Mirtazapine

• 1. Introduction

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  The singer Hayley Williams wrote and released a song titled Mirtazapine, describing her positive experience with the medication. Mirtazapine, sold under the brand name Remeron among others, is an atypical tetracyclic antidepressant taken by mouth. It is used primarily to treat depression, and it is often chosen when depression is complicated by anxiety or insomnia. The drug has a strange reputation among pharmacologists. It does not work the way most antidepressants are expected to work. Its sleepiness follows a dose pattern that seems to run backwards. Veterinarians prescribe it to cats and dogs. This documentary asks how a drug can treat depression without touching the usual targets. It asks why researchers still argue about whether it beats its rivals. And it follows the drug into places far from the pharmacy counter.

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• 2. Not a Reuptake Inhibitor

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  Measured against the human serotonin transporter, mirtazapine shows a binding value above 10,000 nanomolar, and the smaller that number is, the stronger the grip. That figure is essentially a shrug. Unlike many other antidepressants, mirtazapine does not inhibit the reuptake of serotonin, norepinephrine or dopamine, and it does not inhibit monoamine oxidase either.

  What it does instead is block receptors. It is a potent antagonist or inverse agonist of the α2A, α2B and α2C adrenergic receptors, of the serotonin 5-HT2A and 5-HT2C receptors, and of the histamine H1 receptor. Chemists classify it as a tetracyclic piperazine-azepine. Some describe it as a noradrenergic and specific serotonergic antidepressant, abbreviated NaSSA, though the source notes that the evidence for that label has been regarded as poor.

  The logic runs through the α2 receptors, which act largely as brakes on nerve signaling. Blocking those brakes enhances adrenergic and serotonergic transmission, especially signaling through the 5-HT1A receptor in the dorsal raphe nucleus and the hippocampus. For that reason mirtazapine has been called a functional indirect agonist of the 5-HT1A receptor. Increased activation of that receptor is thought to be a major mediator of how most antidepressants work.

  In rats, blocking the α2 and 5-HT2C receptors disinhibited dopamine and norepinephrine activity in the prefrontal cortex. Mirtazapine is also said to increase dopamine release in that region. Its strongest single activity, however, lies elsewhere, in a histamine receptor that explains why many people feel its effects within an hour of the evening dose.

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• 3. The Sleepy Dose Curve

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  A single 15 mg dose given to healthy volunteers produced over 80% occupancy of the H1 histamine receptor and intense sleepiness. Antagonism of H1 is by far the strongest thing mirtazapine does. It ranks among the most potent H1 inverse agonists of any tricyclic or tetracyclic antidepressant, and of antihistamines in general. At doses of 15 mg or less, the drug almost exclusively occupies H1, 5-HT2A and 5-HT2C receptors.

  Higher doses behave in a way that looks paradoxical. At those levels, inverse agonism of the α2A, α2B and α2C adrenergic receptors begins to offset the activity at H1. Somnolence decreases, and some patients report a subjective sensation of activation. So a larger dose can leave a person less drowsy than a smaller one.

  A 2012 review of antidepressants and sleep found a mixed record. Mirtazapine reduced the time it took to fall asleep and improved sleep quality in many people whose sleep disorders were caused by depression. Yet it could also disturb sleep in many others, especially at higher doses. Restless leg syndrome appeared in 8 to 28% of people, and REM sleep behavior disorder appeared in rare cases.

  A separate study compared 32 antidepressants from every pharmacological class. Mirtazapine was among those most likely to cause nightmare disorder, sleepwalking, restless legs syndrome, night terrors and sleep paralysis.

  Tolerance helps with the daytime problem. After a short period of chronic treatment, the H1 receptor tends to sensitize and the antihistamine effects become easier to bear. Many patients also take the dose at night, which the source describes as an effective strategy for combating drowsiness. Whether the drug is better at lifting depression than its competitors was a separate question, and regulators answered it with caution.

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• 4. Racing the Rivals

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  Mirtazapine's effects may take up to four weeks to arrive, but they can show up as early as one to two weeks. That timing is the heart of its sales pitch. A 2011 Cochrane review found a faster onset in people for whom the drug worked, measured at two weeks. By six weeks, its efficacy was about the same as other antidepressants. Another finding compared the first week of use and found an earlier onset of action than with selective serotonin reuptake inhibitors.

  The pharmacology offers an explanation. Selective serotonin reuptake inhibitors acutely increase activity at the 5-HT2A, 5-HT2C and 5-HT3 receptors, which produces anorexia, insomnia, nausea and diarrhea. Most of those effects fade as 5-HT2A receptors down-regulate and 5-HT3 receptors desensitize, often within a week or less. That delay is why those drugs act slowly and can occasionally cause acute anxiety first. Mirtazapine antagonizes the 5-HT2A receptor, and antagonists there typically induce reverse tolerance, so its antidepressant and anxiety-relieving effects can arrive sooner.

  In 2010, the National Institute for Health and Care Excellence recommended generic selective serotonin reuptake inhibitors as first-line choices. It called them "equally effective as other antidepressants and have a favourable risk-benefit ratio." For mirtazapine it found no difference on any efficacy measure. It saw a statistical advantage in remission and in reducing symptoms compared with those drugs, but not a clinical one.

  The institute did find strong evidence that patients on mirtazapine were less likely to leave treatment early because of side effects. A 2018 analysis of 21 antidepressants found them fairly similar overall. It placed mirtazapine tentatively in the more effective group, and in the middle for tolerability. The remaining question is what patients pay for that tolerability, beginning with a number: 17%.

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• 5. Side Effects and Warnings

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  Increased appetite affects 17% of people taking mirtazapine, and it sits among the very common side effects, defined as an incidence of 10% or more. Constipation, dry mouth and sleepiness complete that list. Common effects, at 1 to 10%, include weakness, confusion, dizziness, muscle twitches, swelling of the lower limbs, and abnormal lab results such as elevated transaminases, triglycerides and total cholesterol.

  The 2011 Cochrane review set the trade-offs against other drug families. Mirtazapine was more likely to cause weight gain and sleepiness. It was less likely than tricyclic antidepressants to cause tremors, and less likely than selective serotonin reuptake inhibitors to cause nausea and sexual dysfunction.

  It is also not considered to carry the risk of many side effects associated with selective serotonin reuptake inhibitors, such as insomnia, diarrhea, urinary retention and excessive sweating. It may even improve some of them when taken alongside those drugs.

  Some warnings apply to antidepressants as a group. They can paradoxically worsen depression or anxiety, or cause suicidal ideation. Despite its sedating action, mirtazapine is believed capable of this too. In the United States and certain other countries it carries a black box warning, especially for people under the age of 25. Mirtazapine may also induce arthralgia, a non-inflammatory joint pain.

  Several studies have linked mirtazapine to a higher risk of death than other antidepressants. The source judges it more likely that residual differences between people prescribed mirtazapine and those prescribed a selective serotonin reuptake inhibitor explain the gap. Stopping the drug carries its own risks, and the source recommends a gradual, slow reduction in dose.

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• 6. Overdose and Metabolism

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  Twelve deaths have been attributed to mirtazapine overdose. Its fatal toxicity index, in deaths per million prescriptions, is 3.1, with a 95% confidence interval from 0.1 to 17.2. That is similar to the figure for selective serotonin reuptake inhibitors. The source calls mirtazapine relatively safe in overdose, though slightly more toxic than most of those drugs, with citalopram the exception.

  The comparison with tricyclics is sharper. At 7 to 22 times the maximum recommended dose, mirtazapine showed no significant cardiovascular adverse effects. That fits its profile, since it has weak or no activity as an anticholinergic and none as a sodium or calcium channel blocker, unlike most tricyclic antidepressants.

  What the body does with the pill is just as precise. Oral bioavailability is about 50%, and about 85% of the drug binds to plasma proteins. The liver metabolizes it mainly through N-demethylation and hydroxylation. Conjugation occurs in the kidney, and 75% of the drug leaves in urine and about 15% in feces.

  The elimination half-life is 20 to 40 hours, regardless of dose. Desmethylmirtazapine is an active metabolite with a half-life of about 25 hours, thought to contribute 3 to 10% of the drug's overall effects. After five daily doses of 7.5 mg, steady-state serum concentrations range from 33 to 56 nanomoles per liter. At 15 mg they range from 41 to 74.

  Those figures shift when the liver or kidneys falter. Liver impairment and moderate chronic kidney disease reduce oral clearance by about 30%. Severe kidney disease reduces it by 50%.

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• 7. When Drugs Collide

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  Three liver enzymes, CYP1A2, CYP2D6 and CYP3A4, do most of the work of breaking mirtazapine down. Drugs that inhibit or induce them change its concentrations. Fluoxetine and paroxetine, which inhibit these enzymes, modestly raise mirtazapine levels. Carbamazepine, an inducer, considerably lowers them.

  Combining mirtazapine with a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor or a tricyclic is considered relatively safe as an augmentation strategy, and is often used. Fluvoxamine is the exception. Adding it may cause a significant increase in mirtazapine concentration, and the dose may need adjusting. Case reports also document serotonin syndrome when mirtazapine was combined with olanzapine, quetiapine, tramadol or venlafaxine.

  Serotonin syndrome is rare here, because mirtazapine does not have pro-serotonergic activity. There are no reports of the syndrome with mirtazapine alone, even in overdose. The 5-HT2A receptor is the predominant receptor thought to drive the syndrome, and mirtazapine is a potent antagonist there. Cyproheptadine shares that property and works as an antidote to serotonin syndrome.

  That logic explains a disputed rule. Manufacturers say mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor, and the reverse also holds. Yet adding mirtazapine to such an inhibitor does not appear to cause serotonin syndrome.

  The clonidine problem is different. A case report published in 2000 described mirtazapine counteracting clonidine and causing a dangerous rise in blood pressure. Clonidine lowers pressure by stimulating presynaptic α2 autoreceptors, which are the same receptors mirtazapine blocks. Patients abruptly stopping clonidine sometimes (20%) suffer a rapid hypertensive rebound, so adding mirtazapine can precipitate withdrawal-like effects.

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• 8. Origins and Names

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  At Organon, a team of organic chemists developed mianserin, and mirtazapine came from that same team. The difference between the two molecules is a single added nitrogen atom in one of the rings. Mirtazapine is a racemic mixture of two enantiomers, and the (S)-(+) form is known as esmirtazapine. The (S) form blocks the 5-HT2A and 5-HT2C receptors and is the stronger antihistamine. The (R)-(-) form blocks the 5-HT3 receptor, and may relieve chemotherapy-related and advanced cancer-related nausea. Setiptiline and aptazapine are also analogues.

  A published synthesis begins with a condensation of 2-chloro-3-cyanopyridine and 1-methyl-3-phenylpiperazine. Hydrolysis then turns the cyanide group into a carboxylic acid, and reduction yields an alcohol. An acid-mediated cyclisation completes the molecule.

  Organon first synthesized the drug and published the work in 1989. The Netherlands approved it for major depressive disorder in 1994. The United States followed in 1996 under the name Remeron. The patent expired in 2004 and generic versions are now available. In 2023 it was the 99th most commonly prescribed medication in the United States, with more than 6 million prescriptions. In the United States, the Food and Drug Administration approves it for major depressive disorder in adults.

  The name travels in many forms. Mirtazapine is the English and French generic name, mirtazapina in Spanish, Italian and Portuguese, and mirtazapin in German, Turkish and Swedish. Brand names run to well over a hundred, among them Avanza, Norset, Remergil, Zispin and Mi Er Ning. Many of those products have been tested for much more than depression.

  Eight case reports in five papers described mirtazapine for treating hives, as of 2017. That small body of evidence sits among a long list of off-label uses. The drug is sometimes prescribed for generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, low appetite, insomnia, itching, headaches and migraine.

  Nausea is another target. Mirtazapine significantly improves pre-existing nausea, vomiting, diarrhea and irritable bowel syndrome in affected individuals, and may serve as an inexpensive alternative to ondansetron. It has lowered drug-seeking behaviour toward methamphetamine in human and animal studies, and with substance abuse counseling it has been investigated for reducing methamphetamine use. It has also served as a hallucinogen antidote, blocking the effects of psilocybin and lysergic acid diethylamide.

  Parkinson's disease psychosis produced a notable case report. Mirtazapine reduced visual hallucinations in one patient, in line with findings that inverse agonists at the 5-HT2A receptors ease such symptoms. Researchers have also explored it for antipsychotic-induced akathisia, for autism-related secondary symptoms and for schizophrenia as an adjunct.

  Not every trial succeeded. Mirtazapine was found ineffective for sleep apnea. The BETTER-B trial tested it against severe breathlessness in patients with COPD or interstitial lung diseases, and found it ineffective and potentially harmful.

  Then there are cats and dogs. Veterinarians sometimes prescribe mirtazapine as an appetite stimulant for animals with chronic kidney disease or with appetite loss from acute post-surgical pain. It is especially useful when poor appetite and nausea occur together. Tablets are given by mouth, and an ointment is applied to the inner surface of the ear. Its most common side effects include local irritation, increased meowing and hyperactivity.

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