Mirtazapine is mainly used as a second or third line antidepressant. However, it has many other beneficial uses, ranging from the treatment of anxiety and insomnia to improving symptoms of OCD and PTSD. It is a drug with a complex mechanism of action, but it shows promising results in a number of off-label uses.

Disclaimer: By writing this post, we are not recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it, and we are simply providing information that is available in the clinical and scientific literature. Please discuss your medications with your doctor.

What is Mirtazapine?

Mirtazapine also sold under the brand name Remeron, is a medication primarily used in the treatment of major depression/major depressive disorder (MDD) and was approved by the FDA for this indication in 1996.

Mirtazapine is not often used as first-line treatment, however, it is a particularly useful choice in patients who have had sexual dysfunction while using other antidepressants, or patients that have insomnia in combination with their depression [1].

Mirtazapine is not only effective but generally well tolerated when it comes to side effects in comparison with other antidepressants [2].

It works quickly, with symptom relief beginning within a week. This is a faster onset compared to medications in the selective serotonin receptor inhibitor (SSRI) class [2].

It is effective for long-term use in the treatment of depression and is comparable to the effectiveness of other drugs such as amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, and venlafaxine [2].

Mechanism of Action

Mirtazapine is classified as a tetracyclic antidepressant (TeCA) and noradrenergic and specific serotonergic antidepressant (NaSSA) that blocks two classes α2-adrenergic (auto and hetero) receptors as well as 5-HT2 (A and C) and 5-HT3 receptors. These two properties cause an increase in the release of norepinephrine and decreased inhibition on serotonin-releasing neurons. This results in higher levels of norepinephrine and increased overall serotonergic signaling. It also inhibits histamine receptors (H1) [3, 4].

Mirtazapine Uses

1) Improves Depression

In eight trials (randomized controlled trials) of major depression, improvement began in the first week of treatment and was greater than placebo and equal to that of the tricyclic antidepressant (TCA) amitriptyline [5].

Mirtazapine is also as effective as trazodone in short-term randomized controlled trials of patients with moderate or severe depression, including elderly patients that also had anxiety or sleep disturbance [6].

Mirtazapine was more effective than SSRIs and the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine after two weeks and short-term therapy for major depression [7].

However, in terms of long-term efficacy, it was only equally as effective as TCAs and SSRIs in treating major depression [8, 9].

Mirtazapine combined with other antidepressants improves efficacy in the treatment of depression and, in conjunction with SNRIs, has successfully used to treat treatment-resistant major depression [10, 11].

Mirtazapine reduces depression by:
  • Blocking α2-adrenoceptors, which lead to enhanced release of norepinephrine [12].
  • Potent blocking of serotonin 5-HT2 and 5-HT3, which decreases inhibition of serotonin-releasing neurons, increasing overall serotonergic signaling [4].
  • Blocking the histamine H1 receptors, causing a sedative effect, and improvement of sleep [13].
  • Activating mu- and kappa3-opioid receptors, which reduces pain [14].
  • Decreasing glutamate in rats [15].

2) May Improve Anxiety and Panic Disorder

Mirtazapine is not usually used as a first-line treatment for anxiety disorders.

Mirtazapine is an effective treatment for many types of anxiety, and the symptoms that accompany it.

In a study (open-label) of 44 patients with a generalized anxiety disorder who had an average duration of the symptoms for 12.3 years, the positive response rate was as high as 79.5%. Approximately 44% of patients felt a full relief of symptoms. It also helped people who were previously on benzodiazepines discontinue their use [16].

Here are a few clinical examples in which mirtazapine has had a positive effect on anxiety disorders:

  • Mirtazapine reduced pre-surgery anxiety and insomnia more than placebo and comparatively to diazepam (double-blind randomized controlled trial) [17].
  • Mirtazapine reduced anxiety, sleeping difficulties, and nausea caused by chemotherapy (prospective open-label) [18].
  • Mirtazapine helped 7 out of 10 people with major depression, who also suffered from generalized anxiety disorder and panic disorder (small open-label pilot study) [19, 20].
  • Mirtazapine reduced the intensity of panic attacks in patients with panic disorder, showing effectiveness comparable to fluoxetine [21, 20, 22, 23, 21].
  • Three out of six patients with severe, chronic PTSD benefited from mirtazapine [23, 21].
  • Social anxiety was reduced in 5 out of 12 patients [24].
Mirtazapine’s Anti-Anxiety Mechanisms:
  • Blocks 5-HT2a and 5-HT3 receptors [13].
  • Significantly increased GABA and decreased glutamate (nucleus accumbens, rats) [15].

3) May Improve Memory and Thought Retention

In rat models, mirtazapine has been shown to improve memory [25].

Depressed patients often retain more negative information about themselves. In a small study (double-blind randomized controlled trial), mirtazapine caused patients to be more likely to retain positive information regarding themselves [26].

4) May Improve Chronic Pain

Antidepressants have been used as non-traditional pain relief options in patients with chronic pain and mirtazapine has shown promising results in the treatment of chronic pain. A patient’s chronic back pain did not respond to the drug amitriptyline but responded to mirtazapine [27].

Mirtazapine activates the k-opioid receptors, which may be a large contributor to the pain-relieving effects [28].

5) May Improve Symptoms of PTSD

Mirtazapine is more effective than placebo at improving specific measurements of PTSD. One study (pilot study) also concluded that mirtazapine can improve some symptoms of general anxiety disorder [29].

Another study (retrospective review) found that after four weeks, half of the patients that received mirtazapine reported a significant reduction in the severity of PTSD symptoms [30].

6) May Improve OCD Symptoms

One small study (randomized controlled trial) found that all patients responded positively to mirtazapine treatment based on the Yale-Brown Obsessive Compulsive Scale (YBOCS) and the authors concluded that mirtazapine may be an effective therapy for OCD [31].

Another study (randomized controlled trial) in 49 patient found that mirtazapine in combination with citalopram resulted in “much improved” or “very much improved” ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) by the fourth week, compared to the citalopram and placebo groups that did not see real results until the eighth week [32].

7) May Improve Headaches

A double-blind randomized controlled trial in patients with chronic tension-type headaches found that mirtazapine decreased their frequency, duration, and intensity [33].

Mirtazapine is thought to improve headaches through inhibiting histamine and 5-HT2 receptors and activating 5-HT1 receptors [34].

8) May Provide Itch and Pruritus Relief

Mirtazapine has been observed in case studies to improve itching. This is thought to be related to its ability to bind to serotonin and histamine receptors in the skin and/or brain [35].

Pruritus is the unwanted desire to scratch. In a case study, it was effective at relieving pruritus [36].

9) May Improve Sleep/Insomnia

Mirtazapine, like antihistamines, inhibits the histamine H1 receptor, which is how it is thought to cause its sedating effects [37].

In case studies mirtazapine increases deep sleep (SWS), sleep onset, and sleep continuity. Mirtazapine was shown to decrease cortisol and ghrelin throughout the night, while leptin and melatonin increased [37, 38].

Mirtazapine also improves sleep in patients with cancer and major (retrospective review) [39, 40].

However, mirtazapine was found to show a slight, but not a significant reduction in REM sleep. Tricyclic antidepressants, MAOIs, and SSRIs are all shown to strongly suppress REM sleep (retrospective review) [41, 42].

10) May Improve Low Appetite/Anorexia Nervosa Associated with Depression

Mirtazapine may have an appetite-stimulating effect in patients taking it. Weight gain and increased appetite are among the most commonly reported side effects of the medication [43].

The appetite-stimulating effects of mirtazapine and antidepressant effects of the medication show it as a promising drug in the use of patients that have anorexia caused by depression, or depression caused by anorexia [44].

Mirtazapine worked on some case studies of anorexia nervosa [45].

Mechanisms of mirtazapine-induced weight gain:
  • Blocking 5HT2C and H1 receptors [46].
  • Mirtazapine possibly reduces the energy your body expands, which results in weight gain [47].

Mirtazapine Side Effects

While Mirtazapine is seen as more tolerable than SSRIs, common side effects from Mirtazapine include drowsiness, dizziness, strange dreams, vision changes, dry mouth, constipation, increased appetite and/or weight gain [2].

1) Weight Gain

One study observed a significant increase in weight gain in the first week of therapy [48].

2) Liver Toxicity

Mirtazapine has shown in rare cases to cause liver damage [49, 50].

3) May Reduce Ability to Recognize Emotional Cues

Mirtazapine impaired patient’s ability to recognize fearful facial expressions. This shows that mirtazapine, similarly to SSRIs, may reduce a patient’s ability to recognize emotional cues in other people [51].

4) May Increase the Inflammatory Process

Mirtazapine increases TNF-α, which is synthesized by lymphocytes and monocytes and may increase the inflammatory process. TNF-α is the main factor in processes associated with several inflammatory diseases which could result in implications of mirtazapine treatment in these patients [52].

Contraindications

They include [3]:

  • Prior hypersensitivity reactions to mirtazapine or any of its components.
  • Mirtazapine should not be used with monoamine oxidase inhibitors (MAOIs) and a period of 14 days should be between the use of each medication if switching from one to the other due to an increased risk of serotonin syndrome.
  • Patients should not take mirtazapine while taking intravenous (IV) methylene blue or linezolid also because of an increase in the risk of serotonin syndrome.

Use During Pregnancy and Breastfeeding

The use of mirtazapine in pregnancy appears to be safe, however, it is not known if the drug is safe while breastfeeding [53].

Warnings and Cautions

  • Alcohol increases the nervous system side effects of mirtazapine.
  • Clinical worsening and suicide risk.
  • Agranulocytosis: In very rare cases agranulocytosis has been observed with mirtazapine treatment. If a patient develops a sore throat, fever, stomatitis, or other signs of infection along with a low WBC, treatment with mirtazapine should be discontinued and monitored. In the cases observed the agranulocytosis was reversed upon cessation.
  • Serotonin Syndrome: Mirtazapine should be avoided with other serotonin increasing drugs, and monitored closely in conjunction with SSRIs.
  • Angle-Closure Glaucoma: Mirtazapine should be carefully monitored in patients with angle-closure glaucoma, and in rare cases, mirtazapine could cause angle-closure glaucoma.
  • QT Prolongation and Torsades de Pointes: Caution should be exercised before starting this medication in patients with known heart disease, or family history of QT prolongation, and in concurrent use of other drugs believed to affect the QTc interval.
  • High Cholesterol: Mirtazapine may significantly elevate blood triglyceride and total cholesterol levels. Patients with preexisting high levels of fats in the blood should be monitored closely.

Drug Interactions

Mirtazapine has a number of interactions with other medications that you should be aware of [54]:

  • H2 Antagonists (cimetidine, ranitidine, etc.) decrease the breakdown of mirtazapine resulting in increased levels of the drug in the body.
  • Phenytoin and carbamazepine increase the breakdown of mirtazapine resulting in decreased levels of the drug in the body.
  • Antibiotics (macrolides: erythromycin, clarithromycin, etc.) and antifungals (metronidazole) can also cause increased levels of mirtazapine in the body when taken together.
  • Beta-blockers (metoprolol, propranolol, etc.), vasodilators (hydralazine, prazosin, doxazosin, etc.), centrally-acting antihypertensives (clonidine), ACEIs (lisinopril, captopril, etc.), calcium channel antagonists (nifedipine and verapamil), and thiazide diuretics (hydrochlorothiazide) taken with mirtazapine can increase the risk of postural hypotension (low blood pressure associated with a change in body position).
  • Anticoagulants (warfarin) can have an increased effect when taken with mirtazapine.
  • Antihistamines (chlorphenamine, hydroxyzine, promethazine, cetirizine, loratadine, etc.), phenothiazines (prochlorperazine), nabilone, and hyoscine can cause increased sedation when taken with mirtazapine.
  • Hypnotics (temazepam and promethazine), benzodiazepines (diazepam, alprazolam, lorazepam, etc.), antipsychotics (chlorpromazine, haloperidol, clozapine, and olanzapine), opioids (oxycodone, hydrocodone, codeine, morphine, etc.), and buprenorphine can also cause increased sedation when taken with mirtazapine.
  • Monoamine oxidase inhibitors (MAOIs: phenelzine and tranylcypromine), triptans (sumatriptan), lithium, fentanyl, tramadol, and St. John’s wort can increase your risk for serotonin syndrome if taken together with mirtazapine.

Mirtazapine Dosage

Mirtazapine is available as tablets and orally disintegrating tablets (ODTs). It seems to be more sedating at lower doses and more activating at higher doses. In patients simply trying to treat insomnia, it is not unheard of to use 7.5 mg. The normal starting dosage is 15 to 30 mg and can be titrated up to a maximum dosage of 45 mg [2, 3, 55].

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