Antidepressants | How Do Antidepressants Work?

Antidepressants help alleviate the symptoms of depression and are one of the three most prescribed medication classes in America.

Antidepressants are used in the management of depression to help alleviate symptoms. Antidepressant drugs are one of the three most commonly prescribed therapeutic drug classes, and the use of antidepressants in the treatment of various mental health conditions has increased significantly in recent years.

Understanding how antidepressant medications work and why they may help manage depression or other mental health disorders can be beneficial when discussing treatment options with a doctor.

What Are Antidepressants?

Antidepressant medications are used to alleviate symptoms associated with depression, such as fatigue, loss of interest, trouble sleeping, overwhelming feelings of guilt or worthlessness or thoughts of suicide. They work by augmenting different natural chemicals in the brain, also known as neurotransmitters, to influence a person’s mood.

Background and History

The history of antidepressants began in the 1950s, with the thought that changing the balance of certain natural chemicals in the brain would cause changes in mood and could produce euphoria or feelings of happiness.

The first two antidepressants to show success in the management of depression were iproniazid, a monoamine oxidase inhibitor (MAOI) that was originally developed for the treatment of tuberculosis, and imipramine, a tricyclic antidepressant (TCA). The success of these medications in the management of depression and the subsequent accepted use by prescribers led to the development of other medications in these two drug classes. However, these medications came with considerable side effects, including weight gain, fatigue and the potential of death from overdose.

The 1980s and 90s marked a drastic change in the management of depression as groundbreaking developments were made with the introduction of new medications called selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants.

These medications had greater clinical success with fewer side effects than the previously used medications, making them much more popular for the management of depression. The first was Prozac (fluoxetine), an SSRI, which was introduced to the American market in 1987, and was received with monumental popularity with annual sales soon topping $1 billion.

Currently, the Centers for Disease Control and Prevention (CDC) report that approximately 1 in 10 people aged 12 years and older take an antidepressant, with the use of antidepressants approximately doubling between 1999 to 2014.

Use in Treating Mental Illness

Antidepressants have become widely accepted as effective in the management of depression as well as other mental illnesses, including anxiety disorders, compulsion disorders and other mood disorders.

The American Psychiatric Association recommends the use of antidepressants for depression to modify an individual’s brain chemistry, which may be causing the symptoms of depression. These medications have successfully managed depression because they are not habit-forming and they do not act as stimulants or sedatives.

Antidepressants for anxiety can help alleviate anxiety symptoms while also reducing the symptoms of depression that commonly accompany anxiety disorders as coexisting conditions.

How Do Antidepressants Work?

There are three naturally occurring chemicals, also known as neurotransmitters, in the brain that are linked with the regulation of mood and emotions. These chemicals are serotonin, norepinephrine and dopamine, and they are part of a larger group of chemicals known as monoamines.

The theory behind the role of these three neurotransmitters in depression is known as the monoamine hypothesis, first accepted in the 1960s. This theory proposes that people with depression have depleted concentrations of serotonin, norepinephrine and dopamine in the brain, resulting in the symptoms associated with depression.

The different types of antidepressants vary in how they affect the concentrations of these brain chemicals. Because of the time that it takes to change the concentrations of these chemicals in the brain, it can take at least three to four weeks or up to four months for a patient to notice a significant difference in their mood when starting or switching an antidepressant medication.

Also, everyone’s brain chemistry is slightly different so what works for one person, most likely will not work exactly the same for another person. Therefore, one of the most important factors that affect what antidepressants do is the individual makeup and concentrations of serotonin, norepinephrine and dopamine in each person.

Types of Antidepressants

Antidepressants are classified based on how they work, also known as their mechanism of action. A comprehensive antidepressant list would include up to nearly 50 different medications that have been used over time in the management of depression, whether it was diagnosed by itself or as a co-occurring disorder with other mental health conditions.

However, the list of common antidepressants is much smaller and includes:

Prozac (fluoxetine)
Cymbalta (duloxetine)
Paxil (paroxetine)
Zoloft (sertraline)
Wellbutrin (bupropion)
Lexapro (escitalopram)
Celexa (citalopram)
Effexor (venlafaxine)
Remeron (mirtazapine)

These common antidepressants come from a couple of different classes that are defined by their mechanism of action.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants as they are typically the first-line agents of choice when initiating treatment for a patient. Essentially, SSRI drugs work by targeting serotonin in the brain to prevent reuptake, resulting in an increase in serotonin in the brain.

Some SSRI medications include:

Celexa (citalopram)
Lexapro (escitalopram)
Luvox (fluvoxamine)
Prozac (fluoxetine)
Paxil (paroxetine)
Zoloft (sertraline)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs), or SNRI drugs, inhibit the reuptake of the neurotransmitters serotonin and norepinephrine in the brain. How these medications affect the brain is dose-dependent, meaning that at lower doses, they only affect the reuptake of serotonin, but at higher doses, they affect the reuptake of norepinephrine also.

Some SNRI medications include:

Effexor (venlafaxine)
Pristiq (desvenlafaxine)
Cymbalta (duloxetine)
Fetzima (levomilnacipran)

Related Topic: SSRI vs SNRI

Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants (TCAs) were the most commonly prescribed class of antidepressants until the introduction of SSRIs in the 1980s and 1990s. Similar to SNRIs, TCA drugs work mainly by inhibiting the reuptake of serotonin and norepinephrine.

The use of TCA drugs is mainly reserved for patients who have been well-controlled on these medications for many years or for patients who do not respond well to SSRIs or SNRIs. The use of TCA drugs has decreased because they tend to cause more side effects and they require more monitoring through laboratory tests because an overdose of a TCA can be deadly.

Some TCA medications include:

Elavil (amitriptyline)
Tofranil (imipramine)
Norpramin (desipramine)
Pamelor (nortriptyline)
Anafranil (clomipramine)
Silenor (doxepin)

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors, also known as MAOIs, work by inhibiting specific enzymes that are responsible for a class of chemicals called monoamines. For the treatment of depression, the three monoamines of interest are serotonin, dopamine and norepinephrine. By inhibiting the breakdown of these chemicals, also known as neurotransmitters, MAOIs trigger an increase in serotonin, norepinephrine and dopamine.

The different MAOIs available prevent the breakdown of different monoamines depending on their specific chemical structure. Because these medications affect more monoamines than just those involved in depression, it is common to see this class of medication used in the treatment of other conditions, such as Parkinson’s Disease.

Typically, MAOIs are used as a last-line option for the treatment of depression because they have many interactions with other drugs, and an overdose can be deadly.

Some MAOI medications include:

Nardil (phenelzine)
Parnate (tranylcypromine)

Atypical Antidepressants

Atypical antidepressants is the term used to classify the remaining available antidepressants that have unique mechanisms of action and do not fall under another, more specific, category.

Atypical antidepressants include:

Wellbutrin (bupropion)
Remeron (mirtazapine)
Serzone (nefazodone)
Desyrel (trazodone)
Viibryd (vilazodone)
Trintellix (vortioxetine)

Effectiveness of Antidepressants

Antidepressant medications are widely accepted as effective and beneficial for the management of depression. The simple answer to the question “Do antidepressants work?” is yes; however, it can take several weeks for these medications to reach full effectiveness, making it a slow, sometimes frustrating process when choosing or switching antidepressant medications.

Because there are so many options available for depression treatment, recently there has been increasing debate regarding which options are the best for first-line treatment. A recent review evaluating the results of over 500 clinical studies concluded that five antidepressants appear to be more effective, better tolerated and less likely to be changed after eight weeks of treatment than other drugs. These drugs are:

Lexapro (escitalopram)
Paxil (paroxetine)
Zoloft (sertraline)
Remeron (mirtazapine)
Agomelatine (a medication that is not marketed in the United States)

When evaluating the most effective antidepressant medications, the effectiveness of a certain medication is dependent on the person’s brain chemistry. Although the findings of the above-mentioned study may provide some guidance regarding good first-line options for treatment, a doctor should consider a person’s unique symptoms, medical history, and risk for side effects when choosing the most appropriate option for a patient.

Because antidepressants generally take several weeks to achieve full effectiveness, it is very important to take the medication on a regular basis, to follow-up with a doctor routinely and to not stop the medication abruptly, which could cause withdrawal reactions.

Side Effects

Common side effects of antidepressants include:

Nausea and vomiting
Weight gain
Diarrhea or stomach upset
Sleep disturbances, such as feeling very sleepy or having difficulty falling asleep
Sexual dysfunction

Some antidepressants can have serious side effects and these side effects should be discussed with your doctor:

Suicidal thinking
Birth defects
High blood pressure

When researching antidepressants, there is a lot of controversy regarding the long-term effects of antidepressants. Some research suggests that the use of antidepressants may increase the risk for a person dying prematurely. However, many prescribers maintain that the appropriate use of these medications can help patients lead happier and healthier lives.

Also, due to the nature of how antidepressant medications work and the neurotransmitters that they affect, it is possible for patients to experience a decrease in effectiveness over time due to the brain becoming less responsive to the medications, also known as tolerance.

Typically, the most bothersome side effects for patients are antidepressants’ sexual side effects and weight gain. Weight gain is a possible side effect with nearly all antidepressants except Wellbutrin (bupropion). Bupropion is commonly considered the medication of choice for patients who would benefit from possible antidepressant weight loss.

When considering the possible side effects of any medication, including antidepressants, it is important for prescribers and patients to weigh the risks and benefits of taking a certain medication. If the benefits outweigh the risks, then it is a good choice. It is important to be upfront with a doctor regarding expectations for treatment to have the best chance for treatment success.

Risk of Suicide

Antidepressants and suicide have become increasing concerns in the health care community. In 2004, the Food and Drug Administration (FDA) required manufacturers to add a boxed warning to all antidepressant medications to highlight the increased risk of suicidal thinking or behavior in children and adolescents during the initiation of treatment. In 2007, this warning was expanded to include young adults up to the age of 24 years old.

Because of the potential for antidepressants causing suicidal thoughts, routine follow-up and closing monitoring are very important in helping prevent a tragic outcome. Patients should inform their health care provider immediately if they begin to feel worse or develop new symptoms, especially after changing their medication or dose.

If you or someone you know is having suicidal thoughts, don’t wait to get help. Call your doctor immediately, go to an emergency room or call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255). If you’d rather not speak to a person, you can reach the Crisis Text Line by texting HOME to 741741 from anywhere in America.

Serotonin Syndrome

Because some antidepressant medications achieve their effectiveness by increasing the amount of serotonin in the brain, they have the risk of causing serotonin syndrome. Serotonin syndrome is a potentially life-threatening condition with symptoms like:

Agitation
Muscle tremors
Racing heartbeat
Vomiting
Diarrhea
Increased sweating
Muscle rigidity

Serotonin syndrome has been reported with SSRIs and SNRIs. Serotonin syndrome can occur when SSRIs and SNRIs are taken alone, but the risk of experiencing this condition rises when these drugs are taken with other serotonergic agents, like St. John’s Wort and tricyclic antidepressants and triptans, or other drugs like fentanyl, lithium, tramadol and amphetamines.

If someone believes that they are experiencing serotonin syndrome, they should discontinue their medication immediately and seek medical treatment right away. The risk for serotonin syndrome increases during treatment initiation and dose increases. It is important to discuss the signs and symptoms of serotonin syndrome with a health care provider when taking medications that may increase levels of serotonin in the body.

Possible Interactions

Antidepressant interactions exist with many other medications (prescription and over-the-counter), supplements and food. Specifically, MAOIs are the most notable antidepressant class for having interactions with other medications, supplements and food. However, TCAs, SNRIs and SSRIs carry the risk for serotonin syndrome among other interactions. Because depression commonly occurs with other medical conditions, it is important to discuss the potential for drug interactions with a health care provider.

One example of a common combination of medications is antidepressants and antipsychotics. The antidepressants and antipsychotics interaction happens because SSRIs and some antipsychotics compete in the liver for a limited amount of enzymes that are responsible for the metabolism of the medication. With a decrease in the metabolism of these medications, drug levels in the blood will fluctuate and may lead to decreased effectiveness of the medication or drug levels that are too high.

Also, antidepressants can have interactions with certain foods and beverages. One very serious interaction is between antidepressants and alcohol. Alcohol has multiple ways of interacting with antidepressants, and it can negatively affect depression and can worsen the side effects of certain antidepressants, such as SSRIs. It is important to discuss the possibility of antidepressant interactions when speaking with a health care provider.

Taking Antidepressants While Pregnant

Many women of childbearing age will ask their doctors about the possible effects of antidepressants on pregnancy. Taking antidepressants while pregnant is not a concern for some antidepressants. However, some other antidepressant medications might harm an unborn baby if an expectant mother takes them during pregnancy. If someone is considering taking an antidepressant medication and is pregnant, plans to become pregnant or is breastfeeding, it’s best to consult a doctor before taking antidepressants.

Stopping Antidepressants

There are many reasons why a patient may consider or be considered by their health care provider for discontinuation of their antidepressant treatment. When discontinuing antidepressants, it is important to taper (gradually decrease the dose) over at least several weeks to prevent antidepressant withdrawal.

The specific recommendations of how to taper off antidepressants is dependent on the specific antidepressant(s) that a patient is taking. It is important to discuss any questions regarding stopping an antidepressant with a health care provider.

What to Do in Case of Overdose

Antidepressant overdose can be very serious and must be treated by trained medical professionals. What happens when you overdose on antidepressants depends on the type of antidepressant(s) you are taking. Most SSRIs are noted as being considered generally safe, but when taken in excessive dosages, they have a risk for a serious heart arrhythmia called QTc prolongation. Additionally, TCAs and MAOIs can be fatal when taken in excess.

If you think someone may have taken an overdose of an antidepressant (or any drug), call poison control at 1-800-222-1222 immediately as assistance is available 24 hours a day.

Get More Information on Antidepressants

If you or someone you know needs more information regarding antidepressants, you can gather more information regarding these medications by:

Speaking with a mental health professional or therapist
Talking with a primary care doctor
Visiting MedlinePlus: Antidepressants
Visiting HelpGuide: Antidepressant Medications

Do you or does someone you love struggle with drug or alcohol addiction and depression? The Recovery Village is here to help with comprehensive, compassionate treatment. We have several facilities that can offer treatment for depression and addiction. To speak with a caring representative, call The Recovery Village today.

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Editor – Camille Renzoni

Cami Renzoni is a creative writer and editor for The Recovery Village. As an advocate for behavioral health, Cami is certified in mental health first aid and encourages people who face substance use disorders to ask for the help they deserve. Read more