Atypical Antidepressants: Uses, Side Effects, & More

What Are Atypical Antidepressants?

Atypical antidepressants are a class of medications used to treat depression, but they differ from traditional antidepressants in their mechanism of action. Unlike traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants don’t fit neatly into these categories and may target various chemicals in the brain. Some examples of atypical antidepressants include bupropion, mirtazapine, and agomelatine.¹

What Is the Difference Between SSRIs & Atypical Antidepressants?

Selective serotonin reuptake inhibitors (SSRIs) and atypical antidepressants differ in how they function in the brain. SSRIs primarily focus on increasing levels of serotonin in the brain. Atypical antidepressants, however, have a broad range of different effects on the brain. Some may increase serotonin in the brain through different mechanisms than SSRIs. These atypical antidepressants may also impact other chemicals in the brain, such as norepinephrine and dopamine.

How Do Atypical Antidepressants Work?

Atypical antidepressants are a class of medications that work through various mechanisms. Some atypical antidepressants work by increasing or changing serotonin in the brain. Other atypical antidepressants work by increasing norepinephrine or dopamine in the brain. These chemicals – serotonin, norepinephrine, and dopamine – play an important role in our moods and behaviors.

Types of Atypical Antidepressants

There are three antidepressants that are classified as atypical antidepressants. These antidepressants are bupropion, mirtazapine, and agomelatine. Each of these antidepressants has a unique impact on the brain. Because of this, some individuals may respond better to one atypical antidepressant over another.

Here are the available types of atypical antidepressant medications:

• Bupropion (Wellbutrin): Bupropion works by increasing levels of norepinephrine and dopamine in the brain.²
• Mirtazapine: Mirtazapine works by enhancing serotonin and norepinephrine in the brain.³
• Agomelatine: Agomelatine works by enhancing dopamine and norepinephrine in the brain while also working to improve melatonin function, an important chemical for sleep. This medication is currently not available in the United States.⁴

What Are Atypical Antidepressants Used to Treat?

Atypical antidepressants, such as bupropion and mirtazapine, are approved by the FDA for the treatment of major depressive disorder. Bupropion is also FDA-approved for the treatment of seasonal affective disorder and smoking cessation.⁵ However, these medications also have off-label uses.

Off-label means the medication is used for a condition not specifically approved by the U.S. Food and Drug Administration. A healthcare provider may choose to prescribe a medication off-label if, in their professional judgment, they believe the medication will still benefit someone.

Off-label uses of bupropion include treating antidepressant-induced sexual dysfunction, attention-deficit/hyperactivity disorder (ADHD), depression associated with bipolar disorder, and obesity.⁵ Off-label uses of mirtazapine include insomnia, panic disorder, chronic tension-type headache, social anxiety disorder, post-traumatic stress disorder (PTSD), and fibromyalgia.⁶

Benefits of Atypical Antidepressants

Atypical antidepressants can offer distinct advantages over typical antidepressants. These medications can be particularly helpful for individuals who are unresponsive to the typical antidepressants. Additionally, atypical antidepressants can cause different side effects, which may be more tolerable for some individuals. Atypical antidepressants can sometimes address specific symptoms, such as insomnia, that allow for a more tailored approach to depression treatment.

Side Effects of Atypical Antidepressant Drugs

The side effects of atypical antidepressants are dependent on the specific type of medication being used. The side effects can vary from person to person. Most side effects of these medications are mild and resolve over time. However, some side effects can be severe or persistent, requiring immediate medical attention.

Common Side Effects of Atypical Antidepressants

The common side effects of atypical antidepressants, such as mirtazapine and bupropion, are typically mild and resolve as the body adjusts to the new medication. The side effects will vary from person to person and depend on the specific medication being taken.

Common side effects of bupropion include:²

• Headache
• Dry mouth
• Nausea
• Constipation
• Abdominal pain
• Insomnia
• Dizziness
• Agitation

Common side effects of mirtazapine include:³

• Sleepiness
• Increased appetite
• Weight gain
• Dizziness
• Dry mouth
• Nausea
• Constipation
• Abnormal dreams

Serious Side Effects of Atypical Antidepressants

Although most side effects are mild and resolve over time, there is a risk for side effects to be severe or persistent. It is important to be aware of these potential side effects and to seek immediate medical attention if they occur.

Serious side effects of atypical antidepressants may include:^{2, 3}

• Serotonin syndrome: Medications, such as mirtazapine, that increase serotonin can cause serotonin syndrome. This is a potentially life-threatening condition with symptoms that include that causes mental status changes, rapid heart rate, changes in blood pressure, and seizures.
• Antidepressant withdrawal: When stopping their medication, some individuals may experience withdrawal symptoms, also called antidepressant discontinuation syndrome. Symptoms may include dizziness, nausea, and insomnia. This risk can be lowered by a gradual tapering of the medication.
• Seizures: Atypical antidepressants may increase the risk for seizures and should be taken with caution in individuals with a seizure disorder.
• Manic episodes: Antidepressants can increase the risk of individuals experiencing manic or hypomanic episodes. This risk is higher for those with bipolar disorder.

Atypical Antidepressant Discontinuation

Abruptly stopping atypical antidepressants can lead to withdrawal symptoms and potential complications, also called antidepressant discontinuation syndrome. These symptoms may include dizziness, nausea, sleep problems, and return of depression symptoms. It’s important to work closely with a healthcare provider to taper off the medication gradually. This gradual process helps mitigate the risks that can occur with antidepressant discontinuation syndrome.

Atypical Antidepressant Dosages for FDA-Approved Treatment

The dosages of atypical antidepressants can vary significantly among individuals due to factors such as age, weight, health history, and the specific condition being treated. Antidepressants are often started at the lowest recommended dose, and changes are made as needed depending on the response to the medication.

The recommended dosage range also varies depending on the specific atypical antidepressant being used and the formulation of that medication. Bupropion dosages can vary from 150-522 mg per day, depending on the formulation. Mirtazapine dosages range from 15-45 mg per day.⁷

Forms & Strengths of Atypical Antidepressants

Atypical antidepressants are available in various forms and strengths, allowing healthcare providers to tailor treatment to the specific needs of each patient. These medications are commonly found in oral formulations, such as tablets and capsules. These forms may also include immediate-release, extended-release, or sustained-release formulations.

The selection of the most appropriate form and strength is determined by several factors, including the individual’s medical history, symptoms, and response to previous treatments. Additionally, prescribers may choose extended-release or sustained-release formulations for improved convenience. Most atypical antidepressants take 2-4 weeks for effects to be noticed.

Atypical antidepressants are available in the following forms and strengths:⁶

• Bupropion tablet: 75 mg, 100 mg
• Bupropion SR tablet (sustained-release): 100mg, 150 mg, 200 mg
• Bupropion XL tablet (extended-release): 150 mg, 300 mg, 450 mg
• Bupropion hydrobromide tablet (extended-release): 174 mg, 378 mg, 522 mg
• Mirtazapine tablet: 7.5 mg, 15 mg, 30 mg, 45 mg
• Mirtazapine disintegrating tablet: 15 mg, 30 mg, 45 mg

What Happens If I Miss a Dose of Atypical Antidepressants?

If you miss a dose of mirtazapine, take the medication as soon as you remember it.⁸ However, if it is almost time for your next dose, skip the previous dose and resume your regular dosing schedule.

If you miss a dose of bupropion, skip the missed dose and continue your regular dosing schedule.⁹ Never take a double dose to make up for a missed dose of any antidepressant.

Can You Overdose on Atypical Antidepressants?

Overdose from atypical antidepressants is possible if too much is taken at one time or if the medications are taken with other medications. These symptoms will vary depending on the specific medication being taken.

Mirtazapine overdose symptoms may include disorientation, drowsiness, impaired memory, and rapid heart rate.³ Bupropion overdose symptoms may include seizures, loss of consciousness, heart rhythm abnormalities, fever, and muscle rigidity.

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

If you take too much of an atypical antidepressant, all 911 or seek immediate medical attention if severe symptoms occur, such as seizures, difficulty breathing, or loss of consciousness. You may also call the poison control helpline at 1-800-222-1222 for more information about overdosing once your emergency has been addressed.

Atypical Antidepressants Warnings & Precautions

Atypical antidepressants come with specific warnings and precautions. It is important to be aware of these warnings when taking these medications and to seek immediate medical attention or notify your healthcare provider if they occur. Depending on their medical history, some individuals may be at a higher risk for certain side effects.

Warnings and precautions for taking atypical antidepressants include:^{2, 3}

• Increased risk of suicidal thoughts: Antidepressants may increase the risk of suicidal ideation and behaviors in individuals aged 24 and younger.
• Allergic reactions: Although rare, allergic reactions to antidepressants can occur and require immediate medical attention. Symptoms may include difficulty breathing, chest pain, rash, and swelling of the face, mouth, or lips.
• Individuals with a history of bipolar disorder: Those with a history of bipolar disorder are at an increased risk of developing manic episodes when taking atypical antidepressants.
• Individuals with a history of seizures: Those with a seizure disorder are at an increased risk of seizures when taking atypical antidepressants, especially bupropion.
• Individuals with a history of glaucoma: Antidepressant medications can trigger sudden worsening of glaucoma in those with untreated glaucoma.
• Individuals with a history of heart rhythm problems: Atypical antidepressants can increase the risk of heart rhythm abnormalities in those who are at risk. This risk is higher with mirtazapine.
• Pregnancy: The risk of harm to a developing fetus from atypical antidepressants is not well established. The decision to continue taking antidepressants while pregnant should be made in conjunction with a healthcare provider.
• Breastfeeding: Mirtazapine is excreted in breast milk at a low level, but no adverse effects on breastfed infants have been reported. Bupropion is also excreted in breast milk at a low level, and seizures in infants have been reported. The decision to continue breastfeeding while taking these medications should be made in conjunction with a healthcare provider.

Who Should Not Take Atypical Antidepressants?

Individuals with certain health conditions may want to avoid atypical antidepressants due to the risk of severe side effects. The decision to start or continue an atypical antidepressant should be made with consultation from a healthcare provider.

People who may need to avoid taking atypical antidepressants include:²

• Pregnant and breastfeeding women
• People with a seizure disorder
• People with liver or kidney problems
• People with heart problems
• People on certain medications, such as other antidepressants
• Children

What to Avoid When Taking Atypical Antidepressants

When taking atypical antidepressants, individuals should be aware of the potential interactions with various medications, substances, and herbs. Interactions may lead to decreased effectiveness of the antidepressant or an increased risk of side effects. The interactions are dependent on the specific atypical antidepressant being taken.

Seven substances you should avoid while taking bupropion:²

• Blood thinners: Some blood thinners, such as ticlopidine and clopidogrel, may increase the level of bupropion in the blood. Changes in dosage may be necessary for individuals taking these medications.
• Antiviral medications: Some antiviral medications, such as ritonavir, lopinavir, and efavirenz, can decrease the level of bupropion in the body, leading to reduced effectiveness.
• Anti-seizure medications: Some anti-seizure medications, such as carbamazepine, phenobarbital, and phenytoin, may lower the levels of bupropion in the body, leading to reduced effectiveness.
• Other antidepressants: Bupropion can increase the levels of some antidepressants in the body leading to an increased risk of side effects. These antidepressants include venlafaxine, nortriptyline, and fluoxetine.
• Parkinson’s disease medications: Medications used for the treatment of Parkinson’s disease, such as levodopa and amantadine, can increase the risk of severe side effects when taken with bupropion.
• Alcohol: Taking bupropion with alcohol may increase the risk of psychiatric events. Bupropion can also lower the alcohol tolerance.
• Monoamine oxidase inhibitors (MAOIs): Taking bupropion with MAOIs can increase the risk of severe side effects.

Seven substances you should avoid while taking mirtazapine:³

• Monoamine oxidase inhibitors (MAOIs): Taking mirtazapine with MAOIs can increase the risk of serotonin syndrome, which may cause mental status changes, rapid heart rate, changes in blood pressure, and seizures.
• Antidepressants: Taking mirtazapine with other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can increase the risk of serotonin syndrome.
• St. John’s Wort: Taking mirtazapine with the herb St. John’s Wort can increase the risk of serotonin syndrome.
• Antiseizure medications: Some antiseizure medications can decrease the effectiveness of mirtazapine. These medications include phenytoin and carbamazepine.
• Alcohol: Taking mirtazapine with alcohol can increase the impairments of thinking and motor skills.
• Benzodiazepines: Taking mirtazapine with benzodiazepines, such as diazepam and alprazolam, can increase thinking and motor impairments.
• Warfarin: The blood thinner warfarin may have an increased effect when taken with mirtazapine and may require dosage adjustments.

Questions to Ask Your Healthcare Provider About Atypical Antidepressants

Individuals considering the use of atypical antidepressants should start by having a conversation with their healthcare provider. To prepare for this appointment, have a list of specific questions to ask your doctor, psychiatrist, and therapist. In addition to medications, finding the right therapist can be a valuable aspect of depression treatment, as they can offer emotional support, coping strategies, and collaboration with your healthcare team to optimize your mental health.

Questions to ask your care team about atypical antidepressants include:

• Can I use an atypical antidepressant along with therapy to treat depression?
• How soon might I notice side effects from taking an atypical antidepressant?
• 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 harmful 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?
• What are alternative treatment options?
• How often will my medication need to be adjusted or reassessed?
• Are there any lifestyle factors I should be aware of while on this medication?
• What should I do if I miss a dose of my medication?

How to Get an Atypical Antidepressant Prescription

When considering atypical antidepressants as a treatment for depression, start by setting up an appointment with your healthcare provider. This may include a primary care physician or psychiatrist. These providers will evaluate the severity and nature of your symptoms and determine the best course of treatment.

For individuals seeking more specialist care or prefer online access to mental health services, online psychiatry services are a great option. These services allow remote consultations with licensed psychiatrists in the convenience of a virtual appointment.

Atypical Antidepressants in Combination Therapy

Atypical antidepressants can play a crucial role in the treatment of depression. These medications can be used alone for the treatment of depression. However, for some individuals, a combination approach is sometimes necessary. This may include combining atypical antidepressants with a different class of antidepressants to better address certain aspects of depressive symptoms. Similarly, therapy for depression is another important aspect of the treatment of depression.