Mirtazapine
Encyclopedia
Mirtazapine is a tetracyclic antidepressant
(TeCA) used primarily in the treatment of depression. It is also sometimes used as a hypnotic
, antiemetic
, and appetite stimulant
, and for the treatment of anxiety
, among other indications. Along with its close analogues mianserin
and setiptiline
, mirtazapine is one of the few noradrenergic and specific serotonergic antidepressant
s (NaSSAs).
Esmirtazapine
, the (S)-(+)-enantiomer
of mirtazapine, is currently under development for the treatment of insomnia
and menopausal
symptom
s by the same company that produced mirtazapine.
of major depressive disorder. Mirtazapine has been found to be useful in the treatment of generalized anxiety disorder, social anxiety disorder
, obsessive-compulsive disorder
, panic disorder
, post-traumatic stress disorder
, seasonal affective disorder
, insomnia
, nausea
and vomiting
, diminished appetite and associated weight loss
, and itching as well, and it may be prescribed off-label for these conditions.
profile. In a major systematic review
published in 2009 which compared the efficacy and tolerability of 12 popular antidepressants, mirtazapine was found to be superior to all of the included SSRIs and SNRIs, reboxetine
, bupropion
, and mianserin
in terms of antidepressant efficacy, while it was average in regards to tolerability. Mirtazapine has been demonstrated to be superior to trazodone
as well. Mirtazapine has also been shown to be equal in efficacy to many of the TCAs, including amitriptyline
, doxepin
, and clomipramine
, but with a much improved tolerability profile. However, two other studies found mirtazapine inferior to the TCA imipramine
. One study compared the combination of venlafaxine
and mirtazapine versus the MAOI tranylcypromine
and found them to be equally effective, though the MAOI was much less tolerable in terms of side effect
s and drug interaction
s.
s of mirtazapine: dizziness
, blurred vision
, sedation
, somnolence
, malaise
/lassitude, increased appetite
and subsequent weight gain
, dry mouth, constipation
, and vivid, bizarre, lucid dream
s or nightmare
s, joint pain (arthralgia
), muscle pain (myalgia
) and back pain.
Rarer side effects: agitation
/restlessness, irritability
, aggression
, apathy
and/or anhedonia
(i.e., inability to experience pleasurable emotions), loss of interest in previously enjoyed activities, excessive mellowness or calmness
, difficulty swallowing
, shallow breathing
, decreased body temperature, miosis
, nocturnal emission
s, spontaneous orgasm
, loss of balance
, and restless legs syndrome
.
Very rare, potentially serious adverse reaction
s may include allergic reaction, edema
, fainting, seizure
s, bone marrow suppression
, myelodysplasia, and agranulocytosis
.
Mirtazapine has a lower risk to cause many of the side effects encountered with other antidepressants, such as decreased appetite
, insomnia
, nausea
and vomiting
, diarrhea
, urinary retention
, increased body temperature, increased perspiration/sweating
, mydriasis
, and sexual dysfunction
(consisting of loss of libido
and anorgasmia
).
In general, some antidepressants may have the capacity to exacerbate some patients' depression or anxiety
or cause suicidal ideation
, particularly early in the treatment. It has been proven that mirtazapine has a faster onset of antidepressant action compared to SSRIs.
s may cause a withdrawal syndrome
upon discontinuation
. It should be noted that withdrawal effects from most psychoactive drugs (such as antidepressants) are common; but may be less severe than seen with some benzodiazepines. A gradual and slow reduction in dose is recommended in order to minimize withdrawal symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety
, panic attack
s, vertigo
, restlessness, irritability
, decreased appetite
, insomnia
, diarrhea
, nausea
and vomiting
, flu-like symptoms such as allergies and pruritus, headache
, and sometimes hypomania
/mania
.
, CYP2D6
, or CYP3A4
may result in higher or lower concentrations of mirtazapine, respectively. Mirtazapine has dangerous interactions with benzodiazepines and ethanol
. According to the prescribing information, mirtazapine must not be started within two weeks of any MAOI usage; similarly, MAOIs cannot be administered within two weeks of mirtazapine. Contradictorily, a single study regarding the combination reported that it does not result in any incidence of serotonin-related toxicity.
A case report claimed that mirtazapine can be used to treat serotonin syndrome.
Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation
strategy is safe and is often used therapeutically.A case report described mirtazapine as inducing hypertension in a clonidine
-treated patient.
12 fatalities have been attributed to mirtazapine overdose in literature. However, the fatal toxicity index (FTI: deaths per million prescriptions) for mirtazapine is only 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.
/inverse agonist
at the following receptor
s:
As well as an inhibitor
of the following transporters:
All affinities listed were assayed using human
materials except those for α1-adrenergic and mACh which are for rat
tissues, due to human values being unavailable. Though not known to have ever been screened, mirtazapine may act on the 5-HT6
and α2B-adrenergic receptors as well. Notably, mianserin (which is 6-desazamirtazapine) has been shown to have high affinity for 5-HT6 and does not produce cAMP
accumulation (indicating it is an antagonist).
Antagonization of the α2-adrenergic receptors which function largely as autoreceptor
s and heteroreceptor
s enhances adrenergic
and serotonergic
neurotransmission
, notably central
5-HT1A receptor
-mediated transmission in the dorsal raphe nucleus and hippocampus
. Indirect α1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α2-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT. Because of this, mirtazapine has been said to be a functional "indirect agonist
" of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs. Unlike most conventional antidepressants, however, mirtazapine is not a reuptake inhibitor
and has no appreciable affinity for the serotonin
, norepinephrine
, or dopamine transporter
s, nor is it an MAOI or have any efficacy at inhibiting
/inducing
any other enzyme
for that matter.
Antagonism to 5-HT2C receptors appears to provide a mechanism for the treatment of depressive states. In a study mirtazapine's properties in rats were likely to be mediated by its blockade of serotonin receptors, notably 5-HT2C.
In a study the 5-HT2C receptor worked to inhibit the release of the neurotransmitter
s dopamine
and norepinephrine
in various parts of the rat brain, notably in the pleasure center
s such as the ventral tegmental area (VTA) in rats. In a study, by blocking the alpha-2-adrenergic receptors and 5-HT2C receptors, mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.
Mirtazapine's antagonism of the 5-HT2A and 5-HT2C receptors has beneficial effects on anxiety
, sleep
and appetite
, as well as sexual function regarding the latter receptor.
Additionally, antagonism of the 5-HT3 receptor, the mechanism of action of antiemetic
ondansetron
, significantly improves pre-existing symptoms of nausea
, vomiting
, diarrhea
, and general irritable bowel syndrome
in afflicted individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. Blockade of the 5-HT3 receptors has also shown to improve anxiety and to be effective in the treatment of drug addiction in several studies. Mirtazapine appears to enhance memory
function in rats as well and reverses scopolamine
-induced memory deficits in mice and rats, effects which may be attributed to 5-HT3 antagonism. In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors, leading to a host of negative changes and side effects, the most prominent of which include anorexia
, insomnia
, sexual dysfunction
(impaired libido
and anorgasmia
), nausea
, and diarrhea
, among others. As a result, mirtazapine is often used in conjunction with these drugs to reduce their side effect profile and to produce a stronger antidepressant effect.
Mirtazapine is a very strong H1 receptor antagonist and as a result, it can cause powerful sedative
and hypnotic
effects. After a short period of chronic treatment, however, the H1 receptor tends to sensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies
, pruritus, nausea
, and insomnia
in afflicted individuals; hence, this may actually be a positive thing for some. It may also contribute to weight gain
, however. Mirtazapine has very low affinity for the muscarinic acetylcholine receptor
s and therefore lacks significant anticholinergic
properties at clinically used doses.
Similarly to many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice and reduces the intensity of painful stimuli in mice, and it has been suggested that this may contribute to its antidepressant efficacy in mice. Unlike with SSRIs and similar antidepressants, however, these effects in mice may be produced through different pathways and appear to result from downstream modulation of μ
- and κ3-opioid receptor
s, an indirect action possibly related to its antagonism of the α2-adrenergic receptor.
of approximately 20–40 hours. Like most other antidepressants, because of the therapeutic-latency mirtazapine may require as long as 2–4 weeks until the therapeutic benefits of the drug become evident.
s and the (S)-(+)-enantiomer is known as esmirtazapine
.
A four step chemical synthesis
of mirtazapine has been published.
in the United States
in 1990 for the treatment of depression.
of sleep apnea
/hypopnea syndrome, headache
s such as migraine
s, tension headache
s, post-dural puncture headaches and cluster headache
s, hyperemesis gravidarum
, irritable bowel syndrome
, gastroparesis
, dysgeusia
, undifferentiated somatoform disorder
, autism
and other pervasive developmental disorder
s, and neuroleptic-induced akathisia
.
Tetracyclic antidepressant
Tetracyclic antidepressants are a class of drugs used primarily as antidepressants that were first introduced in the 1970s. They are named after their chemical structure which contains four rings of atoms and are closely related to the tricyclic antidepressants which contain three rings of...
(TeCA) used primarily in the treatment of depression. It is also sometimes used as a hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
, antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
, and appetite stimulant
Orexigenic
An orexigenic is a drug or hormone that increases appetite. This can be a naturally occurring neuropeptide hormone such as ghrelin, orexin or neuropeptide Y, or a medication which increases hunger and therefore enhances food consumption...
, and for the treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, among other indications. Along with its close analogues mianserin
Mianserin
Mianserin is a psychoactive drug of the tetracyclic antidepressant chemical class which is classified as a noradrenergic and specific serotonergic antidepressant and has antidepressant, anxiolytic, hypnotic, antiemetic, orexigenic, and antihistamine effects...
and setiptiline
Setiptiline
Setiptiline , also known as teciptiline, is a tetracyclic antidepressant which acts as a noradrenergic and specific serotonergic antidepressant...
, mirtazapine is one of the few noradrenergic and specific serotonergic antidepressant
Noradrenergic and specific serotonergic antidepressant
Noradrenergic and specific serotonergic antidepressants are a class of psychiatric drugs used primarily as antidepressants. They act by antagonizing various adrenergic and serotonin receptors, of which typically consist of α1-adrenergic and α2-adrenergic, and 5-HT2A, 5-HT2C, and 5-HT3, respectively...
s (NaSSAs).
Esmirtazapine
Esmirtazapine
Esmirtazapine is a drug which is under development by Organon for the treatment of insomnia and vasomotor symptoms associated with menopause. As of 2009 it is in phase III clinical trials...
, the (S)-(+)-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
of mirtazapine, is currently under development for the treatment of insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
and menopausal
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s by the same company that produced mirtazapine.
Medical uses
Mirtazapine's primary use is the treatmentTherapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of major depressive disorder. Mirtazapine has been found to be useful in the treatment of generalized anxiety disorder, social anxiety disorder
Social anxiety disorder
Social anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
, obsessive-compulsive disorder
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
, panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
, post-traumatic stress disorder
Post-traumatic stress disorder
Posttraumaticstress disorder is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity,...
, seasonal affective disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, diminished appetite and associated weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, and itching as well, and it may be prescribed off-label for these conditions.
Efficacy and tolerability
Mirtazapine has been found to be one of the most effective antidepressants available and has a generally tolerable side effectAdverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
profile. In a major systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
published in 2009 which compared the efficacy and tolerability of 12 popular antidepressants, mirtazapine was found to be superior to all of the included SSRIs and SNRIs, reboxetine
Reboxetine
Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...
, bupropion
Bupropion
Bupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
, and mianserin
Mianserin
Mianserin is a psychoactive drug of the tetracyclic antidepressant chemical class which is classified as a noradrenergic and specific serotonergic antidepressant and has antidepressant, anxiolytic, hypnotic, antiemetic, orexigenic, and antihistamine effects...
in terms of antidepressant efficacy, while it was average in regards to tolerability. Mirtazapine has been demonstrated to be superior to trazodone
Trazodone
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
as well. Mirtazapine has also been shown to be equal in efficacy to many of the TCAs, including amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
, doxepin
Doxepin
Doxepin is a psychotropic agent with tricyclic antidepressant and anxiolytic properties, known under many brand-names such as Aponal, the original preparation by Boehringer-Mannheim, now part of the Roche group; Adapine, Doxal , Deptran, Sinquan and Sinequan...
, and clomipramine
Clomipramine
Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
, but with a much improved tolerability profile. However, two other studies found mirtazapine inferior to the TCA imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
. One study compared the combination of venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
and mirtazapine versus the MAOI tranylcypromine
Tranylcypromine
Tranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
and found them to be equally effective, though the MAOI was much less tolerable in terms of side effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s and drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s.
Adverse effects
Common side effectAdverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
s of mirtazapine: dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, blurred vision
Blurred vision
-Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....
, sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, malaise
Malaise
Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...
/lassitude, increased appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
and subsequent weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
, dry mouth, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, and vivid, bizarre, lucid dream
Dream
Dreams are successions of images, ideas, emotions, and sensations that occur involuntarily in the mind during certain stages of sleep. The content and purpose of dreams are not definitively understood, though they have been a topic of scientific speculation, philosophical intrigue and religious...
s or nightmare
Nightmare
A nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...
s, joint pain (arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
), muscle pain (myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
) and back pain.
Rarer side effects: agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
/restlessness, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
and/or anhedonia
Anhedonia
In psychology and psychiatry, anhedonia is defined as the inability to experience pleasure from activities usually found enjoyable, e.g. hobbies, exercise, social interaction or sexual activity....
(i.e., inability to experience pleasurable emotions), loss of interest in previously enjoyed activities, excessive mellowness or calmness
Calmness
Calmness is the mental state of being free from agitation, excitement, or disturbance. Calmness can most easily occur for the average person during a state of relaxation, but it can also be found during much more alert and aware states. Some people find that focusing the mind on something external,...
, difficulty swallowing
Swallowing
Swallowing, known scientifically as deglutition, is the process in the human or animal body that makes something pass from the mouth, to the pharynx, and into the esophagus, while shutting the epiglottis. If this fails and the object goes through the trachea, then choking or pulmonary aspiration...
, shallow breathing
Shallow breathing
Shallow breathing, thoracic breathing, or chest breathing is the drawing of minimal breath into the lungs, usually by drawing air into the chest area using the intercostal muscles rather than throughout the lungs via the diaphragm. Shallow breathing can result in or be symptomatic of rapid...
, decreased body temperature, miosis
Miosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...
, nocturnal emission
Nocturnal emission
A nocturnal emission involves either ejaculation during sleep for a male, or lubrication of the vagina for a female. It is also called a wet dream, and is sometimes considered a type of spontaneous orgasm....
s, spontaneous orgasm
Orgasm
Orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
, loss of balance
Balance disorder
A balance disorder is a disturbance that causes an individual to feel unsteady, for example when standing or walking. It may be accompanied by feelings of giddiness or wooziness, or having a sensation of movement, spinning, or floating...
, and restless legs syndrome
Restless legs syndrome
Restless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...
.
Very rare, potentially serious adverse reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s may include allergic reaction, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, fainting, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, bone marrow suppression
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...
, myelodysplasia, and agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
.
Mirtazapine has a lower risk to cause many of the side effects encountered with other antidepressants, such as decreased appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, urinary retention
Urinary retention
Urinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
, increased body temperature, increased perspiration/sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, mydriasis
Mydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
, and sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
(consisting of loss of libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
and anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
).
In general, some antidepressants may have the capacity to exacerbate some patients' depression or anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
or cause suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
, particularly early in the treatment. It has been proven that mirtazapine has a faster onset of antidepressant action compared to SSRIs.
Discontinuation
Mirtazapine and other antidepressantAntidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s may cause a withdrawal syndrome
Withdrawal syndrome
A withdrawal syndrome, also called a discontinuation syndrome, occurs when a person suddenly stops taking or reduces the dosage of some types of medications...
upon discontinuation
Discontinuation
Discontinuation is the process of quitting a procedure, such as, the course of treatment with a drug or a consumer product line.*Discontinuation of a treatment is to stop taking a drug...
. It should be noted that withdrawal effects from most psychoactive drugs (such as antidepressants) are common; but may be less severe than seen with some benzodiazepines. A gradual and slow reduction in dose is recommended in order to minimize withdrawal symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, panic attack
Panic attack
Panic attacks are periods of intense fear or apprehension that are of sudden onset and of relatively brief duration. Panic attacks usually begin abruptly, reach a peak within 10 minutes, and subside over the next several hours...
s, vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, restlessness, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, decreased appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, flu-like symptoms such as allergies and pruritus, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, and sometimes hypomania
Hypomania
Hypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...
/mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
.
Interactions
Concurrent use with inhibitors or inducers of CYP1A2CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
, CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
, or CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
may result in higher or lower concentrations of mirtazapine, respectively. Mirtazapine has dangerous interactions with benzodiazepines and ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
. According to the prescribing information, mirtazapine must not be started within two weeks of any MAOI usage; similarly, MAOIs cannot be administered within two weeks of mirtazapine. Contradictorily, a single study regarding the combination reported that it does not result in any incidence of serotonin-related toxicity.
A case report claimed that mirtazapine can be used to treat serotonin syndrome.
Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation
Augmentation (psychiatry)
Augmentation is the combination of two or more drugs to achieve better treatment results....
strategy is safe and is often used therapeutically.A case report described mirtazapine as inducing hypertension in a clonidine
Clonidine
Clonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
-treated patient.
Overdose
Mirtazapine is relatively safe if an overdose is taken. Unlike the TCAs, mirtazapine shows no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose. Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively non-toxic, compared to TCAs.12 fatalities have been attributed to mirtazapine overdose in literature. However, the fatal toxicity index (FTI: deaths per million prescriptions) for mirtazapine is only 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.
Pharmacodynamics
Mirtazapine is an antagonistReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
/inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
at the following receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s:
- 5-HT2A receptor5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(Ki = 69 nM) - 5-HT2B receptor5-HT2B receptor5-hydroxytryptamine receptor 2B, also known as HTR2B, is a 5-HT2 receptor, but also denotes the human gene encoding it.-Function:...
(Ki = ? (~20-fold lower than for 5-HT2A/2C)) - 5-HT2C receptor5-HT2C receptorThe 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
(Ki = 39 nM) - 5-HT3 receptor5-HT3 receptorThe 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
(Ki = ? (similar to 5-HT2A/2C))(mouse neuroblastoma cell) - 5-HT7 receptor5-HT7 receptorThe 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin The 5-HT7 receptor is coupled to Gs and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various...
(Ki = 265 nM)
- α1-adrenergic receptor (Ki = 608 nM)(rat)
- α2A-adrenergic receptor (Ki = 20 nM)
- α2C-adrenergic receptor (Ki = 18 nM)
- H1 receptor (Ki = 1.6 nM)
- mACh receptorsMuscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
(Ki = 794 nM)(rat)
As well as an inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
of the following transporters:
- Norepinephrine transporterNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(Ki = 4,600 nM)
All affinities listed were assayed using human
Human
Humans are the only living species in the Homo genus...
materials except those for α1-adrenergic and mACh which are for rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
tissues, due to human values being unavailable. Though not known to have ever been screened, mirtazapine may act on the 5-HT6
5-HT6 receptor
The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gs/Go and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.-Distribution:The 5-HT6 receptor is...
and α2B-adrenergic receptors as well. Notably, mianserin (which is 6-desazamirtazapine) has been shown to have high affinity for 5-HT6 and does not produce cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
accumulation (indicating it is an antagonist).
Antagonization of the α2-adrenergic receptors which function largely as autoreceptor
Autoreceptor
An autoreceptor is a receptor located on presynaptic nerve cell membranes and serves as a part of a feedback loop in signal transduction. It is sensitive only to those neurotransmitters or hormones that are released by the neuron in whose membrane the autoreceptor sits.Canonically, a presynaptic...
s and heteroreceptor
Heteroreceptor
A heteroreceptor is a receptor regulating the synthesis and/or the release of mediators other than its own ligand.Heteroreceptors are presynaptic receptors that respond to neurotransmitters, neuromodulators, or neurohormones released from adjacent neurons or cells...
s enhances adrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
and serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
, notably central
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
5-HT1A receptor
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
-mediated transmission in the dorsal raphe nucleus and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. Indirect α1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α2-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT. Because of this, mirtazapine has been said to be a functional "indirect agonist
Indirect agonist
In pharmacology, an indirect agonist or indirect-acting agonist is a substance that enhances the release or action of an endogenous neurotransmitter but has no specific agonist activity at the neurotransmitter receptor itself...
" of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs. Unlike most conventional antidepressants, however, mirtazapine is not a reuptake inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
and has no appreciable affinity for the serotonin
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
, norepinephrine
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
, or dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
s, nor is it an MAOI or have any efficacy at inhibiting
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
/inducing
Enzyme induction and inhibition
Enzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
any other enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
for that matter.
Antagonism to 5-HT2C receptors appears to provide a mechanism for the treatment of depressive states. In a study mirtazapine's properties in rats were likely to be mediated by its blockade of serotonin receptors, notably 5-HT2C.
In a study the 5-HT2C receptor worked to inhibit the release of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
in various parts of the rat brain, notably in the pleasure center
Pleasure center
Pleasure center is the general term used for the brain regions involved in pleasure. Discoveries made in the 1950s initially suggested that rodents could not stop electrically stimulating parts of their brain, mainly the nucleus accumbens, which was theorized to produce great pleasure...
s such as the ventral tegmental area (VTA) in rats. In a study, by blocking the alpha-2-adrenergic receptors and 5-HT2C receptors, mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats.
Mirtazapine's antagonism of the 5-HT2A and 5-HT2C receptors has beneficial effects on anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
and appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, as well as sexual function regarding the latter receptor.
Additionally, antagonism of the 5-HT3 receptor, the mechanism of action of antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
, significantly improves pre-existing symptoms of nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, and general irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
in afflicted individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. Blockade of the 5-HT3 receptors has also shown to improve anxiety and to be effective in the treatment of drug addiction in several studies. Mirtazapine appears to enhance memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
function in rats as well and reverses scopolamine
Scopolamine
Scopolamine, also known as levo-duboisine, and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae family of plants, such as henbane, jimson weed and Angel's Trumpets , and corkwood...
-induced memory deficits in mice and rats, effects which may be attributed to 5-HT3 antagonism. In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors, leading to a host of negative changes and side effects, the most prominent of which include anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
(impaired libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
and anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
), nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, among others. As a result, mirtazapine is often used in conjunction with these drugs to reduce their side effect profile and to produce a stronger antidepressant effect.
Mirtazapine is a very strong H1 receptor antagonist and as a result, it can cause powerful sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
effects. After a short period of chronic treatment, however, the H1 receptor tends to sensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
, pruritus, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
in afflicted individuals; hence, this may actually be a positive thing for some. It may also contribute to weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
, however. Mirtazapine has very low affinity for the muscarinic acetylcholine receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s and therefore lacks significant anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
properties at clinically used doses.
Similarly to many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice and reduces the intensity of painful stimuli in mice, and it has been suggested that this may contribute to its antidepressant efficacy in mice. Unlike with SSRIs and similar antidepressants, however, these effects in mice may be produced through different pathways and appear to result from downstream modulation of μ
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
- and κ3-opioid receptor
Kappa Opioid receptor
The κ-opioid receptor is a protein that in humans is encoded by the OPRK1 gene. The κ-opioid receptor is one of five related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds...
s, an indirect action possibly related to its antagonism of the α2-adrenergic receptor.
Pharmacokinetics
Mirtazapine is typically prescribed in doses ranging from 15 mg to 45 mg. However, in severely depressed individuals, doses as high as 120 mg have been used with success. Mirtazapine has a half-lifeHalf-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of approximately 20–40 hours. Like most other antidepressants, because of the therapeutic-latency mirtazapine may require as long as 2–4 weeks until the therapeutic benefits of the drug become evident.
Chemistry
Mirtazapine is a racemic mixture of enantiomerEnantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s and the (S)-(+)-enantiomer is known as esmirtazapine
Esmirtazapine
Esmirtazapine is a drug which is under development by Organon for the treatment of insomnia and vasomotor symptoms associated with menopause. As of 2009 it is in phase III clinical trials...
.
A four step chemical synthesis
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
of mirtazapine has been published.
History
Mirtazapine was introduced by Organon InternationalOrganon International
Organon is a human pharmaceutical company headquartered in Oss, Netherlands. In November 2007 the company became a part of Schering-Plough Corporation, acquired Organon, active pharmaceutical ingredient producer Diosynth , and its veterinary pharmaceutical sister company Intervet from Akzo Nobel. ...
in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in 1990 for the treatment of depression.
Research
Mirtazapine has had literature published on its efficacy (or lack thereof) in the following areas: for the treatmentTherapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
of sleep apnea
Sleep apnea
Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
/hypopnea syndrome, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s such as migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
s, tension headache
Tension headache
A tension headache is the most common type of primary headache. The pain can radiate from the neck, back, eyes, or other muscle groups in the body. Tension-type headaches account for nearly 90% of all headaches...
s, post-dural puncture headaches and cluster headache
Cluster headache
Cluster headache, nicknamed "suicide headache", is a neurological disease that involves, as its most prominent feature, an immense degree of pain in the head. Cluster headaches occur periodically: spontaneous remissions interrupt active periods of pain. The cause of the disease is currently unknown...
s, hyperemesis gravidarum
Hyperemesis gravidarum
Hyperemesis gravidarum is a severe form of morning sickness, with "unrelenting, excessive pregnancy-related nausea and/or vomiting that prevents adequate intake of food and fluids." Hyperemesis is considered a rare complication of pregnancy but, because nausea and vomiting during pregnancy exist...
, irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
, gastroparesis
Gastroparesis
Gastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...
, dysgeusia
Dysgeusia
Dysgeusia is the distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is the decrease in taste sensitivity. An alteration in taste or smell may be a secondary process in various disease states, or it may be...
, undifferentiated somatoform disorder
Somatoform disorder
In psychology, a somatoform disorder is a mental disorder characterized by physical symptoms that suggest physical illness or injury - symptoms that cannot be explained fully by a general medical condition, direct effect of a substance, or attributable to another mental disorder . The symptoms that...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
and other pervasive developmental disorder
Pervasive developmental disorder
Pervasive developmental disorders is a diagnostic category refers to a group of disorders characterized by delays or impairments in communication, social behaviors, and cognitive development.Pervasive developmental disorders include Autism, Asperger's syndrome, Rett's syndrome, Childhood...
s, and neuroleptic-induced akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
.