SNRIs vs. Tricyclics: What Is the Difference and Which One Should I Take?

Antidepressants are not one-size-fits-all.

Whether you’re new to antidepressant treatment or feel your current medication is ineffective, learning about all the antidepressants available can be overwhelming.

You may be worried about negative side effects, high drug costs, feeling worse on a new medication, or you may have treatment-resistant depression and need to switch medications. Regardless of the reason, deciding on a new treatment takes some trial and error, a bit of patience, and trusted medical advice from a healthcare provider.

If you’re ready to talk with a licensed provider about the anxiety or depression treatment, Klarity is here to help. In less than 48 hours, you can speak to a board-certified medical provider to learn if one or more of these medications is right for you. Schedule an appointment today.

This article discusses suicide, suicidal ideation, and self-harm. If you or someone you know is experiencing suicidal thoughts or is in crisis, contact the Suicide Prevention Lifeline immediately at 800-273-8255.

When SSRIs Aren’t The Right Choice

Selective serotonin reuptake inhibitors (SSRIs) are currently the standard treatment for most mood and anxiety disorders.

However, SSRIs may not achieve the desired results or could have unfavorable side effects. In these cases, second-line agents such as serotonin-norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants (TCAs) may prove helpful.

In this post, we’re going to explore two alternatives to SSRIs—SNRIs and Tricyclic antidepressants.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

How Do SNRIs Work?

Your brain has several chemicals (neurotransmitters) influencing mood, energy, sleep patterns, appetite, and focus. If neurotransmitter levels are too low, you can experience symptoms of depression and anxiety. SNRIs target two chemical messengers, serotonin and norepinephrine, to alleviate symptoms.

Serotonin is responsible for feelings of well-being, calmness, and restful sleep. Norepinephrine contributes to increased focus, concentration, and energy levels. Despite what you may think, SNRIs do not increase the levels of these neurotransmitters in the body. 

These antidepressant drugs work by increasing the availability of the serotonin and norepinephrine your brain already produces. When you release these neurotransmitters, SNRIs keep your brain from reabsorbing the chemicals too quickly (reuptake inhibition).

What Do SNRIs Treat?

Depression

When a patient is new to antidepressants, a medical provider will usually start by prescribing selective serotonin reuptake inhibitors as a first-line treatment. Many people benefit from this class of medication. Still, sometimes it is only partially effective (in the case of treatment-resistant depression) or has undesirable side effects. 

After one or more trials of different selective serotonin reuptake inhibitors, prescribers then start an SNRI. While SSRIs and SNRIs both regulate serotonin, SNRIs also work on norepinephrine. Because this neurotransmitter is responsible for your energy levels, attention span, and alertness, SNRIs fill in some of the gaps in depression treatment that an SSRI may not. 

Patients with mood disorders typically notice greater motivation, a boost in energy, and better quality sleep when taking an SNRI.

Anxiety

If you are diagnosed with Generalized Anxiety Disorder (GAD), Panic Disorder, Obsessive Compulsive Disorder (OCD), or Post Traumatic Stress Disorder (PTSD), you could also benefit from the effects of SNRIs. 

Anxiety disorders are marked by an exaggerated fight-or-flight response, with large quantities of norepinephrine released into the bloodstream. By regulating norepinephrine and serotonin, SNRIs reduce both physical sensations of anxiety and racing, uncontrollable thoughts.

Unlike SSRIs, SNRIs are also approved to treat certain types of pain, including diabetic nerve pain, fibromyalgia, and chronic musculoskeletal pain. These medications are an excellent solution if you suffer from both mood and pain disorders.

What Are the Most Commonly Prescribed SNRIs?

Here are the four most common SNRIs prescribed in the US:

• Venlafaxine (Effexor)
• Duloxetine (Cymbalta)
• Desvenlafaxine (Pristiq)
• Levomilnacipran (Fetzima)

Among all SNRIs, Cymbalta and Effexor are prescribed more often due to lower costs and because they have the largest number of FDA-approved uses.

Costs

SNRIs tend to be more expensive than SSRIs. Despite being available in brand and generic forms, SNRIs are newer but also considered a first-line choice. As a result, drug companies charge a higher rate, and insurance companies cover less cost. On average, the out-of-pocket cost for a one-month supply of generic SNRIs is roughly $13 more than SSRIs.

The cost for generic forms of Cymbalta and Effexor is $10 – $50 monthly with insurance, depending on the dose. Fetzima, on the other hand, does not yet have a generic equivalent. This medication can cost over $400 for a 30-day supply.

Common Side Effects

Side effects of SNRIs will vary from one individual to another based on dose, metabolism, and even genetics. What may be an issue for one person is hardly recognizable for another. Side effects are typically more noticeable when starting a new medication, although they may persist throughout treatment.

The most common side effects include:

• Nausea/vomiting
• Diarrhea or constipation
• Headache
• Sexual dysfunction (trouble becoming aroused or achieving orgasm)
• Dizziness/lightheadedness
• weight gain or weight loss
• Dry mouth

In addition, the norepinephrine component of SNRIs may trigger the following:

• Sweating
• Racing heart
• Anxiety/panic attacks
• Insomnia

SNRIs have short half-lives, meaning your body quickly removes the medication from your system. For this reason, it is essential to take your medication at the same time every day to avoid discontinuation effects. When discontinuation occurs rapidly or without physician supervision, you may experience many of the side effects listed above.

Warnings for Use

Like all medications, SNRIs are not without risk. You should use them cautiously if you have a history of heart, liver, or kidney problems or high blood pressure. Taking more than the prescribed dose can lead to a potentially life-threatening condition known as serotonin syndrome.

Watch for symptoms such as:

• Agitation
• Excessive sweating
• Muscle tremors or rigidity
• Prolonged elevated heart rate or abnormal heart rhythm
• High blood pressure
• Headache
• Diarrhea
• Insomnia
• Confusion
• Dilated pupils

SNRIs also carry the risk of worsening depression/anxiety and increased risk of suicide in the first few weeks of taking the medication. If you notice these symptoms in you or a loved one, stop the medication immediately, contact your doctor, and go to the nearest emergency room or crisis center for assessment.

Potential Drug Interactions With SNRIs

SNRIs, like other medications, can have interactions with various substances, which may result in heightened side effects or diminished efficacy. To prevent such interactions, it is crucial to inform your healthcare professional about other antidepressants, medications, supplements, and over-the-counter products you are using. Frequent interactions with SNRIs involve:

• Monoamine oxidase inhibitors (MAOIs): Mixing SNRIs and MAOIs, another antidepressant category, might cause serotonin syndrome, a potentially fatal condition with symptoms like agitation, confusion, rapid heart rate, and elevated blood pressure.
• Selective serotonin reuptake inhibitors (SSRIs): Since SSRIs and SNRIs operate similarly, taking them concurrently can heighten the likelihood of serotonin toxicity.
• Tricyclic antidepressants (TCAs): Using SNRIs alongside TCAs can result in elevated TCA levels in the bloodstream, possibly leading to intensified side effects or toxicity.
• Central nervous system (CNS) depressants: Combining SNRIs with other CNS depressants, such as benzodiazepines, opioids, or alcohol, can augment drowsiness and the danger of sedation or respiratory depression.
• Serotonergic drugs: Taking SNRIs with other serotonergic medications, like triptans (employed for migraines), tramadol, or St. John’s wort, can heighten the risk of serotonin syndrome.
• Anticoagulants or antiplatelet drugs: SNRIs can elevate bleeding risk when used with blood thinners like warfarin or antiplatelet medications such as aspirin and clopidogrel.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): Using SNRIs with NSAIDs, like ibuprofen or naproxen, can heighten the possibility of gastrointestinal bleeding.
• Antifungal medications: Certain antifungal medications, including ketoconazole or fluconazole, can influence the metabolism of some SNRIs, possibly resulting in intensified side effects or toxicity.

Tricyclics

How Do Tricyclics Work?

Much like SNRIs, TCAs also inhibit the reuptake of serotonin and norepinephrine, allowing these neurotransmitters to be used more efficiently by the brain. The difference between these two classes of antidepressants lies in their selectivity and side effect profiles.

Whereas all SNRIs target serotonin and norepinephrine equally, TCAs can be more selective for one or the other. TCAs have two subcategories: secondary and tertiary amines. Secondary amines work more on norepinephrine, while tertiary amines target serotonin. 

TCAs also affect three other chemical receptors (cholinergic, muscarinic, and histaminergic) that have no impact on mood but contribute to the medication’s side effects and tolerability. TCAs get their name from their three-ringed chemical structure.

What Do Tricyclic Antidepressants Treat?

Depression

Introduced in 1959, tricyclics are among the oldest antidepressants available. Most TCAs are FDA-approved for treating depression and other mood disorders. This class is a third-line option if SSRIs, SNRIs, or atypical antidepressants have been ineffective or you have treatment-resistant depression.

Anxiety

Anxiety disorders are common off-label indications for tricyclic antidepressants. People with diagnoses of OCD, Panic Disorder, or PTSD can benefit from the mood-elevating properties of serotonin and norepinephrine. In addition, the medication’s histamine-blocking effects can alleviate physical anxiety symptoms and promote sleep.

Tricyclic antidepressants are not limited to treating mental health disorders. Like SNRIs, they are prescribed for chronic pain disorders. You may also take them for insomnia, migraine, or increased urinary frequency.

What Are the Most Commonly Prescribed Tricyclics?

Here are several commonly prescribed tricyclic antidepressants in the US.

Secondary amines:

• Desipramine (Norpramin)
• Nortriptyline (Pamelor)
• Protriptyline (Vivactil)
• Amoxapine (Asendin)

Tertiary amines:

• Amitriptyline (Elavil)
• Clomipramine (Anafranil)
• Doxepin (Sinequan)
• Imipramine (Tofranil)
• Trimipramine (Surmontil)

Costs

TCAs have been around for over 60 years, so these medications are fairly cheap compared to newer antidepressants. Depending on the drug, you can expect to pay $10 – $20 after insurance for a 30-day supply of most tricyclics. However, if you prefer brand-name over generic, the out-of-pocket cost could be hundreds.

Common Side Effects

The most significant disadvantage of TCAs is the side effect profile. As mentioned earlier, this class of antidepressants impacts other chemical receptors in the body that have nothing to do with your mental health. The action of TCAs at these receptor sites is responsible for many of the side effects you may experience when taking a tricyclic.

Most common side effects:

• Dry mouth
• Constipation
• Blurry vision
• Urinary hesitancy

• Drowsiness
• Weight gain
• Sedation 
• Increased appetite
• Sexual dysfunction

Dangerous side effects:

• Rapid/abnormal heart rate/rhythm
• High/low blood pressure
• Congenital abnormalities (birth defects)

Warnings for Use

Newer antidepressants are favored over tricyclics for their superior side effect profile and tolerability at higher doses. If your provider prescribes a TCA, there are key points to remember beyond side effects.

Tricyclics should be avoided or monitored very closely in patients with a personal or family history of any of the following conditions:

• Heart rhythm disorders or sudden cardiac death
• Liver disease
• Seizures
• Urinary retention
• Glaucoma
• Pregnancy
• Breastfeeding

Additionally, TCAs should be closely monitored in older patients, due to their anticholinergic and antihistamine effects.

Drug Interactions For Tricyclic Antidepressants

It is essential to inform your healthcare provider about other antidepressants, medications, supplements, and over-the-counter products you are taking to avoid potential drug interactions. Some common interactions with TCAs include:

• Monoamine oxidase inhibitors (MAOIs): Combining TCAs with MAOIs, another class of antidepressants, can lead to a potentially life-threatening condition called serotonin syndrome, characterized by symptoms such as agitation, confusion, rapid heart rate, and high blood pressure.
• Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): These newer classes of antidepressants can increase the levels of TCAs in the blood, potentially leading to increased side effects or toxicity.
• Anticholinergic medications: TCAs have anticholinergic properties, which can cause side effects such as dry mouth, constipation, and urinary retention. Combining TCAs with other medications with anticholinergic effects can exacerbate these side effects.
• Central nervous system (CNS) depressants: Combining TCAs with other CNS depressants, such as benzodiazepines, opioids, or alcohol, can increase drowsiness and the risk of sedation or respiratory depression.
• Antiarrhythmic medications: TCAs can have an impact on heart rhythm and, when combined with certain antiarrhythmic medications, can increase the risk of developing abnormal heart rhythms.
• Antihistamines: Some antihistamines can increase the concentration of TCAs in the blood, potentially leading to increased side effects or toxicity.
• Blood pressure medications: TCAs can interfere with the effectiveness of some blood pressure medications or cause a sudden drop in blood pressure when standing up (orthostatic hypotension).
• Antifungal medications: Some antifungal medications, such as fluconazole and ketoconazole, can increase the levels of TCAs in the blood, potentially leading to increased side effects or toxicity.

Which Anxiety or Depression Medication is Right For You?

Several factors determine whether or not a medication is right for you. However—

The goal of antidepressants is to find a drug that offers the most benefits with the fewest side effects.

While firmly rooted in the science of medicine, psychiatry is still relatively new. There is no one-size-fits-all approach to antidepressants. Your provider must consider your personal medical history, family history, previous medication trials, and costs. Try the following:

• Get the most from conversations with your mental health provider by knowing what antidepressants have (or haven’t) worked for you. 
• Explain what side effects are most bothersome. 
• When treating depression on a new antidepressant, keep a log of your mood and side effects, whether it’s an SNRI, TCA, or some other medication. 

Reporting this information to your provider can help tailor your treatment to suit you and avoid any unnecessary complications.

With so many antidepressants on the market, there is a best fit for you out there.

If You Suffer from Anxiety or Depression, Klarity Can Help

Whether you have treatment-resistant depression or want to try a different antidepressant medication, Klarity can help you connect with a board-certified medical provider who can diagnose and prescribe anxiety and depression treatment online. Get started today and Klarity will connect you with a medical provider in 48 hours or less.

Sources:

Jennifer Fink. “Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs).” Healthline. https://www.healthline.com/health/depression/serotonin-norepinephrine-reuptake-inhibitors-snris

Jennifer Fink. “Tricyclic Antidepressants.” Healthline. https://www.healthline.com/health/depression/tricyclic-antidepressants-tcas

Mayo Clinic Staff. “Serotonin and norepinephrine reuptake inhibitors (SNRIs).” Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20044970

Mayo Clinic Staff. “Tricyclic antidepressants and tetracyclic antidepressants.” Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20046983

Recovery Village Staff. “Tricyclic Antidepressants vs. SSRIs.” The Recovery Village. https://www.therecoveryvillage.com/prescription-drug-addiction/tricyclic-antidepressants-vs-ssri/

Sansone, R. A., & Sansone, L. A. (2014). Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innovations in clinical neuroscience, 11(3-4), 37–42.