Tetracyclic Antidepressants

What Are Tetracyclics?

Tetracyclic antidepressants are used to treat major depressive disorder with symptoms such as depressed mood, feelings of worthlessness, nervousness, trouble sleeping, loss of pleasure, low energy, and suicidal thoughts.^1,2

They have become less commonly prescribed, however, with the development of newer drugs. In fact, they are no longer considered a first-line treatment for depression because of their side effects. Instead, they may be used to treat severe or treatment-resistant depression, as adjunct therapeutics to be used in addition to other psychiatric medications or, in the case of mirtazapine, for the off-label management of anxiety, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and certain other conditions.^3,4

Tetracyclic agents include:

• Mirtazapine (Remeron).
• Maprotiline (Ludiomil).
• Amoxapine (Asendin; amoxapine is sometimes classified as a tricyclic).

How Do They Work?

Tetracyclics have somewhat different primary mechanisms of action. But, to varying extents, they increase activity in the serotonin and/or noradrenergic (norepinephrine) neurotransmitter systems in the brain. Serotonin is thought to play a role in emotion, mood, sleep and appetite, and norepinephrine is an important biochemical player in processes like memory and physiological arousal.^5,6

Maprotiline and mirtazapine also have pronounced antihistamine properties (i.e., inhibit the H1 receptor), which may help explain their ability to cause sedation.⁵

What Are the Side Effects?

Common side effects of mirtazapine include:^1,10

• Drowsiness.
• Increased appetite.
• Weight gain.
• Dizziness.
• Elevated cholesterol levels.
• Dry mouth.
• Constipation.

Serious side effects include: ^1,10

• Suicidal thoughts.
• Manic mood.
• Angle-closure glaucoma (eye pain, vision changes, and swelling or redness in or around the eye).
• Drug-induced agranulocytosis (dangerously low white blood cell count—can increase the risk of infection.
• Serotonin syndrome—diarrhea, confusion, tight muscles, fever, seizures, and possible death.
• Hyponatremia (low sodium levels in the blood)—can cause headache, nausea, confusion, muscle weakness, and fatigue.

Side effects of maprotiline include:^2,10

• Fatigue.
• Dizziness.
• Drowsiness.
• Blurred vision.
• Dry mouth.
• Constipation.
• Nausea.
• Orthostatic hypotension (fall in blood pressure when standing).
• Confusion.
• Urinary retention.
• Sexual dysfunction.

Serious side effects of maprotiline include:¹⁰

• Cardiac arrhythmia.
• Seizures.
• Stroke.
• Manic mood.

Does Use of Tetracyclics Lead to Withdrawal Symptoms?

Stopping tetracyclics cold turkey is not advised. Suddenly stopping them can trigger withdrawal symptoms.

Typically, antidepressant withdrawal symptoms are mild and last about 1 to 2 weeks. They usually begin within 3 days of stopping the medication.¹¹

To best minimize or avoid withdrawal effects, it’s often necessary for people to gradually taper off the medication. Physicians will generally lower the dose over a period of a week or more, but some sources indicate that the tapering period might take up to 6 to 8 weeks.¹¹

Do These Medications Interact With Any Drugs?

The interaction of tetracyclics with certain other medications may give rise to dangerous side effects.

Mirtazapine may interact with monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). A person is also at increased risk of serotonin syndrome if they take mirtazapine with other medications that raise serotonin levels in the brain, such as other antidepressants, triptans (medications used to treat migraines), tramadol (Ultram), and linezolid—an antibiotic medication.¹

Maprotiline can also negatively interact with a wide range of medications. Some of these drugs include:²

• Monoamine oxidase inhibitors (MAOIs).
• Antipsychotics (risperidone, thioridazine, phenothiazines).
• Medications for Parkinson’s disease, such as biperiden and levodopa (Sinemet).
• Phenytoin (Dilantin).
• Sedating medications such as diazepam (Valium).
• Methylphenidate (Ritalin).
• Warfarin (Coumadin).
• Certain cardiac medications (e.g., propranolol, clonidine, reserpine, methyldopa).
• Certain treatments for diabetes, including insulin and sulfonylurea drugs.
• Thyroid medications.
• Cimetidine (Tagamet).
• Medications to relieve muscle spasms, such as baclofen (Gablofen, Lioresal).

Is Overdose Possible?

Though the data is limited, there have been reports of overdose with tetracyclics, both alone and in combination with other substances.

Symptoms of a mirtazapine overdose include:⁵

• Disorientation.
• Drowsiness.
• Memory impairment.
• Rapid heart rate.
• Heart rhythm disturbances (at extremely high doses).

Symptoms of a maprotiline overdose include:²

• Trouble concentrating.
• Restlessness.
• Agitation.
• Seizures.
• Severe drowsiness.
• Loss of muscle coordination.
• Stupor.
• Coma.
• Shortness of breath.
• Fast, slow, or irregular heartbeat.
• Low blood pressure.
• Vomiting.
• Sweating.
• Urinary problems.

Clinical and case studies suggest the mirtazapine is not likely to cause serious complications in overdose. One study looked at admissions to a toxicology unit from 1987 to 2013 and found no fatalities from mirtazapine overdose. However, fatalities are possible with doses that are much higher than the therapeutic dose, particularly if the drug is combined with other substances.^5,12

Tetracyclics and Substance Abuse

Tetracyclic medications are not controlled substances and are not considered to have a high risk of abuse. Clinical trials for mirtazapine revealed no drug-seeking behavior associated with its use; however, the drug has not been systematically evaluated for abuse, tolerance, or physical dependence liability.⁵

A comprehensive review of antidepressant abuse found no case studies of mirtazapine abuse, though there were cases of tricyclic antidepressant abuse. According to these reports, people had abused these antidepressants to achieve a euphoric high, become more sociable, and to feel a distorted sense of time.¹³

Doctors advise that people abstain from alcohol while taking tetracyclics. Alcohol not only decreases the therapeutic effectiveness of these medications, but it may increase drowsiness and dizziness, impair motor and cognitive skills, and raise the risk of experiencing combined substance toxicity.^1,2,14

Are They Right for You?

Only your doctor can decide whether tetracyclics are right for you. They will take into account your medical history, overall health, other drugs you are taking, and how you’ve responded to other treatments prior to making a prescription. Like other antidepressants, tetracyclics may be most effective when used in conjunction with other forms of treatment such as therapy.

Some people may need to experiment for a while before they find the antidepressant that will work best for them. A drug that works well for one person may not work for another. Finding the right medication is an individual process that should be undertaken with a supervising physician’s help.

Sources

[1]. National Alliance on Mental Illness. (2018). Mirtazapine (Remeron).

[2]. New Zealand Medicines and Medical Devices Safety Authority. (2016). Ludiomil.

[3]. Stahl, S. (2014). Prescriber’s Guide: Antidepressants: Stahl’s Essential Psychopharmacology. Cambridge University Press.

[4]. Begert, J. and Bradley, B. (2015). Off-label use of mirtazapine for anxiety. The Mental Health Clinician, 5(6), 265-270.

[5]. U.S. National Library of Medicine, DailyMed. (2018). Remeron.

[6]. Boeree, C.G. (2009). Neurotransmitters. Shippensburg University.

[7]. Alam, A., Voronovich, Z, and Carley, J. (2013). A Review of Therapeutic Uses of Mirtazapine in Psychiatric and Medical Conditions. The Primary Care Companion for CNS Disorders, 15(5).

[8]. Watanabe, N. (2011). Mirtazapine versus other antidepressive agents for depression. Cochrane.

[9]. Wang, G. (2017). Effectiveness Study of Mirtazapine Combined With Paroxetine in Major Depressive Patients Without Early Improvement. U.S. National Library of Medicine, ClinicalTrials.gov.

[10]. Hamilton, R. (2017). Tarascon Pharmacopoeia. Jones & Bartlett Learning.

[11]. Warner, C., Bobo, W., Reid, S., and Rachal, J. (2006). Antidepressant Discontinuation Syndrome. American Family Physician, 74(3), 449-456.

[12]. Berling, I., and Isbister, G.K. (2014). Mirtazapine overdose is unlikely to cause major toxicity. Clinical Toxicology (Philadelphia), 52(1), 20-24.

[13]. Evans, E. and Sullivan, M. (2014). Abuse and misuse of antidepressants. Substance Abuse and Rehabilitation, 5, 107-120.

[14]. Food and Drug Administration. (2010). Remeron.