirtazapine exposure, current DPWG guidance concludes that the evidence does not demonstrate enough clinical impact to justify genotype-based dose modification.

Does CYP2C19 Affect Mirtazapine?

Current DPWG evidence does not support a clinically important CYP2C19–mirtazapine interaction, and no genotype-based adjustment is recommended.

Which Genes Are Most Relevant to Mirtazapine Pharmacodynamics?

Biologically relevant candidate genes include:

• ADRA2A
• ADRA2C
• HTR2A
• HTR2C
• HTR3-related genes
• HRH1 However, none currently has an established mirtazapine genotype-based prescribing guideline.

References

• https://health-products.canada.ca/dpd-bdpp/info?code=67852&lang=eng&wbdisable=true
• [https://health-products.canada.ca/dpd-bdpp/search-fast-recherche-rapide?lang=eng&no=0143928003&no=0143928003)
• [https://health-products.canada.ca/dpd-bdpp/search-fast-recherche-rapide?lang=eng&no=0143928002&no=0143928002)
• [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b4b9b66e-87a1-4dbb-9eaf-71221bcb2265)
• https://pdf.hres.ca/dpd_pm/00075141.PDF