Mechanism of action and pharmacokinetics
Mirtazapine has a tetracyclic structure and is classified as a noradrenergic and specific serotonergic antidepressant (NSSA). Acting as an antagonist of “inhibitory” central presynaptic α-2 autoreceptors, interfering with negative feedback and causing the release of norepinephrine. Blockade of heteroreceptors, α-2 receptors contained in serotonin neurons, enhances the release of serotonin, increasing the interaction between serotonin and 5-HT1 receptors and thereby promoting the anxiolytic effect of mirtazapine. Mirtazapine also acts as a weak antagonist of 5-HT1 receptors and as a strong antagonist of 5-HT2 (especially subtypes 2A and 2C) and 5-HT3 receptors. Blockade of these receptors may explain the lower incidence of side effects such as anxiety, insomnia and nausea, which are common with SSRI antidepressants. Mirtazapine also exhibits significant antagonism at histamine H1 receptors, resulting in sedation. Mirtazapine does not affect the reuptake of norepinephrine and serotonin, and also has minimal activity at dopaminergic and muscarinic receptors.
- Bioavailability about 50%
- Equilibrium concentration in the blood is established after 3–4 days
- Half-life 20-40 hours
- Actively metabolized in the liver by demethylation and oxidation followed by conjugation
- Metabolized by cytochromes P450 2D6, P450 1A2 and P450 3A4.
- Eating does not affect absorption
Relevance
Depression is one of the main factors that determine our health.
Unfortunately, more and more individuals are susceptible to this disease and, according to preliminary data, by 2030 depression will become the leading cause of disability in countries with a high level of economic development. Typically, the first step in drug therapy for depression is the prescription of antidepressants. But monotherapy is not effective in all cases. Researchers in the UK conducted a multicentre phase 3 trial to evaluate the effectiveness of combining mirtazapine (a tricyclic antidepressant) with a serotonin reuptake inhibitor (SSRI) or a serotonin-noradernaline reuptake inhibitor (SNRI) in the treatment of treatment-resistant depression.
Treatment regimen
◊ Dosage and dose selection
- For depression: 15-45 mg/day
- Initial dose – 15 mg in the evening; increase every 1-2 weeks until the effect is achieved; maximum – 45 mg/day
- Sedation will not increase with increasing dose
- Crushing the 15 mg tablet into two halves will increase sedation [1].
- For hot flashes: 7.5 mg-60 mg
- Insomnia/PTSD: 15-45 mg
- If anxiety, insomnia, agitation, or akathisia occur at the beginning of treatment or after interruption of treatment, the possibility of bipolar disorder should be considered and switched to a mood stabilizer or an atypical antipsychotic
◊ How quickly it works
- In patients with insomnia and anxiety, it may take immediate effect.
- Begins to act after 2-4 weeks
- If there is no effect after 6-8 weeks, you need to increase the dose or switch to another drug
- To prevent relapse, it can be taken for many years.
◊ Expected result
- Complete remission.
- After the symptoms of depression disappear, you should continue taking it for one year if this was the treatment of the first episode. If this is to treat a recurrent episode, treatment can be extended indefinitely.
- Use in the treatment of anxiety may be indefinite.
◊ If it doesn't work
- Change the dose, switch to another medicine or add an auxiliary drug;
- Connect psychotherapy;
- Review the diagnosis by identifying comorbid conditions;
- In patients with undiagnosed bipolar affective disorder, the effectiveness of treatment may be low, in which case it is necessary to switch to a mood stabilizer [1].
◊ How to stop taking it
It can be reduced gradually, but there is no need [1].
◊ Treatment combinations
- For fatigue, drowsiness, loss of concentration: modafinil [3].
- Use combinations with other antidepressants with caution because they may precipitate bipolar disorder and suicidal ideation.
- Combination with venlafaxine (“California Rocket Fuel”) is a strong combination, but watch for risk of bipolar disorder and suicidal ideation [1]
- Benzodiazepines
- For bipolar depression, psychotic depression, treatment-resistant depression, treatment-resistant anxiety disorder: mood stabilizers, atypical antipsychotics
- For anxiety disorder: gabapentin, tiagabine
Mirtazapine Canon (15mg, 30mg, 45mg)
Pediatric patients
Mirtazapine should not be used in children and adolescents under 18 years of age. Suicidal behavior (suicide attempts and suicidal ideation) and hostility (primarily aggression, oppositional behavior and anger) were observed significantly more often in clinical trials in children and adolescents taking antidepressants compared with age-matched patients taking placebo. If, based on clinical need, a decision is made to use the drug, the appearance of suicidal symptoms in patients should be carefully monitored. In addition, there are no long-term safety data regarding growth, maturation, and cognitive and behavioral development in children and adolescents.
Suicide/suicidal thoughts or clinical worsening of the disease
Any depressive disorder itself increases the risk of suicidal thoughts and behavior. This risk persists until significant remission is achieved. Since improvement may not occur during the first few weeks of therapy (or longer), patients should be closely monitored until improvement occurs. Clinical observations indicate that the risk of suicide may increase in the early stages of recovery.
Patients who have a history of suicidal behavior, as well as patients who had significant suicidal intentions before starting therapy, are at increased risk of developing suicidal thoughts or suicide attempts and should be closely monitored. A meta-analysis of results obtained from placebo-controlled clinical trials of antidepressants in adult patients with mental disorders revealed a higher risk of suicidal behavior in patients receiving antidepressants compared with the placebo group in the age group under 25 years.
Patients receiving antidepressant therapy (especially patients at increased risk) should be closely monitored, especially at the beginning of therapy, and also in case of dose adjustment. Patients (and their caregivers) should be warned to promptly identify any signs of clinical deterioration, suicidal behavior, suicidal ideation, or unusual behavior, and to promptly report the occurrence of these symptoms to their physician. Taking into account the possibility of suicide, especially at the beginning of therapy, the patient should be prescribed the smallest number of tablets of the drug in order to reduce the risk of overdose.
Bone marrow suppression
Cases of bone marrow suppression, usually manifested as granulocytopenia or agranulocytosis, have been reported with the use of mirtazapine. During clinical trials of the drug, reversible agranulocytosis was observed in rare cases. During post-marketing surveillance, agranulocytosis was reported in very rare cases, and in most cases it was also reversible, however, a few deaths were noted, which were reported mainly in patients over 65 years of age. The doctor should pay close attention (and inform the patient) to symptoms such as fever, sore throat, stomatitis and other signs of influenza-like syndrome; If such symptoms appear, you should stop treatment and have a blood test done.
Jaundice
If signs of jaundice appear, treatment should be stopped.
Conditions requiring medical supervision
The drug should be prescribed with caution, and patients should be monitored regularly and closely for the following conditions/diseases:
— Epilepsy and organic brain lesions.
Although clinical experience shows that epileptic seizures are rare with both mirtazapine and other antidepressants,
should be used with extreme caution in patients with epileptic
any history of seizures. Treatment must be stopped if
development or increase in the frequency of epileptic seizures.
— Liver failure
. When mirtazapine was administered orally at a dose of 15 mg, the clearance of mirtazapine was reduced by approximately 35% in patients with mild to moderate hepatic impairment compared with patients with normal hepatic function. The mean plasma concentration of mirtazapine increased by approximately 55%.
— Kidney failure
. When mirtazapine was administered orally at a dose of 15 mg in patients with moderate (creatinine clearance 10-40 ml/min) or severe renal insufficiency (creatinine clearance less than 10 ml/min), the clearance of mirtazapine was reduced by approximately 30% and 50%, respectively, compared with with healthy volunteers. The mean plasma concentrations of mirtazapine increased by 55% and 115%, respectively. In patients with mild renal failure (creatinine clearance 40-80 ml/min), no significant differences were observed compared with the control group.
— Heart disease such as conduction abnormalities, angina, and recent myocardial infarction
. In these cases, the usual precautions are necessary when prescribing mirtazapine and concomitant therapy.
— Low blood pressure.
— Diabetes
. In patients with diabetes, antidepressants may affect blood glucose levels. Adjustment of the dose of insulin and/or dose of oral hypoglycemic drugs may be required. Close monitoring is recommended.
As with other antidepressants, the following conditions may occur when using mirtazapine:
- Possible worsening of psychotic symptoms when using antidepressants to treat patients with schizophrenia or other psychotic disorders; Paranoid ideas may increase.
— The depressive phase of bipolar disorder during treatment can transform into a manic phase. Patients with a history of mania/oligomania should be closely monitored. Mirtazapine should be discontinued if the patient enters a manic phase.
— Although mirtazapine is not addictive, post-marketing experience with the drug suggests that abrupt cessation of treatment after prolonged use may sometimes cause withdrawal symptoms. Most withdrawal reactions are mild and self-limiting. The most commonly reported withdrawal symptoms were dizziness, agitation, anxiety, headache and nausea. Although these have been reported as withdrawal symptoms, it should be considered that these symptoms may be related to an underlying medical condition. Treatment with mirtazapine is recommended to be discontinued gradually (see Dosage and Administration).
— Mirtazapine should be prescribed with caution to patients with urinary disorders, including prostatic hypertrophy, as well as patients with acute angle-closure glaucoma and increased intraocular pressure (however, a negative effect of taking mirtazapine is unlikely due to the fact that the anticholinergic activity of the drug is very weak expressed).
- Akathisia/psychomotor agitation: the use of antidepressants is associated with the development of akathisia, which is characterized by subjectively unpleasant or anxious agitation with increased motor activity. These symptoms are most likely to appear during the first few weeks of treatment. Increasing the dose in this case may have a negative impact on the patient's health.
— The effect of mirtazapine on the QTc interval was assessed in a randomized, placebo-moxifloxacin-controlled clinical trial involving 54 healthy volunteers using an exposure-response analysis. This study showed that mirtazapine doses of 45 mg (therapeutic) and 75 mg (supertherapeutic) had no effect on clinically significant prolongation of the QTc interval. During post-marketing use of mirtazapine, cases of ECG QT prolongation, ventricular tachycardia (including torsade de pointes) and sudden death have been reported. However, in most cases, these symptoms were observed in the setting of an overdose or in patients with other risk factors for prolongation of the QTc interval, including simultaneous use of two or more drugs that cause prolongation of the QT interval (see sections Interactions with other drugs and Side effects). Caution should be exercised when prescribing mirtazapine to patients with cardiovascular disease, a family history of prolonged QT interval, or concomitant therapy with other drugs that may cause QTc prolongation.
- Hyponatremia. Extremely rare cases of hyponatremia have been reported with the use of mirtazapine. In patients at risk (elderly patients or patients taking drugs that can cause hyponatremia), Mirtazapine Canon should be prescribed with caution.
- Serotonin syndrome. With the simultaneous use of selective serotonin reuptake inhibitors and other serotonergic drugs, serotonin syndrome may occur (see section Interactions with other drugs). Symptoms of serotonin syndrome may include fever, rigidity, myoclonus, autonomic nervous system disturbances with possible rapid fluctuations in vital signs, mental status changes including confusion, irritability, and severe agitation progressing to confusion and coma. Caution and close clinical monitoring should be used when these drugs are coadministered with mirtazapine. If such symptoms occur, treatment with mirtazapine should be discontinued and symptomatic treatment initiated. Post-registration experience with the drug shows that serotonin syndrome occurs very rarely in patients receiving mirtazapine monotherapy (see section Side effects).
— Use in elderly patients. Elderly patients tend to be more sensitive, especially to the side effects of antidepressants. In clinical studies, it was not noted that adverse reactions occur more often in elderly patients than in other age groups.
- Alcohol should be avoided during treatment with mirtazapine.
Impact on the ability to drive vehicles and machinery
The drug Mirtazapine Canon may reduce concentration. During treatment, you should avoid performing potentially hazardous activities that require a high speed of psychomotor reactions, such as driving vehicles or other mechanisms.
Special patient groups
◊ Patients with kidney problems
With caution [1].
◊ Patients with liver disease
- Carefully;
- Lower doses are recommended [1].
◊ Patients with heart disease
- Carefully;
- Consider the risk of low blood pressure [1].
◊ Elderly patients
For some patients, it is better to stay at low doses [1].
◊ Children and teenagers
- Safety and benefit have not been proven
- It is necessary to regularly and personally check the patient's condition, especially in the first weeks of treatment.
- Inform adults about the risks.
◊ Pregnant women
- There have been no adequate studies in pregnant women [1].
- Not recommended for pregnant women, especially in the first trimester
- All risks should be weighed and compared
◊ Breastfeeding
- The medicine passes into breast milk.
- If the infant shows signs of irritation or sedation, stop feeding or taking mianserin
- However, treatment after childbirth may be necessary, so the risks should be weighed.
Side effects and other risks
◊ Mechanism of side effects
Most side effects occur immediately after starting treatment and go away over time, while the therapeutic effects increase over time. The action on the histamine receptor explains the sedation.
◊ Side effects
- Dry mouth, constipation, increased appetite
- Sedation, unusual dreams
- Low pressure
- Dangerous side effects: seizures, blood dyscrasia, mania
- Weight gain: very common
- Sedation: very common (worsens over time)
- Sexual dysfunction: no
◊ What to do about side effects
- Wait;
- Change drug [1].
◊ Long-term use
Safely
◊Addiction
Not expected.
◊ Overdose
- Rare cases of fatal overdoses have been associated with the use of mirtazapine along with other substances
- Sedation, disorientation, memory impairment.
