Tetracyclic Antidepressants: An Overview

What Are Tetracyclic Antidepressants?

Tetracyclic antidepressants are a class of medications used to treat depression and related mood disorders. They work by affecting neurotransmitters in the brain, helping to alleviate symptoms of depression, such as low mood and lack of energy. Tetracyclic antidepressants include the drugs mirtazapine and maprotiline. To learn more about their mechanism of action and how they compare to other antidepressants, you can explore our comprehensive article on antidepressants.

How Do Tetracyclic Antidepressants Work?

Tetracyclic antidepressants work by affecting the levels of brain chemicals, specifically norepinephrine and serotonin. They block certain receptors, increasing the availability of these chemicals, which can help regulate mood and alleviate symptoms of depression. This class of antidepressants is similar to tricyclic antidepressants (TCAs), as they have a similar chemical structure and mechanism of action.¹

Tetracyclics, such as mirtazapine and maprotiline, also have pronounced antihistamine properties, which may help explain their ability to cause sedation. They offer an alternative treatment option for individuals struggling with depression and related conditions.

How Effective Are Tetracyclic Antidepressants?

Tetracyclic antidepressants have long been found to be effective in treating depression in many individuals. Studies have demonstrated their efficacy in improving mood and reducing depressive symptoms. Studies have also demonstrated the effectiveness of drugs like mirtazapine alone and as a potential add-on therapy in some patients, mentioning that it has a rapid and often sustained improvement in depression symptoms for patients.²

What Are the Most Common Tetracyclic Antidepressants?

Tetracyclic drugs include mirtazapine, amoxapine, and maprotiline which are often prescribed due to their effect in managing depressive symptoms. They primarily target the neurotransmitters norepinephrine and serotonin, helping to regulate mood and alleviate depression.

Within the tetracyclic antidepressant category, there is a distinction between selective and non-selective medications. Selective tetracyclics, like mirtazapine, primarily affect norepinephrine and serotonin receptors, making them a more targeted option for individuals with specific neurotransmitter imbalances. Non-selective tetracyclics, on the other hand, may interact with a wider range of receptors and neurotransmitters, potentially offering a broader therapeutic effect but with a different side effect profile.

Here are the available types of tetracyclic antidepressant medications:^3,4,5

• Mirtazapine: Mirtazapine is approved to treat depression. It is also known for its strong sedative effect and appetite stimulation, making it a possible off-label* treatment for individuals with sleep problems and weight loss related to depression. It is also available as the brand name Remeron and Remeron Soltab.
• Maprotiline: Maprotiline is a non-selective tetracyclic antidepressant that primarily targets norepinephrine. It has been discontinued and is no longer available as a brand name or as a generic medication.
• Amoxapine: Amoxapine is unique among tetracyclics as it also has antipsychotic properties. It is occasionally used to treat depressive symptoms in individuals with both depression and psychosis. It was previously available as the brand name Asendin, but is now only available as a generic medication.

*An off-label use is one that is not an FDA-approved use for the medication. Healthcare prescribers may use their professional judgment to choose to use a medication off-label because they believe it can offer a benefit to the patient.

What’s the Difference Between Selective Serotonin Reuptake Inhibitor (SSRI) & Tetracyclic Antidepressants?

The main difference between selective serotonin reuptake inhibitors (SSRIs) and tetracyclic antidepressants is how they work in the brain and their side effects.⁶

SSRIs primarily focus on increasing the levels of serotonin, a mood-regulating chemical, in the brain. They are commonly used and have milder side effects, often causing sexual issues or nausea.

Tetracyclic antidepressants, like mirtazapine, affect both serotonin and norepinephrine. They may make you feel drowsy and can increase your appetite, but they usually don’t cause sexual problems. Although it’s important to remember that all medications can carry a risk of side effects. You should talk with your healthcare provider about all risks with any medication before you start treatment.

What’s the Difference Between Tricyclic & Tetracyclic Antidepressants?

Tricyclic and tetracyclic antidepressants are two types of medications used to treat depression, but they differ in their chemical structures and how they affect the brain. Tricyclic antidepressants have a three-ring structure versus a four-ring tetracyclic structure and mainly target norepinephrine and serotonin. They can both be effective for the treatment of depression but may demonstrate different side effect profiles.

What Are Tetracyclic Antidepressants Used to Treat?

Tetracyclic medications, such as mirtazapine, have a history dating back to some of the earliest antidepressant treatments. They are primarily prescribed for the treatment of depression and related mood disorders. But may also be used off-label for insomnia, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, headaches, and migraines.

While the FDA approves specific uses for these drugs, medical professionals may also employ them “off-label.” An off-label use of a medication is a use that is not FDA-approved, but prescribers may choose to do so based on their professional judgment if they believe it can provide therapeutic benefits to patients, even beyond the officially approved indications.

Tetracyclic antidepressants may be used as an FDA-approved medication to treat:(FN3)

• Major depressive disorder (MDD) in adults

Tetracyclic antidepressants may also be used off-label (non-FDA-approved) for treating:³

• Insomnia
• Panic disorder
• Prophylaxis of chronic tension-type headache
• Social anxiety disorder
• Post-traumatic stress disorder (PTSD) when used in combination with SSRI
• Fibromyalgia

Who Should Not Take Tetracyclic Antidepressants?

Tetracyclic antidepressants should not be taken by individuals who have a known allergy or hypersensitivity to the medication or its components. Additionally, those currently using monoamine oxidase inhibitors (MAOIs) or who have used them within the past 14 days should avoid tetracyclic antidepressants to prevent the risk of dangerous interactions between the two classes of drugs. Elderly patients may also be more sensitive to the sedative effects of this drug class and should exercise caution.³

People who may need to avoid taking tetracyclic antidepressants include:³

• Pregnant and breastfeeding women
• People with pre-existing health conditions
• Anyone taking seizure or migraine medications
• People with a history of severe medical conditions, such as epilepsy or kidney disease
• Patients who are already taking antidepressant medications, especially MAOIs such as phenelzine or selegiline

Tetracyclic Antidepressant Dosages for FDA-Approved Treatment

Dosages of tetracyclic antidepressants like mirtazapine can vary significantly from one individual to another. Typically, the initial dose falls within a range of 15 to 45 milligrams daily for adults with depression. However, it’s essential to understand that factors such as age, the specific condition being treated, and individual response to the medication can influence dosages. For example, older adults may require lower initial doses due to increased sensitivity to potential side effects, while those with generalized anxiety disorder may start with a different dosage than someone with major depressive disorder.¹

Tetracyclic antidepressants are typically approved for use in adults, but their use in pediatric populations, specifically under 18 years of age, is limited and often subject to special considerations and close monitoring due to potential risks.

Forms & Strengths of Tetracyclic Antidepressants

Tetracyclic antidepressants like mirtazapine may be available in oral tablet or orally disintegrating tablet (ODT) forms, offering various strengths, including 15 mg, 30 mg, and 45 mg, depending on the specific medication. These medications are generally administered in immediate-release forms, meaning they are designed to be absorbed quickly into the bloodstream.¹

The choice of the most appropriate form and strength for an individual depends on several factors. Prescribers consider the patient’s age, the condition being treated, and the individual’s tolerance for potential side effects.

Tetracyclic antidepressants are available in the following forms and strengths:^1,4,5

• Amoxapine tablets – 25 mg, 50 mg, 100 mg, 150 mg
• Mirtazapine tablets – 15 mg, 30 mg, 45 mg
• Mirtazapine orally disintegrating tablets – 7.5 mg, 15 mg, 30 mg, 45 mg

What Happens If I Miss a Dose of Tetracyclic Antidepressants?

It is crucial not to stop taking tetracyclic antidepressants abruptly or attempt to make up for missed doses. Tetracyclic medications, like mirtazapine, should be taken as prescribed by a healthcare professional. Suddenly discontinuing these drugs or taking extra doses can lead to withdrawal symptoms, which may include irritability, anxiety, dizziness, and insomnia.¹

Side Effects of Tetracyclic Antidepressant Drugs

Tetracyclic antidepressants can cause side effects due to their direct action on neurotransmitters. These side effects may include drowsiness, increased appetite, weight gain, and dry mouth. The drowsiness can be particularly prominent, which is why they are often taken in the evening to minimize daytime sleepiness.¹

Common Side Effects of Tetracyclic Antidepressants

Common side effects of tetracyclic antidepressants like mirtazapine can include drowsiness, increased appetite, and weight gain. While these side effects are generally not considered life-threatening, they can be bothersome and may require medical attention if they become severe or impact an individual’s well-being.¹

Common side effects of tetracyclic drugs include:¹

• Drowsiness or sedation
• Increased appetite
• Weight gain
• Dry mouth
• Dizziness, particularly when changing positions.
• Constipation or other gastrointestinal issues.
• Mild tremors or shaking.
• Changes in sexual desire or function, though these are generally less common compared to some other antidepressant classes

*All medications, including tetracyclic antidepressants, can cause side effects which can be mild or serious. This is not a comprehensive list of all possible side effects. You should talk with your doctor about any questions you have and to understand the potential side effects and benefits of any medication.

Serious Side Effects of Tetracyclic Antidepressants

Serious side effects of tetracyclic antidepressants may require immediate medical attention. These effects can manifest in a variety of ways, affecting the heart, liver or an individual’s mental state. It’s crucial to be vigilant and seek medical help if any unusual or severe symptoms arise.

Serious side effects of tetracyclic antidepressants may include:¹

• Serotonin syndrome: Caused by an excess of serotonin in the brain, leading to a range of symptoms that can include agitation, confusion, rapid heartbeat, dilated pupils, and even seizures.
• Antidepressant withdrawal: Symptoms of antidepressant discontinuation syndrome (withdrawal) include mood swings, irritability, dizziness, nausea, and other physical and psychological effects.
• Severe allergic reactions: Rare but possible, these can lead to symptoms like rash, itching, swelling, severe dizziness, or difficulty breathing.
• Significant heart rhythm abnormalities: Tetracyclics can cause irregular heartbeats or arrhythmias, which may present with symptoms like palpitations, chest pain, or fainting.
• Unusual bleeding or bruising: This may manifest as nosebleeds, easy bruising, or blood in the urine or stool.
• Signs of liver problems: Symptoms like dark urine, jaundice (yellowing of the skin or eyes), or upper abdominal pain may indicate potential liver issues.
• Severe dizziness or fainting: Individuals may experience severe lightheadedness, loss of consciousness, or fainting, which should be evaluated promptly.
• Severe confusion or hallucinations: These visual disturbances can be concerning and warrant immediate medical attention.
• Suicidal thoughts or behaviors: Antidepressants, including tetracyclics, can increase the risk of suicidal thoughts or actions, particularly when starting or changing the dose, necessitating urgent medical interventions

*All medications, including tetracyclic antidepressants, can cause side effects which can be mild or serious. This is not a comprehensive list of all possible side effects. You should talk with your doctor about any questions you have and to understand the potential side effects and benefits of any medication.

Tetracyclic Antidepressant Discontinuation

Abruptly stopping a tetracyclic antidepressant can lead to various complications, including discontinuation symptoms like nausea, anxiety, insomnia, and vivid dreams. It’s crucial to work with a physician to create a gradual tapering plan when discontinuing antidepressant medication.

Tetracyclic Antidepressants Warnings & Precautions

Tetracyclic antidepressants come with specific warnings for an increased risk of suicidal thoughts, especially in the early stages of treatment or when there are dosage adjustments. Therefore, close monitoring and medical attention are crucial, particularly for those with a history of depression or suicidal tendencies.

Tetracyclics can also impact cognitive and motor skills, potentially affecting one’s ability to drive or operate machinery. Moreover, these medications may interact with other drugs or substances, such as alcohol or certain medications, which can result in adverse effects.

Warnings and precautions for taking tetracyclic antidepressants include:¹

• Increased risk of suicidal thoughts: Tetracyclic antidepressants, like mirtazapine, can increase the risk of suicidal thoughts, particularly in the early stages of treatment or during dosage adjustments.
• Cognitive and motor impairment: Tetracyclics may cause drowsiness or dizziness, affecting cognitive and motor skills. Caution is advised when driving or operating machinery.
• History of epilepsy or seizure disorders: Patients who are predisposed to seizures should exercise caution when taking any medication within this class.
• Activation of mania or hypomania: Patients with bipolar disorder should be screened prior to starting a tetracyclic antidepressant.
• Increased appetite/weight gain: Mirtazapine tablets have been associated with increased appetite and weight gain.
• QT prolongation: Use mirtazapine tablets with caution in patients with risk factors for QT prolongation.
• Agranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with drugs like mirtazapine should be discontinued and the patient should be closely monitored.

What to Avoid When Taking Tetracyclic Antidepressants

Tetracyclic antidepressants, like mirtazapine, have the potential to interact with various medications, substances, and herbs, which can lead to harmful effects. These interactions may involve other antidepressants, such as MAOIs, which can lead to a dangerous condition called serotonin syndrome, characterized by symptoms like agitation, rapid heartbeat, and high body temperature.

5 substances you should avoid while taking tetracyclic antidepressants include:¹

• Monoamine oxidase inhibitors (MAOIs): Combining tetracyclics with MAOIs can lead to serotonin syndrome, a serious condition characterized by symptoms like agitation, rapid heartbeat, and high body temperature.
• Antiarrhythmic medications: Medications that affect heart rhythm, such as antiarrhythmics, may increase the risk of irregular heartbeats when taken in combination with tetracyclic antidepressants.
• Alcohol: Alcohol can enhance the sedative effects of tetracyclics, impair cognitive and motor skills, and should be consumed with caution while taking these medications.
• St. John’s wort: St. John’s wort is an herbal supplement that may influence serotonin levels and should not be used concurrently with tetracyclic antidepressants, as it can increase the risk of serotonin syndrome.
• CYP2D6 inhibitors: Medications that inhibit the CYP2D6 enzyme can affect the metabolism of tetracyclics, potentially altering their effectiveness or increasing the risk of side effects. It’s essential to consult with a healthcare provider to manage these interactions appropriately.
• Warfarin: The concomitant use of warfarin with mirtazapine tablets may result in an increase in INR, leading to dangerous accidental bleeding.

This is not a comprehensive list of the possible interactions with tetracyclic antidepressants. You should talk with your healthcare provider and your pharmacist about all prescription and over-the-counter medications, herbs, and supplements you take before starting any tetracyclic antidepressant.

Can You Overdose on Tetracyclic Antidepressants?

Overdose is possible with tetracyclic antidepressants, while uncommon. Signs and symptoms associated with overdose were associated with disorientation, drowsiness, and impaired memory. Serious outcomes (including fatalities) may occur at doses higher than recommended, especially with mixed overdoses involving other medications. In case of an overdose, immediate help should be sought out so supportive treatment can be administered. It is important to note that there are no specific antidotes for tetracyclic antidepressants.

What Should You Do If You Take Too Much Tetracyclic Antidepressant Medication?

If you or someone you know has taken too much medication and is experiencing symptoms of an overdose, it’s crucial to seek immediate medical help. Call emergency services or go to the nearest hospital as soon as possible. Providing healthcare professionals with information about the type and amount of medication ingested, as well as the individual’s condition and symptoms, can aid in prompt and effective treatment. Time is of the essence in overdose situations, and seeking medical attention without delay is the safest course of action to prevent potentially life-threatening consequences.

Questions to Ask Your Healthcare Provider About Tetracyclic Antidepressants

If someone is considering using a tetracyclic antidepressant and wishes to know more about potential side effects, it’s essential to engage in an open and informed discussion with their doctor, psychiatrist, and therapist. Questions to ask may include inquiring about the common side effects of tetracyclics, how these side effects might affect their daily life, and whether any lifestyle or dietary adjustments are necessary.

Additionally, finding the right therapist is a valuable aspect of depression treatment, as therapy can complement medication by addressing the emotional and psychological aspects of depression.

Questions to ask your care team about tetracyclic antidepressants include:

• Can I use a tetracyclic along with therapy to treat depression?
• How soon might I notice side effects from taking a tetracyclic?
• Am I at risk for more severe symptoms if I am already taking other anxiety /depression medications?
• What is the best dosage to ensure fewer side effects?
• Are there drugs I am taking that could have negative interactions?
• When should I reach out to you if I am experiencing side effects?
• Is there anything I should tell my therapist about this new medication?
• Are there any dietary or lifestyle restrictions I should be aware of while taking this medication?
• What is the expected timeline for improvement in my symptoms?
• What should I do if I miss a dose, or if I accidentally take too much?
• How will we monitor my progress while on this medication, and what should I do if I experience any unusual symptoms?

How to Get a Tetracyclic Antidepressant Prescription

Tetracyclic antidepressants are generally not considered first-line treatment for depression, so the process of considering it for an individual often requires either the failure of another medication or consideration for it as an add-on therapy. A healthcare provider will assess an individual’s condition and decide if a medication like mirtazapine might help their condition, and then work with them to develop a treatment plan to monitor their progress.

For those seeking the convenience of online psychiatry services, many platforms now offer virtual consultations with licensed psychiatrists who can evaluate your condition, prescribe medication, and provide ongoing monitoring through telehealth.

For Further Reading

• Treatment Resistant Depression: Signs, Symptoms, & Treatment Options
• Key Signs of High-Functioning Depression & How to Cope with Symptoms