Mirtazapine Generic name Available brands Available strengths and formulations Available in generic Mirtazapine Remeron, Remeron SolTab 7.5-mg, 15-mg, 30-mg, and 45-mg tablets 15-mg, 30-mg, and 40-mg orally disintegrating tablets (SolTab) Yes GENERAL INFORMATION Mirtazapine (Remeron) is a tetracyclic antidepressant that exerts its action in the brain principally by enhancing neurotransmission of the neurotransmitters serotonin and norepinephrine. It is postulated that depression and other neuropsychiatric disorders (e.g., anxiety) may be caused by low levels of the neurotransmitters serotonin, norepinephrine, or dopamine in the brain. These neurotransmitters are also known as monoamines because they share a common group (an amine group) in their chemical structures. The theory posits that deficiency in one or another of these monoamine neurotransmitters is involved in the etiology of depression. This theory that depression is due to deficiency of monoamine neurotransmitters is known as the monoamine hypothesis. The theory, however, is ineffective in explaining the cause of depression because studies have failed to consistently correlate depression with deficiency of neurotransmitters. The cause of depression is not simply deficiency of monoamine neurotransmitters, but it may be found in other areas of biology, such as genetics. Most antidepressants increase the levels of one or more neurotransmitters by their varied mechanisms of action. Some antidepressants have a direct action on the receptors of the neurotransmitter. The action of antidepressants in neurotransmission is almost immediate, but clinical response is usually more gradual. Patients may see clinical improvement within the first 2 weeks of therapy, with further improvements in their symptoms over the course of several weeks. Mirtazapine is effective for treating depression. When mirtazapine is used alone, however, patients often report oversedation, which may limit its use. Used in combination with another antidepressant, such as fluoxetine (e.g., Prozac), a selective serotonin reuptake inhibitor (SSRI), mirtazapine augments the antidepressant effects, especially for patients whose depression is difficult to treat with a single antide- 139
Page 2 of 5 ANTIDEPRESSANTS pressant. Moreover, because mirtazapine is associated with few sexual side effects, switching from an SSRI to mirtazapine or adding a low dosage of mirtazapine to an SSRI may sometimes mitigate SSRIinduced sexual side effects. The U.S. Food and Drug Administration (FDA) approved mirtazapine only for the treatment of major depressive disorder. The use of a medication for its FDA-approved indications is called its labeled use. In clinical practice, however, practitioners often prescribe medications for unapproved indications (off-label uses) when published clinical studies indicate the efficacy, and the standards of medical practice support the safety, of those treatments. Mirtazapine s off-label uses, for example, include treatment of anxiety disorders, nausea, and, at low doses, insomnia. DOSING INFORMATION The recommended starting dosage of mirtazapine is 15 mg, taken once a day, preferably in the evening prior to bedtime. After 1 2 weeks, the dose may be increased in increments of 15 mg/day at intervals of 1 2 weeks up to a maximum recommended dose of 45 mg/day. Mirtazapine is available in rapidly dissolving tablets (Remeron SolTab) for ease of swallowing. COMMON SIDE EFFECTS The most common side effects associated with mirtazapine are dry mouth, drowsiness, dizziness, elevated cholesterol and triglycerides, and weight gain. Somnolence is a frequent complaint with mirtazapine and is reported in about 54% of treated patients. Daytime sleepiness may be managed by taking a single dose close to bedtime and allowing a full night of sleep. Because sedation may impair performance, patients should be cautioned about engaging in activities that require alertness, especially operating a motor vehicle. For some patients taking mirtazapine, increased appetite and weight gain may be problematic. In controlled studies, about 17% of patients treated with mirtazapine reported increased appetite, and 7.5% of patients gained 7% or more of body weight from baseline. In addition, mirtazapine may have effects on cholesterol and triglycerides. Cholesterol may significantly increase in about 15% and triglycerides in about 6% of patients taking mirtazapine. Management of weight gain is usually accomplished by controlling appetite and diet and through exercise. Cholesterol and triglyceride levels should be checked before and periodically (at least annually) during treatment with mirtazapine. Unlike SSRIs, mirtazapine infrequently induces sexual dysfunction. It is a useful alternative to other antidepressants that cause sexual dysfunction. ADVERSE REACTIONS AND PRECAUTIONS Patients should not discontinue mirtazapine without first consulting their practitioner. It should be discontinued gradually by tapering the dose. Stopping the medication abruptly, especially after taking it regularly for long periods, may trigger discontinuation (withdrawal) symptoms, including headaches, nausea, vomiting, diarrhea, insomnia, tremors, tingling of hands and/or legs (paresthesia), and possibly other unpleasant symptoms. Patients taking mirtazapine may experience dizziness upon standing from a recumbent position, which may lead to syncope, the loss of consciousness resulting from insufficient blood flow to the brain. This is due to the opposing effect of mirtazapine on blood vessels that normally compensate for postural change, resulting in a momentary drop in blood pressure. Dizziness ensues when insufficient blood is supplied to the brain. This reaction is known as orthostatic hypotension and is occasionally seen with mirtazapine. Patients generally develop tolerance to orthostatic hypotension, but they should be cautious when rising too quickly, especially when starting therapy or when increasing doses. Elderly patients and 140
Mirtazapine Page 3 of 5 patients taking medications for high blood pressure may be more prone to orthostatic hypotension and are susceptible to syncope (fainting) and falling. Dose reduction may help ameliorate orthostatic hypotension, but reducing the dose too much may lead to reemergence of depressive symptoms. Using compression or support stockings may help with blood circulation (i.e., venous return) and offset hypotension. As a precaution, patients should be aware of positional shifts and not rise to their feet suddenly. When lying down, they should get up gradually to a sitting position before standing. If feeling lightheaded or dizzy, they should sit and wait for a minute or two before standing up to allow the blood pressure to adjust. Patients should be cautioned about a reaction known as serotonin syndrome when taking mirtazapine, which is a serotonergic medication. Serotonergic medications enhance serotonin, a neurotransmitter in the central nervous system (CNS). If excessive, serotonin syndrome ensues. Serotonin syndrome is potentially a life-threatening situation requiring immediate cessation of the offending medications and medical attention. Typical symptoms include lethargy, confusion, restlessness, flushing, profuse sweating, tremor, and uncontrollable muscular twitching and jerking. If untreated, serotonin syndrome can progress to elevated temperature and blood pressure, excessive muscle tension, muscle breakdown (rhabdomyolysis), kidney failure, coma, and death. Cases of serotonin syndrome have been reported with mirtazapine, but usually these cases involved taking two or more medications that augmented serotonin. With antidepressant therapy, there may be risks of suicidal thinking and behavior in children and adolescents with depressive disorders and other neuropsychiatric disorders. The risk with antidepressants is age related, associated with patients younger than age 24 years, and higher during the early course of treatment. The FDA advises practitioners to exercise caution when treating pediatric patients and added warnings of suicidal risk to the labeling for all antidepressants. RISK DURING PREGNANCY AND BREAST-FEEDING There are no well-controlled studies of mirtazapine in pregnant women. Its risk in pregnancy is gleaned from reported cases and animal reproductive studies. From reported cases of mothers who took mirtazapine during pregnancy, and in some cases with other psychiatric medications, mirtazapine was not associated with teratogenicity (congenital malformations). Furthermore, animal reproductive studies that exposed animals to high doses of mirtazapine during gestation showed no teratogenic effects. It is not recommended that women take mirtazapine during pregnancy, if possible. Use of mirtazapine during pregnancy may be justified if discontinuing the antidepressant poses greater known risk to the mother than the potential risk to the fetus. Some women may experience a relapse of depression if they stop their antidepressant, and relapse may pose a greater risk to the baby. Women of childbearing age should be cautioned of the potential hazards to the fetus if they become pregnant while taking this drug. Nursing mothers should not take mirtazapine because it can pass into breast milk and be ingested by the baby. If stopping the drug is not an alternative, breast-feeding should not be started or should be discontinued. POTENTIAL DRUG INTERACTIONS Some medications can interfere with the breakdown (metabolism) of mirtazapine in the liver, which may elevate its blood levels, potentially to toxic levels. Mirtazapine can also inhibit the metabolism of other drugs, thus elevating blood levels, and the drug interaction can increase the risk of toxicity of the affected drug. Examples of drugs that may block mirtazapine metabolism and increase blood levels include cimetidine, itraconazole, ketoconazole, paroxetine, fluvoxamine, and protease inhibitors for treatment of HIV (e.g., nelfinavir, ritonavir). Alternatively, drugs such as carbamazepine (e.g., Tegretol), when combined with mirtazapine, can induce the accelerated metabolism of mirtazapine and significantly decrease its blood levels, thus decreasing its efficacy. The extent of these potential drug interactions depends on other factors as well. For example, if dosing is spaced out during the day, the impact of the interaction may be less. 141
Page 4 of 5 ANTIDEPRESSANTS Antidepressants known as monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, selegiline, isocarboxazid, tranylcypromine) and the antibiotic linezolid (Zyvox) are contraindicated with mirtazapine because when combined, their serotonergic actions greatly increase the risk of serotonin syndrome. A washout period of 14 days should be allowed when stopping an MAOI before starting mirtazapine and similarly when stopping mirtazapine before introducing an MAOI. Moreover, other drugs that boost serotonin levels in the CNS have an additive effect with mirtazapine s serotonergic action and can increase risk of serotonin syndrome. Serotonergic drugs, for example, include triptans for migraine headache (e.g., sumatriptan), tramadol, serotonergic antidepressants (e.g., SSRIs, tricyclic antidepressants), and St. John s wort. OVERDOSE Relative to some other antidepressants, such as tricyclic antidepressants, mirtazapine is fairly safe in overdose. However, when multiple medications are involved in overdose, the other medications may increase the risk of more serious complications. Any suspected overdose should be treated as an emergency. The person should be taken to the emergency department for observation and treatment. The prescription bottle of medication (and any other medication suspected in the overdose) should be brought along as well because the information on the prescription label can be helpful to the treating practitioner in determining the number of pills ingested. The American Association of Poison Control Centers (www.aapcc.org) can also be contacted via their helpline at 1-800-222-1222, and they can provide the location of the local poison center. TREATMENT SUMMARY The risk of suicide is inherent in depression and may persist until the individual responds to treatment. After starting or changing antidepressant therapy, the person, especially a child or adolescent, should be closely observed for signs of worsening depression, and the family or caregiver should communicate any concerns to the practitioner. Warning: Always let your practitioner or a family member know if you have suicidal thoughts. Notify your practitioner whenever your depressive symptoms worsen or whenever you feel unable to control suicidal urges or thoughts. Do not discontinue mirtazapine without consulting your practitioner. Mirtazapine should be discontinued gradually by tapering the dose. Stopping the medication abruptly may trigger discontinuation symptoms. If you miss a dose, take it as soon as possible. If it is close to the next scheduled dose, skip the missed dose and continue on your regular dosing schedule. Do not take double doses. Mirtazapine may be taken with or without food. Allow the SolTab to dissolve completely in the mouth before drinking some water. Mirtazapine is very sedating. Be aware of how the medication affects you, and exercise caution when operating a vehicle or performing tasks that require alertness. Avoid alcohol while taking mirtazapine because alcohol can increase the CNS side effects of the medication. Be aware that mirtazapine can induce dizziness and light-headedness upon standing from a recumbent position, which may lead to orthostatic hypotension. This reaction is more prone to occur when starting the medication and in elderly patients. Rise slowly and allow your body to adjust to the change in position. Keep in mind that the benefits of mirtazapine may not be noticeable right away. It may take weeks before the benefits from mirtazapine are fully achieved. 142
Mirtazapine Page 5 of 5 Store the medication in its originally labeled, light-resistant container, away from heat and moisture. Heat and moisture may precipitate breakdown of your medication, and the medication may lose its therapeutic effects. Keep your medication out of reach of children. If you have any questions about your medication, consult your medical practitioner or pharmacist. Copyright 2017 American Psychiatric Association. The purchaser of this book is licensed to distribute copies of these handouts in limited amounts. Please see copyright page for further information. The authors have worked to ensure that all information on this handout concerning drug dosages, schedules, routes of administration, and side effects is accurate as of the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community and accepted psychiatric practice. This handout does not cover all possible uses, precautions, side effects, or interactions of the drug. For a complete listing of side effects, see the manufacturer s package insert, which can be obtained from your physician or pharmacist. As medical research and practice advance, therapeutic standards may change. For this reason, and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of a physician who is directly involved in their care or the care of a member of their family. From Chew RH, Hales RE, Yudofsky SC: What Your Patients Need to Know About Psychiatric Medications, Third Edition. Arlington, VA, American Psychiatric Association Publishing, 2017 143