Depression, Risk of Suicide, and Treatment Options

What is Major Depressive Disorder (MDD)?

Depression is not a trivial illness. In fact, according to the National Institute of Mental Health (NIMH), 7.1% of all adults, or 17.3 million people in the U.S. have had at least one depressive disorder.

Depression, also referred to as major depressive disorder (MDD), can result in difficulties with family life, work, and social activities. Depression is not just feeling blue occasionally. Depression affects daily feelings, thoughts, and actions over a longer period of time.

Medical conditions such as arthritis, cancer, and diabetes may worsen, too.

The good news is that depression is treatable with a high rate of success using treatment options such as prescription medications and psychotherapy (talk therapy).

What Are the Symptoms of Depression?

Many people with depression have a severe low mood, tearfulness, or a sense of hopelessness that has lasted for at least 2 weeks. Other symptoms may include irritability, anxiety, or short-tempers.

Participation in enjoyable activities declines and many people may withdrawal from family or friends. Changes in sleeping or eating habits, constant self-criticism, or drug and alcohol abuse may also surface. One may attempt to hurt themselves or commit suicide.

Signs that someone is thinking about suicide might include talking about death and dying, or engaging in self-destructive or risky behaviors, or threatening to do so.

Could I Be at Risk for Depression?

Depression does not play favorites. Anyone from any age group, socioeconomic status, or ethnic background is subject to depression.

Some groups that tend to have a higher incidence of depression include:

• People between 45 to 64 years of age
• Elderly
• Women
• Blacks, hispanics, and non-hispanics of other color
• Education less than high school degree
• Those who are divorced
• Unemployed
• People without health insurance

Personality traits such as low self-esteem or mental health disorders, traumatic life events, a family history of depression or abuse of alcohol or recreational drugs can also increase the risk of depression.

Do We Know What Causes Depression?

Depression has been suggested in the past to involve changes in brain chemicals (neurotransmitters like serotonin and norepinephrine) that control our mood, although the exact causes of depression are not fully known. Recent research has suggested that changes in neurotransmitters like serotonin may not be the mechanism at all.

Depression may involve multiple factors, such as:

• Genetics or family history
• Chronic or acute health conditions like cancer, pain, stroke or heart disease
• Situations like job loss, workplace stress, financial problems or physical or mental abuse
• Severe grief due to death of a loved one
• Some prescription drug side effects (do not stop treatment without speaking to your doctor
• Abuse of alcohol or drugs
• Hormonal changes in women
• People who are lesbian, gay, bisexual, transgender or queer (LGBTQ) in an unsupportive environment

Are There Different Types of Depression?

Yes. There are many different types of depression, but all are amenable to some form of treatment.

The most common types of depression include:

• Major Depression (or Major Depressive Disorder)
• Dysthymia
• Seasonal Affective Disorder
• Depressive Psychosis
• Postpartum Depression
• Premenstrual Dysphoric Disorder (PMDD)

If you suffer from symptoms resembling depression, please talk to a trusted friend and a healthcare provider. Help is available and may be lifesaving.

You can also call the National Suicide Prevention Hotline at 1-800-273-8255, 24 hours a day, 7 days a week, or have an online chat. All information is confidential and free.

What Kind of Treatments Are Available for Depression?

The most common treatments for depression revolve around two different approaches:

• prescription medications
• talk therapy (psychotherapy) with a trained specialist like a mental health counselor.

Often, these two approaches are effectively used together. There are different types of psychotherapy and this treatment can help you to:

• Set realistic and daily goals
• Work through a crisis situation
• Develop coping and problem solving skills
• Learn to develop positive relationships
• Replace negative thoughts with positive ones

• ECT

In the most severe cases of major depression that have not responded to other treatments, electroconvulsive therapy (ECT) can be a very effective and life-saving option. Although this treatment is controversial, it is administered to keep the patient safe from injury. The patient is under anesthesia for the entire procedure. In the U.S., ECT treatments are usually given 2 or 3 times per week for 3 to 4 weeks, for a total of 6 to 12 treatments.

Options for Antidepressants

No single antidepressant is the best for everyone.

Patients have different responses to antidepressants, such as effectiveness and side effects. Most antidepressants take 4 to 6 weeks for a full effect, and only about half of patients respond to their first treatment. But there are many choices and a trial of one or two different classes may be needed.

Examples of common antidepressant classes include:

• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
• Phenylpiperazine Antidepressants
• Tricyclic Antidepressants
• Tetracyclic Antidepressants
• Monoamine Oxidase Inhibitors
• Other Miscellaneous Antidepressants

Antidepressants: Coping With Side Effects

Many antidepressants are well-tolerated, but a few side effects may occur, especially at the beginning of treatment.

When you start an antidepressant, many initial side effects like upset stomach, headache or anxiety may go away after a short period, usually in two to three weeks. It takes about 4 to 6 weeks for the full effect of most antidepressants to kick in, too. So, it is important to stick with your medicine for at least a month, taking it as prescribed by your doctor.

If your side effects seem intolerable, don't stop taking your antidepressant without speaking to your doctor.

Abruptly stopping some antidepressants may cause withdrawal-like symptoms or worsen your depression and mood. Speak with your doctor. You may just need a dose adjustment. Alternatively, your doctor may switch you to a new drug or class of medicine.

Managing Side Effects: Nausea and Vomiting

It is important to remember you will not experience every antidepressant side effect that's listed in product labeling.

For those who do have common side effects, coping mechanisms can help until the side effect subsides.

Nausea can start fairly quickly after beginning treatment with some antidepressants, usually within the first week, but it may go away within a month. If you experience nausea or vomiting, check with your doctor or pharmacist to see if you can take your medicine with food to help lessen stomach upset.

Be sure to drink plenty of noncarbonated fluids, and eat smaller, but more frequent meals. If your nausea does not subside, talk to your doctor about a temporary dose reduction or another antidepressant.

Managing Side Effects: Sexual Problems

Sexual dysfunction, including reduced sex drive, inability to reach orgasm, erectile dysfunction, and ejaculatory failure, is a common side effect of many antidepressants. Many people consider stopping treatment, but there are effective ways to combat this side effect.

Classes known to cause these side effects include the selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). SSRIs can lead to this effect in about 50% of people. In the SNRIs, venlafaxine has the highest risk of this side effect. Tricyclic and tetracyclic antidepressants and monoamine oxidase inhibitors, which are older and less frequently used antidepressants, can also cause frequent sexual side effects.

Some strategies to cope with sexual side effects that your doctor might recommend include:

• Waiting a few weeks to see if these sexual side effects subside.
• Changing your dose or switching you to another antidepressant with lower sexual side effects
• Add bupropion or change to an antidepressant with lower sexual side effects such as bupropion (Wellbutrin XL, Wellbutrin SR), mirtazapine (Remeron), vilazodone (Viibryd), or vortioxetine (Trintellix)
• For men, consider use of ED drugs such as sildenafil (Viagra), vardenafil (Staxyn), avanafil (Stendra), or tadalafil (Cialis).
• However, avoid unproven remedies such as herbs or supplements that promise enhanced sexual performance. Speak to your doctor pharmacist if you have questions about OTC products.

Keep lines of communication open with your partner. Discuss your concerns over medication use and sexual side effects, and consider if adjustments to your sexual routine are needed, such as enhanced foreplay.

Managing Side Effects: Weight Gain

Weight gain while taking antidepressants can be due to many different factors. Just feeling better with a desire to eat may be one cause. Older age, in general, can be linked to weight gain in some people.

When your mood improves, you may have a better appetite, and this can lead to unexpected weight gain. In addition, lack of physical activity or water retention can also lead to weight gain.

Some antidepressants that are associated with weight gain include:

• Paroxetine (Paxil, Pexeva), a selective serotonin reuptake inhibitor (SSRI)
• Mirtazapine (Remeron), which is an atypical antidepressant
• Older antidepressants known as tricyclic antidepressants (amitriptyline, imipramine, doxepin, trimipramine) and some monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil)

Other tips: As you start to feel better, be sure to engage in regular, doctor-approved exercise that might help to combat any weight gain. Engage in physical activity for at least 30 minutes most days of the week. Cut back on sugar and sweets, avoid saturated and trans fats, see a dietician for meal-planning and diet advise.

Managing Side Effects: Drowsiness, Insomnia, Agitation, Headaches

Drowsiness can be a temporary antidepressant side effect early in treatment, and may subside after a few weeks. It may be possible to take your antidepressant before bed, so that you feel less drowsy in the daytime.

• Paroxetine (common brands: Paxil, Paxil CR, Pexeva, Brisdelle) is an SSRI known to lead to drowsiness. Mirtazapine, trazodone, and the tricyclic antidpressants can also cause this side effect. Of the MAOIs, phenelzine may cause the most sedation.
• It's important you do not drive when you are drowsy. If drowsiness persists, talk to your doctor. You may be able to switch to another antidepressant with a lower risk of sedation.

On the flip side, maybe your antidepressant causes insomnia? Trouble sleeping is a common side effect with some antidepressants like fluoxetine (Prozac). If your antidepressant keeps you up at bedtime, ask your doctor if you can take your dose in the morning, although htis may not fully remedy the insomnia. Sertraline, vilazodone, immediate-release bupropion and some MAOIs may cause lower levels of insomnia.

• Activating antidepressants can cause anxiety or agitation, too; be sure to contact your doctor to be sure you don't have an undiagnosed bipolar disorder if ongoing agitation or insomnia is a problem.
• Avoid caffeine in the afternoon, and be sure to engage in regular exercise which can boost your mood and help with restlessness and insomnia.

Mild headaches are common with initial antidepressant therapy and should subside in a few weeks; if not, contact your doctor.

The Selective Serotonin Reuptake Inhibitors (SSRIs)

Names of common SSRIs include:

• citalopram (Celexa)
• escitalopram (Lexapro)
• paroxetine (Paxil, Paxil CR, Brisdelle, Pexeva)
• fluoxetine (Prozac)
• sertraline (Zoloft)

For a full list of SSRIs, visit here.

Side effects among this class can vary, but include include sexual dysfunction, drowsiness, weight gain, insomnia, anxiety, dizziness, headache, and dry mouth. A higher risk of stomach bleeding or diabetes (which may be linked with weight gain) or bone loss are other possible side effects noted in observational studies.

Review side effects in more detail here.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Venlafaxine (Effexor, Effexor XR), desvenlafaxine (Pristiq), duloxetine (Cymbalta) and levomilnacipran (Fetzima) are classified as Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). Although the exact mechanism is unknown and controversial, they have been proposed to work by increasing the levels of brain neurotransmitters serotonin and norepinephrine to treat depression.

Common side effects may include:

• nausea (especially with venlafaxine); nausea may be transient and subside after a few weeks
• dry mouth
• insomnia
• drowsiness, dizziness
• anxiety
• sexual problems (especially with venlafaxine)
• headache
• excessive sweating
• constipation
• loss of appetite

The SNRIs can usually be given once-a-day, and venlafaxine may be useful in patients who have hard-to-treat depression.

Duloxetine (Cymbalta) is also used for painful conditions like osteoarthritis, neuropathic pain, and fibromyalgia, but may increase blood pressure and worsen sweating.

Miscellaneous (Atypical) Antidepressants

Atypical antidepressants work by like other antidepressants by changing brain neurotransmitters (such as such as dopamine, serotonin or norepinephrine) called to help regulate mood and relieve depression. They are atypical because they all work in their own unique way.

However, trazodone, nefazodone and vilazodone may also be referred to as serotonin modulators.

Atypical antidepressants include:

• trazodone
• nefazodone
• mirtazapine (Remeron)
• vilazodone (Viibryd)
• bupropion (Wellbutrin XL, Wellbutrin SR, Forfivo XL, )
• bupropion hydrobromide extended-release tablets (Aplenzin)
• vortioxetine (Trintellix)

Bupropion, vilazodone, trazodone or nefazodone may result in less sexual dysfunction, and bupropion may lead to weight loss. Mirtazapine may be linked weight gain more than others in this group. Vortioxetine, vilazodone or higher doses of trazodone may cause worse stomach upset, nausea or diarrhea than others in this group.

Trazodone, nefazodone, and mirtazapine can be sedating, which may be a plus in patients who are depressed and also have trouble sleeping. Nefazodone has been linked to liver failure, be sure to tell your doctor if you've ever had liver problems as you may not be able to use this drug.

In rare cases, trazodone has been linked to heart rhythm problems and priapism, a long-lasting painful erection of the penis not associated with sexual arousal. Priapism is considered an emergency so get help medical right away (or call 911).

Bupropion may be added SSRI treatment to help reverse sexual dysfunction; it can also help boost patients who feel fatigued. Bupropion must be avoided in patients with a risk for seizures, as higher doses of bupropion can increase this risk and in those with an eating disorder such as bulimia or anorexia.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs include:

• selegiline transdermal (Emsam)
• phenelzine (Nardil)
• isocarboxazid (Marplan)
• tranylcypromine (Parnate)

Side effects such as lightheadedness (especially when standing up), weight gain, drowsiness, headache, insomnia, nausea, constipation, dry mouth, or sexual dysfunction may occur.

Tyramine found in dried fruit, aged cheeses, pickles, smoked meats, fava beans, and red wine can lead to a spike in blood pressure, headache, nausea, and other serious effects when combined with this drug class.

MAOIs are not used as first-line depression treatment as there are more tolerable antidepressants with fewer food and drug interactions. If one is prescribed, be sure to avoid these foods and drinks and follow a list of low tyramine foods.

Tricyclic Antidepressants (TCAs)

The tricyclic antidepressants (TCAs) are a large class of older antidepressants that include:

• amitriptyline
• amoxapine
• desipramine
• imipramine
• doxepin
• nortriptyline
• protriptyline
• trimipramine

TCA side effects include dry mouth, dizziness, constipation, blurred vision, sedation, urine retention, fast heart rate, and weight gain; many of these side effects are due to anticholinergic action of the TCAs.

Like the MAOIs, TCAs are rarely used initially as first-line treatments for depression; however, they may be used in adults for other indications, including nerve pain and migraine headache prevention.

A TCA overdose can be fatal. Heart rhythm disturbances, seizures, and depressed breathing are serious overdose complications.

Trintellix: A Serotonergic Antidepressant

In 2013 the FDA approved Trintellix (vortioxetine) to treat adults with major depressive disorder (MDD). More than 7,500 patients aged 18 to 88 years old were enrolled in clinical trials demonstrating Trintellix effectiveness.

Trintellix’s proposed mechanism of action is to enhance serotonin activity in the brain by blocking serotonin reuptake and may be referred to as a serotonin modulator. Trintellix has several other actions at serotonin receptors, and is a unique agent with this combination of serotonergic activity.

The most common side effects reported by participants taking Trintellix in clinical trials included nausea, constipation and vomiting. Trintellix is available in 10 mg and 20 mg tablets and is taken once a day.

Fetzima: A Once-Daily SNRI

Fetzima (levomilnacipran extended-release capsules), a once-daily serotonin and norepinephrine reuptake inhibitor (SNRI) was FDA-approved for treatment of Major Depressive Disorder (MDD) in adults in 2012. Levomilnacipran is the active enantiomer of milnacipran (Savella) which is only approved for the treatment of fibromyalgia.

In Phase III studies of adults with MDD, a significant improvement in depression was seen with Fetzima given once daily compared to placebo.

Common side effects occurring in greater than 5% of patients included nausea, constipation, and sweating.

Rexulti and Abilify MyCite

In July 2015, the FDA approved Rexulti (brexpiprazole), an oral antipsychotic medication for schizophrenia that is also approved to treat major depressive disorder (MDD) in combination with an antidepressant. Rexulti is a serotonin-dopamine activity modulator (SDAM) and second-generation version of aripiprazole (Abilify), with a reduced incidence of a bothersome side effect known as akathisia (restlessness).

• Common side effects seen in the depression studies included restlessness, diarrhea, nausea, weight gain, headache and somnolence.
• Rexulti is not approved for use in psychotic conditions related to dementia. In addition, healthcare providers should see the label for significant drug interactions that can affect the dose of Rexulti.

In November 2017, the FDA approved Otsuka’s Abilify MyCite (aripiprazole), an atypical antipsychotic for depression in adults that is meant to improve adherence and monitoring.

• The Abilify tablet formulation is embedded with the ingestible Proteus sensor that allows patients (and doctors and caregivers if given acess by the patient), to track ingestion of the medication on a smartphone or web-based portal.
• The system sends a message from the pill’s sensor to a wearable patch on the patient, which then transmits to the device.
• Abilify can be used without the sensor for adjunctive treatment of depression, as well (in combination with an antidepressant).

Serious Class Effect: Risk of Suicide

In general, antidepressants are safe medications that can have a profound beneficial effect in aptients with depression. There are some important warnings for the class as a whole.

The FDA requires a Boxed Label on all antidepressant prescribing information to include strong warnings about risks of suicidal thinking and behavior, known as suicidality, in children, adolescents and young adults. A Boxed Warning is FDA's most prominent warning. An example of this warning can be seen here on the Paxil label.

This risk may be higher during the initial few months of treatment, when the dose is changed, or with a personal or family history of bipolar disorder or suicidal action. Initially high doses of antidepressants in children have been linked with elevated suicide risk. If you or someone you know has suicidal thoughts or actions when taking an antidepressant, immediately contact your doctor or get emergency help (call 911).

Studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24. There was a reduction in suicide risk with antidepressant use in patients aged 65 and older.

It is important to remember that untreated depression itself is also linked with a risk suicide. Caregivers and healthcare providers should closely monitor patients for suicidal signs and symptoms within the first few months of treatment initiation and with any dose or drug change.

SSRI Use in Children: The FDA's Overview

In an FDA review, no suicides occurred among 2,200 children treated with SSRI medications, according to the National Institutes of Mental Health. However, about 4 out of 100 of those children taking SSRIs experienced suicidal thinking, including attempts, at twice the rate of those taking placebos.

Due to this increased risk, the FDA requires a "Boxed Warning" about the risk for suicide or attempted suicide in children and adolescents on all antidepressant labels.

Some studies suggest that the benefits of antidepressants may outweigh the risks to certain children with major depression and anxiety disorders. However, only two SSRI agents are approved for use in pediatrics for depression:

• fluoxetine (Prozac) is currently approved to treat major depressive disorder in children and adolescents over the age of 8 years.
• escitalopram (Lexapro) is approved for the acute and maintenance treatment of major depressive disorder in adolescents 12 years of age and older.

Some antidepressants are also approved in children for other diagnoses like obesessive compulsive disorder, anxiety or bipolar depression.

How to Manage the Risk of Suicide

You can call 988 OR 1-800-273-TALK (8255) at any time for the National Suicide Prevention Lifeline. Do not hesitate to call this number for free and confidential emotional support, available 24/7. Online chat is also avaialble at https://988lifeline.org/chat/

• To better understand the risk of suicide, patients and caregivers are strongly encouraged to review and discuss with a healthcare provider the FDA Medication Guide available for all antidepressants.
• According the scientific data in patients taking antidepressants, the risk for suicide is not increased in adults older than 24 years. Adults 65 years and older taking antidepressants actually have a decreased risk of suicidality.
• It is not known if any one antidepressant is more or less likely to result in suicidal thoughts or action.

Do Not Abruptly Stop Taking your Antidepressant

Do not stop taking your antidepressant without first talking to your doctor, even when you have a side effect. Why?

Abruptly stopping an antidepressant can lead to a host of unpleasant withdrawal symptoms such as:

• anxiety
• worsened depression
• moodiness
• irritability
• fatigue
• headaches
• dizziness
• nausea/vomiting
• diarrhea.

Your doctor may recommend that the antidepressant be slowly discontinued (also referred to as "tapered") to help prevent withdrawal side effects. They will tell you how you can best taper the medication dose over a period of time.

Serotonin Syndrome: A Rare But Serious Effect

Many antidepressants alter the levels of neurotransmitters like serotonin in the brain.

Serotonin helps to facilitate chemical messages in the brain and it is thought this helps with the symptoms of depression.

Taking multiple drugs or an overdose of a drug that boosts serotonin levels can lead to an overload of serotonin in the body and unpleasant, dangerous and potentially fatal side effects such as:

• Confusion
• Hallucinations
• Nausea-vomiting
• Rapid heart rate
• High fever
• Incoordination

Anytime you start or even stop a medication, be sure to have your doctor or pharmacist review for potential drug interactions. This includes prescription drugs, over-the-counter (OTC) treatments, herbal or supplements, and even vitamins.

Drug Interactions Can Lead to Serotonin Syndrome

Serotonin syndrome can occur rarely when two drugs that increase brain serotonin are taken together.

Do not start new medicines without first checking with your healthcare provider.

Examples of drugs that may cause serotonin syndrome include:

• Triptan migraine medications
• Certain monoamine oxidase inhibitors (a class of antidepressants)
• L-tryptophan
• St. John’s Wort
• Dextromethorphan
• Meperidine (Demerol)
• Some drugs of abuse, such as Ecstasy and LSD

Antidepressants and Cost Concerns

Prescription medications can be costly for many patients, especially those without adequate health insurance. However, many of the most effective and well-tolerated antidepressants are now available in generic forms.

Generic formulations can save a patient literally hundreds -- or maybe thousands -- of dollars per month. Talk to your doctor or pharmacist about available generic alternatives for antidepressants, which include:

• fluoxetine
• citalopram
• paroxetine
• venlafaxine
• bupropion
• trazodone
• mirtazapine

What if My Antidepressant Does Not Work?

If the first antidepressant you try does not work or results in intolerable side effects, there are other options, so do not give up. If you have no improvement in your symptoms after four to six weeks, talk to your doctor about switching to a different antidepressant or antidepressant class, or adjusting your dose.

If you think you should stop taking your antidepressant, speak with your doctor FIRST so that another agent can be tried or a tapering schedule can be started if needed.

Finally, consider talk therapy with a trained professional who can offer methods to help lessen your depression, boost positive and appropriate thoughts and feelings, and increase your quality of life.

Spravato Nasal Spray: A Novel Antidepressant

Difficult-to-treat or resistant depression can be a challenge for clinicians and patients alike, especially because it can often take weeks for the drug to become fully effective.

In March 2019 the FDA approved Janssen’s Spravato (esketamine), a rapidly-acting non-competitive N-methyl D-aspartate (NMDA) receptor antagonist used with an oral antidepressant for treatment-resistant depression. It is given as a nasal spray.

Spravato is a controlled substance in DEA Schedule III and can only be accessed via a restricted distribution system (REMS). Patients will receive the drug at a certified doctor's office and cannot take the drug home.

• In Phase 3 studies of over 1,700 adults, all patients received an oral antidepressant, and either intranasal placebo or Spravato. In the group that received Spravato, superior improvement in depression symptoms was seen at four weeks compared to the placebo plus oral antidepressant group.
• However, most of Spravato’s treatment difference compared to placebo was observed at 24 hours instead of several weeks, as with many other antidepressants
• Patients receiving Spravato plus an oral antidepressant were over 50% less likely to relapse as compared to patients on placebo.

The most common side effects were a disassociation, or a feeling of being detached from one’s surroundings, dizziness, and nausea, among other side effects.

Zulresso: The First Treatment Approved For Postpartum Depression

In March 2019 the FDA approved Zulresso (brexanolone) injection from Sage Therapeutics for the treatment of postpartum depression (PPD) in women. PPD symptoms may include:

• sadness
• withdrawal
• lack of self-worth
• reduced maternal-infant bond
• suicidal tendencies.

Zulresso is a gamma-aminobutyric acid A (GABA-A) receptor positive allosteric modulator and is the first drug specifically approved for PPD. It is administered as an intravenous infusion over 60 hours in a certified clinic because there is a risk of sedation and loss of consciousness during administration. It is also prescribed via a restricted REMS program due to these risks.

Other drug classes, such as SSRIs and SNRIs have long been used to treat post-partum depression, even though they may not have that specific indication.

In clinical studies, Zulresso was superior to placebo in improvement of moderate and severe PPD symptoms at the end of the first infusion and at the end of a 30-day follow-up period.

Side effects include sleepiness, dry mouth, loss of consciousness and flushing. Zulresso can also cause serious side effects such as suicidal thoughts or actions.

Auvelity, a Novel and Rapid-Acting Antidepressant

Auvelity (dextromethorphan and bupropion), from Axsome Therapeutics, is the first oral N-methyl-D-aspartate (NMDA) receptor antagonist approved for the treatment of MDD. Auvelity uses the first new oral mechanism of action for depression in more than 60 years. It was approved by the FDA in August 2022.

• It is thought to work by modulating glutamatergic neurotransmission. The dextromethorphan component is an NMDA receptor antagonist / sigma-1 receptor agonist and bupropion is an aminoketone and CYP2D6 inhibitor which serves to increase and prolong the blood levels of dextromethorphan.
• In placebo-controlled clinical studies with more than 1,100 patients, Auvelity exhibited a rapid and statistically significant antidepressant effect starting at one week
• The initial recommended dose is one tablet once daily in the morning, which is increased to one tablet twice daily after 3 days.

Auvelity carries a Boxed Warning for suicidal thoughts and behaviors. Other warnings and precautions include: increased seizure risk, increased blood pressure / hypertension, mania or hypomania, psychosis and other neuropsychiatric reactions, angle-closure glaucoma, dizziness, serotonin syndrome, and embryo-fetal toxicity.

Common side effects (≥5%) are dizziness, headache, diarrhea, somnolence (drowsiness), dry mouth, sexual dysfunction, and hyperhidrosis (excessive sweating).