Atypical Antidepressants: Benefits, Side Effects, and How They Differ from SSRIs

Depression is a complex condition that often requires medication to manage its symptoms. Most people are familiar with the common classes of antidepressants like SSRIs (Selective Serotonin Reuptake Inhibitors) or SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors), but atypical antidepressants offer an alternative when these first-line treatments aren’t effective or cause intolerable side effects. This guide explains what atypical antidepressants are, how they work, and what to expect if you're prescribed one.

• Atypical Antidepressants: How They Work and What to Expect
• How Atypical Antidepressants Work: Mechanisms of Action
• When Are Atypical Antidepressants Prescribed?
• Advantages
• Potential Risks
• How to Choose the Right Atypical Antidepressant
• Final Considerations for Patients Starting Atypical Antidepressants
• Combining Atypical Antidepressants with Other Therapies
• Managing Side Effects of Atypical Antidepressants
• Key Takeaways
• FAQs
• Resources

Atypical Antidepressants: How They Work and What to Expect

What Are Atypical Antidepressants?

Atypical antidepressants differ from standard SSRIs and SNRIs because they don’t fit into the major categories of antidepressants and have unique mechanisms of action. Rather than working solely on serotonin or norepinephrine systems, these drugs often target other neurotransmitters like dopamine or act on multiple systems.

Key Examples Include:

Bupropion (Wellbutrin)

• Mechanism: Norepinephrine-Dopamine Reuptake Inhibitor (NDRI).
• Uses: Often prescribed when patients suffer from fatigue, low energy, or if they’ve experienced sexual side effects with SSRIs. It’s also FDA-approved for smoking cessation.

Mirtazapine (Remeron)

• Mechanism: Works by enhancing the activity of norepinephrine and serotonin but is also known for its potent antihistaminic action, making it sedating.
• Uses: Ideal for individuals who experience insomnia or significant weight loss. It is often chosen for people whose depression symptoms are linked with sleep disturbances or poor appetite.

Trazodone

• Mechanism: Classified as a serotonin antagonist and reuptake inhibitor (SARI), it impacts serotonin differently than SSRIs.
• Uses: Though originally developed as an antidepressant, trazodone is now primarily prescribed for its sedative properties, helping patients with insomnia associated with depression.

How Atypical Antidepressants Work: Mechanisms of Action

Bupropion

Inhibits the reuptake of dopamine and norepinephrine, leading to increased availability of these chemicals in the brain. This makes it particularly helpful for treating anhedonia (lack of pleasure) and fatigue, common in depression.

One major benefit of bupropion is that it does not significantly affect serotonin, which often results in fewer sexual side effects compared to SSRIs.

• Benefit: Fewer sexual side effects.

Mirtazapine

Works by blocking specific serotonin receptors (5-HT2 and 5-HT3), which enhances the release of norepinephrine and serotonin. It also acts on histamine receptors, which is why it tends to cause drowsiness and increased appetite.

• Benefit: Effective for those with sleep disturbances or weight loss associated with depression.

Trazodone

Trazodone has a dual action. It prevents serotonin reuptake and blocks serotonin receptors, offering mild antidepressant effects. However, at lower doses, it acts primarily as a sedative, making it more effective for insomnia than for mood improvement.

• Benefit: More effective for insomnia than for mood improvement.

When Are Atypical Antidepressants Prescribed?

Bupropion

Commonly prescribed for individuals who have low energy, lack of motivation, or need an activating antidepressant. It's also a first-line option for patients who are concerned about sexual dysfunction.

• Additional Use: Useful for patients with a history of smoking, as it is FDA-approved for smoking cessation.

Mirtazapine

Often recommended for patients with insomnia or appetite loss. It’s an excellent option for individuals who need help gaining weight or improving their sleep cycle alongside treating depression.

• Benefit: Its sedative properties make it helpful for those with agitation or anxiety-related sleep issues.

Trazodone

Trazodone is less commonly used for its antidepressant effects and more frequently for its ability to help patients who suffer from severe insomnia related to their depression.

• Reason for Use: Its sedative properties are beneficial for sleep without significantly impacting mood.

Advantages

Lower Risk of Sexual Dysfunction

One of the major drawbacks of SSRIs and SNRIs is the potential for sexual side effects (e.g., reduced libido or difficulty achieving orgasm). Atypical antidepressants, particularly bupropion, are often used to combat this. Bupropion, due to its minimal effect on serotonin, is known for having a lower incidence of sexual side effects.

Sedation for Sleep Disorders

Mirtazapine and trazodone are particularly beneficial for patients who struggle with insomnia. Mirtazapine’s sedative properties are a great option for those who need both antidepressant effects and a sleep aid, while trazodone is commonly prescribed off-label for sleep at lower doses.

Addressing Fatigue and Low Motivation

Bupropion can help patients with depression-related fatigue or lack of motivation. Its activating properties can be beneficial for patients who feel sluggish or lethargic, which is often a hallmark of certain types of depression.

• Benefit: Improves alertness and motivation.

Potential Risks

Bupropion and Seizures

One of the main risks associated with bupropion is an increased risk of seizures, particularly at higher doses. This is especially concerning for individuals with a history of seizure disorders, or those with eating disorders like bulimia, as these conditions also raise the risk of seizures.

• Risk: Increased likelihood of seizures at higher doses.

Mirtazapine and Weight Gain

Mirtazapine is highly effective for those struggling with weight loss and poor appetite due to depression. However, for patients who are concerned about weight gain, it may not be the best choice. Mirtazapine is known for increasing appetite and can lead to significant weight gain, particularly in individuals who are predisposed to weight issues.

• Risk: Significant weight gain due to increased appetite.

Trazodone and Daytime Sedation

While trazodone is a helpful medication for insomnia, its sedative properties can be problematic for some individuals, leading to daytime drowsiness and impaired concentration. If not appropriately dosed, it can affect a person’s functionality during waking hours.

• Risk: Daytime drowsiness and impaired concentration.

How to Choose the Right Atypical Antidepressant

Energy Levels and Motivation

If a patient’s depression is characterised by fatigue, low energy, or lack of motivation, bupropion is often a preferred option. Its stimulant-like effects can help improve alertness, focus, and overall energy.

Sleep and Insomnia

For patients struggling with insomnia or restless sleep, mirtazapine or trazodone are the most commonly recommended options. Mirtazapine is especially helpful if the patient also needs an appetite boost, while trazodone is used at lower doses primarily for its sedative effects.

Sexual Side Effects

If a patient is experiencing sexual dysfunction with SSRIs or other antidepressants, bupropion may be added to their treatment plan or used as a substitute, as it is known for causing fewer sexual side effects.

Weight Management

If weight gain is a concern, bupropion is again a preferred choice, as it is generally weight-neutral or may even cause mild weight loss in some individuals. On the other hand, mirtazapine would not be ideal for those concerned with weight gain, as it typically increases appetite.

• Consideration: Use bupropion for weight-neutral or weight-loss benefits; avoid mirtazapine if weight gain is a concern.

Combination Therapy

Atypical antidepressants are often used in combination with SSRIs or SNRIs to counteract specific side effects or enhance therapeutic outcomes. For example, bupropion is frequently combined with SSRIs to reduce sexual dysfunction while maintaining the mood-lifting effects of the SSRI.

• Strategy: Combine bupropion with SSRIs to mitigate sexual side effects.

Final Considerations for Patients Starting Atypical Antidepressants

Monitor Your Symptoms

When starting treatment with an atypical antidepressant, it’s important to monitor your mood, energy levels, and sleep patterns closely. Improvement may not be immediate, and side effects can sometimes occur early in the treatment. Keep a journal to track your day-to-day progress and report any concerning changes to your doctor.

Regular Doctor Follow-ups

Regular follow-up appointments are essential to check how well the medication is working and to adjust the dosage if necessary. Many patients require fine-tuning of their treatment plan during the first few months. This is particularly true with atypical antidepressants, which often need to be carefully titrated to avoid side effects like sedation or insomnia.

Tapering Off Medications

Atypical antidepressants, like all antidepressants, should not be stopped abruptly. If you and your doctor decide that the medication isn’t working for you, a gradual tapering process is necessary to avoid withdrawal symptoms, such as irritability, dizziness, or fatigue.

Lifestyle and Self-Care

Alongside medication, maintaining healthy habits can significantly improve the effectiveness of treatment. Consider incorporating regular exercise, a balanced diet, and consistent sleep routines. For instance, exercise can boost mood naturally and complement the effects of medications like bupropion, which already has energising properties.

Set Realistic Expectations

Every patient responds differently to medication. Some may see noticeable improvements within a few weeks, while others might need a combination of treatments or additional therapy to see full benefits. Medications like mirtazapine can help improve sleep early on, but mood improvement might take more time.

• Expectation: Mood improvement may take longer than improvements in sleep or energy.

Psychotherapy as a Complement

In many cases, atypical antidepressants work best when combined with psychotherapy. Cognitive-behavioural therapy (CBT), interpersonal therapy (IPT), or other forms of therapy can be highly effective alongside medications, especially for individuals facing specific challenges like relationship difficulties, stress management, or trauma recovery.

• Benefit: Enhances overall treatment outcomes and addresses underlying emotional issues.

Be Open About Side Effects

Some patients may feel hesitant to report side effects because they’re afraid their doctor will stop the medication. However, most side effects can be managed with simple adjustments. For example, if you’re taking trazodone and experience daytime drowsiness, your doctor might lower your dose or suggest taking it earlier in the evening.

• Advice: Communicate openly with your doctor about any side effects experienced.

Combining Atypical Antidepressants with Other Therapies

Combination with SSRIs/SNRIs

One common practice is to combine atypical antidepressants with SSRIs or SNRIs to enhance their therapeutic effects or reduce side effects. This is known as augmentation therapy.

• Bupropion with SSRIs: This combination is often used to treat patients who experience sexual dysfunction or fatigue on SSRIs. The addition of bupropion can help reduce these side effects while providing a more activating effect, which can improve energy levels and motivation.


• Mirtazapine with SSRIs: Sometimes used for patients who experience insomnia while taking SSRIs. Mirtazapine’s sedative properties can counteract the stimulating effects of SSRIs, especially if the patient has trouble falling asleep or staying asleep.

Atypical Antidepressants and Psychotherapy

While medications can be essential in managing depression, they are often most effective when combined with psychotherapy. Cognitive Behavioural Therapy (CBT), Interpersonal Therapy (IPT), and Emotion-Focused Therapy (EFT) are common therapies that complement the action of antidepressants by addressing underlying thought patterns and emotional issues.

• CBT and Bupropion: CBT can help patients manage the cognitive symptoms of depression, such as negative thinking patterns or difficulty with problem-solving. Paired with bupropion, which boosts focus and energy, this combination can enhance cognitive clarity and help patients stay engaged in their therapy.


• IPT and Mirtazapine: Interpersonal therapy focuses on improving relationships and communication. Mirtazapine can help stabilise mood and improve sleep, allowing patients to participate more fully in interpersonal therapy sessions, especially when their depression is complicated by poor sleep or emotional exhaustion.

Treating Specific Depression Subtypes

Atypical antidepressants are often prescribed when specific subtypes of depression present challenges that standard treatments don’t address well.

• Atypical Depression: This form of depression is characterised by mood reactivity, increased appetite, and hypersomnia (excessive sleep). Bupropion is often an excellent choice here because it is activating and can counteract symptoms like lethargy and weight gain, commonly seen in atypical depression.


• Treatment-Resistant Depression: For patients who don’t respond to typical antidepressants, atypical medications like bupropion or mirtazapine may be added to boost the treatment response. These medications offer different mechanisms of action, making them useful when other drugs have failed.

Managing Side Effects of Atypical Antidepressants

Bupropion (Wellbutrin)

Managing Agitation: Some patients report feelings of agitation or jitteriness, especially when starting bupropion. Starting with a lower dose and gradually increasing it can reduce this issue.

• Strategy: Start with a lower dose and gradually increase.

Insomnia: If bupropion disrupts sleep, taking the medication in the morning can help avoid nighttime disturbances.

• Advice: Take bupropion in the morning to minimise insomnia.

Mirtazapine (Remeron)

Weight Gain: One of the most significant side effects of mirtazapine is increased appetite leading to weight gain. Patients can manage this by monitoring their diet and engaging in regular physical activity.

• Strategy: Monitor diet and maintain regular exercise.

Sedation: Mirtazapine’s sedating effects are beneficial for patients with insomnia but can cause daytime drowsiness. Taking the medication at bedtime helps to limit this issue.

• Advice: Take mirtazapine at bedtime to reduce daytime drowsiness.

Trazodone

Daytime Sleepiness: Since trazodone is often used for sleep, lower doses are prescribed for its sedative effects, and patients are advised to take it shortly before bed to minimise the risk of daytime sleepiness.

• Strategy: Take trazodone shortly before bed to reduce daytime sleepiness.

Key Takeaways

• Atypical antidepressants offer important alternatives to SSRIs and SNRIs, especially when targeting specific symptoms like fatigue, insomnia, or sexual dysfunction.
• They work through multiple mechanisms, affecting neurotransmitters like dopamine, norepinephrine, and serotonin, but not always in the same way as traditional antidepressants.
• Bupropion, mirtazapine, and trazodone are among the most commonly used atypical antidepressants, each with their own unique profile that makes them suitable for different patient needs.
• Clinicians may choose atypical antidepressants to manage side effects of other medications or to provide more targeted treatment for complex cases of depression.
• Patients should be aware of the risks and benefits of these medications, such as the risk of seizures with bupropion or the potential for weight gain with mirtazapine, and should discuss these factors with their doctor before beginning treatment.

FAQs

Are atypical antidepressants stronger than SSRIs or SNRIs?

Not necessarily stronger, but different. Atypical antidepressants are often used when SSRIs or SNRIs are ineffective or produce intolerable side effects. They can target specific symptoms like fatigue (bupropion) or insomnia (mirtazapine).

Do atypical antidepressants cause weight gain?

Mirtazapine is most associated with weight gain due to its appetite-stimulating effects. On the other hand, bupropion is often associated with weight loss or weight neutrality.

Can I take bupropion if I have anxiety?

Bupropion is generally less effective for anxiety compared to SSRIs or SNRIs. In fact, it may increase anxiety symptoms in some individuals. Discussing your anxiety profile with your doctor is crucial before starting bupropion.

Is trazodone addictive?

No, trazodone is not considered addictive. It is often prescribed for sleep issues in people with depression and has a relatively low risk of dependency, especially compared to medications like benzodiazepines.

How long does it take for atypical antidepressants to start working?

Atypical antidepressants can take anywhere from 2 to 6 weeks to start having noticeable effects. Some symptoms, such as improvements in energy or sleep, may improve before mood lifts.

Can I combine atypical antidepressants with SSRIs?

Yes, atypical antidepressants like bupropion are often combined with SSRIs to enhance treatment and reduce side effects such as sexual dysfunction. Always do this under a doctor’s supervision.

What should I do if I experience side effects?

Talk to your healthcare provider immediately. They may adjust your dose or recommend strategies for managing side effects like sedation (from trazodone) or weight gain (from mirtazapine).

Resources

Wikipedia - Provides an overview of atypical antidepressants, including examples like agomelatine, bupropion, and mirtazapine, discussing how they differ from other types of antidepressants.

Mayo Clinic - Explains atypical antidepressants, their uses, potential side effects, and how they work to treat depression differently from other medications.

Mental Health America - Offers a brief guide on atypical antidepressants, discussing their role in treating depression and who might benefit from them.

WebMD - Provides information on different types of antidepressants, including atypical ones, with an emphasis on their effects and uses.