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Antidepressants: Options, Advantages, and Precautions

Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Feb 10, 2020.

Is Depression Common?

Feeling sad or blue is not unusual; it happens to most of us. But ongoing feelings of despair, frequent tearfulness, trouble with eating and sleeping, and withdrawal from family and friends may mean there is a more serious concern of depression. According to the National Institute of Mental Health (NIMH), major depressive disorder is one of the most common mental illnesses in the United States. Depression does not play favorites: it can impact anyone regardless of age, race or socioeconomic status.

According to the 2017 National Survey on Drug Use and Health as reported by the National Institute of Mental Health (NIMH) - their most recent data - roughly 17.3 million adults (7.1%) in the U.S. had at least one major depressive episode in 2017.

  • It's higher among females (8.7%) than males (5.3%), highest in the age groups 18 to 25 years (10.9%), and highest among adults reporting two or more races or ethnic groups (11.3%).
  • The prevalence of adults with a major depressive episode was highest among individuals aged 18-25 (13.1%).
  • Of adults with major depressive episode diagnosed in 2017, 63.8% had severe impairment.
  • Data also shows that of adults with major depressive episode, 35% did not receive any treatment -- either psychotherapy (talk therapy) or medication. 

What Causes Depression?

The exacts causes of depression are not fully known. In general, depression does not have a single cause and the reason why a patient is depressed is often hard to pinpoint. Depression may be due to a mixture of:

  • biological and genetic traits
  • adverse medical conditions
  • situational events such as job loss, divorce, stress, trauma, or violence
  • severe grief after the death of a loved one
  • side effects due to prescription medications
  • alcohol use and substance abuse

What is known is that for most patients, medical treatment can be very effective and possibly life-saving. Good options for treatment for depression include drug therapy, psychotherapy such as cognitive behavioral therapy (CBT), or a combination of the two. The American Psychiatric Association states antidepressant medication is recommended as an initial treatment choice for most patients with major depressive disorder, from mild to severe.

Patients should be screened for bipolar disorder prior to initiation of treatment of major depression.

Learn MoreDepression: Symptoms, Subtypes and Diagnosis

Medical Treatments for Depression

The cornerstone treatments for depression are prescription antidepressants and talk therapy with a trained specialist (psychotherapy) -- and they are often used together most effectively.

  • Drug therapy used in treatment involves medications that alter the chemical messengers (neurotransmitters) in the brain.
  • It generally takes four to eight weeks for most patients to feel the full effects of antidepressant medications.
  • Many patients will need to continue antidepressant medications for six months to a year, or longer.

No single antidepressant medication has been found to be the best treatment for every patient. In general 40% to 60% of patients (4-6 out of 10 patients) will have a positive response to the first antidepressant medication they try. Second generation antidepressants (i.e., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors [SNRIs]) are used preferentially over first generation antidepressants (i.e., tricyclic antidepressants [TCAs] or monoamine oxidase inhibitors [MAOIs]) because of a less toxic side effect profile and better patient tolerability.

Typically, it takes from 4 to 8 weeks to have a full clinical response to an antidepressant. If the first treatment does not work, your doctor might suggest increasing the dose or taking an antidepressant from a different class.

Generic medications may be significantly more affordable. If cost is an issue, patients should tell their physician they prefer generics when possible, and they should check with their pharmacist for available options. There are many affordable generic options for the more common antidepressants.

In addition to depression, certain antidepressants may also be used to treat a range of other conditions, for example:

  • anxiety
  • bed-wetting
  • bulimia nervosa
  • neuropathy, nerve-related pain
  • fibromyalgia
  • hot flashes
  • migraine headache prevention
  • obsessive-compulsive disorder (OCD)
  • panic disorder
  • post-traumatic stress disorder (PTSD)
  • premenstrual dysphoric disorder
  • treatment-resistant depression

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs increase levels of serotonin in the brain by preventing the reuptake of serotonin by nerve cells. They are often selected as a first-line drug treatment for depression due to effectiveness and a lower risk of side effects compared to older antidepressants. Most SSRIs are now available in generic form, making them very affordable.

Table 1: SSRIs Used for Depression

Generic name Brand name examples
citalopram Celexa
escitalopram Lexapro
fluoxetine Prozac, Prozac Weekly*, Rapiflux, Sarafem, Selfemra
fluvoxamine Luvox*, Luvox CR
paroxetine Brisdelle, Paxil, Paxil CR, Pexeva
sertraline Zoloft
vilazodone Viibryd

*brand discontinued

Common side effects in this class may include:

  • insomnia (difficulty sleeping)
  • sexual problems
  • nervousness, anxiety
  • dizziness
  • headache
  • stomach upset
  • possible weight gain
  • sweating
  • diarrhea
  • constipation

Pros and cons:

  • fluoxetine, citalopram and sertraline associated with less weight gain than paroxetine.
  • paroxetine may be associated with higher rates of withdrawal symptoms, sexual side effects.
  • sertraline may result in higher rates of diarrhea.
  • fluoxetine is associated with lower rates of withdrawal symptoms.
  • paroxetine is shown similar to duloxetine for pain treatment in patients with depression.
  • increased risk for stomach bleeding with SSRI treatment as a class.

See also: Selective serotonin reuptake inhibitors (SSRIs)

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs block or delay the reuptake of two neurotransmitters in the brain, serotonin and norepinephrine. By blocking reuptake, the neurotransmitter concentrations are increased in the nerve synapse to help elevate mood or treat other conditions. These agents may also be selected as a first-line treatment option, especially in patients with more severe depression. Several generic SNRIs are now available.

Table 2: SNRIs Used for Depression

Generic name Brand name examples
desvenlafaxine Khedezla, Pristiq 
duloxetine Cymbalta, Irenka
levomilnacipran Fetzima
milnacipran (used for fibromyalgia pain, not depression) Savella
venlafaxine Effexor, Effexor XR

Common side effects in this class may include:

  • nausea
  • dry mouth
  • insomnia (difficulty sleeping)
  • drowsiness
  • dizziness
  • anxiety
  • sexual problems
  • headache
  • sweating
  • loss of appetite

Pros and Cons:

  • Once-a-day dosing with most formulations.
  • SNRIs may be linked with more nausea and vomiting than SSRIs but this typically subsides within one week.
  • SNRIs may be more effective than SSRIs in resistant or refractory (difficult-to-treat) depression.
  • Duloxetine also approved to treat certain pain syndromes (fibromyalgia, chronic musculoskeletal pain, peripheral neuropathy).
  • Venlafaxine or other SNRIs may increase blood pressure.

See also: Serotonin norepinephrine reuptake inhibitors (SNRIs)

Atypical Antidepressants

Atypical antidepressants work by altering one or more neurotransmitters, but do not fit into one specific class. Drugs in this class may be selected as a first-line drug to help avoid a specific side effect, such as sexual dysfunction or weight gain, or for patients who have an inadequate response with first-line agents such as SSRIs.

Table 3: Atypical Antidepressants Used for Depression

Generic name Brand name examples
bupropion Aplenzin, Budeprion XL, Budeprion SR, Buproban, Forfivo XL, Wellbutrin*, Wellbutrin SR, Wellbutrin XL
mirtazapine Remeron, Remeron SolTab

*brand discontinued

Most common side effects: mirtazapine

  • appetite increased 
  • drowsiness and sedation (>25% incidence)
  • dry mouth
  • peripheral edema
  • headache
  • weight gain

Most common side effects: bupropion

  • anxiety
  • dizziness
  • dry mouth
  • excessive sweating
  • fast or irregular heart rate
  • headache
  • nausea, stomach upset
  • sinusitis
  • tremor
  • trouble sleeping (insomnia)

Seizures can occur with higher doses of bupropion and appears to be a dose-related effect. Extended-release and sustained-release bupropion formulations have a lower peak blood level and are associated with a lower incidence of seizures (0.1% to 0.4%) compared to immediate-release formulations (0.4% with doses less than 450 mg/day). Review maximum dosing for bupropion.

Pros and Cons:

  • Bupropion may be associated with modest weight loss, but mirtazapine can cause weight gain.
  • Seizure risk with higher bupropion doses; bupropion is contraindicated in patients with a seizure disorder.
  • Bupropion not associated with sexual dysfunction; mirtazapine has a low risk of sexual problems.
  • Bupropion may be helpful for depressed patients who feel lethargic or fatigued. Mirtazapine can be useful for patients with depression who have trouble sleeping.
  • Bupropion may have a greater effect on potent CYP450 enzyme inhibition (CYP2D6) and lead to more drug interactions than mirtazapine.
  • Mirtazapine may have a faster onset of action than some other antidepressants

See also: Atypical Antidepressants

Serotonin Modulators

Serotonin modulators have multiple mechanisms that exert their antidepressant effect, and they may fall into other groups.

  • They primarily act as antagonists and agonists at post-synaptic serotonin receptors and inhibit (block) the reuptake of serotonin.
  • Nefazodone (Serzone) may also have a weak effect on norepinephrine reuptake.
  • Trazodone is thought to inhibit reuptake of serotonin, and exhibit adrenergic receptor activity, 5HT2a receptor antagonist, 5-HT presynaptic receptor changes, and block histamine (H1) and alpha1-adrenergic receptors.
  • Vortioxetine (Trintellix) may exhibit 5-HT3 receptor antagonism and 5-HT1A receptor agonism in addition to inhibition of the reuptake of serotonin (5-HT).

Table 4: Serotonin Modulators Used for Depression

Generic Name Brand Name Examples
nefazodone Serzone
trazodone Desyrel,* Oleptro*
vortioxetine Trintellix

Common side effects in this class may include:

  • blurred vision
  • constipation
  • diarrhea
  • difficulty sleeping (insomnia)
  • drowsiness, sedation
  • dry mouth

Pros and Cons:

  • Trazodone or nefazodone less likely to cause sexual dysfunction.
  • Nefazodone is a potent inhibitor of CYP3A4 with risk for serious drug interactions, although other serotonin modulators are substrates for various CYP enzymes and may have interactions, as well.
  • Nefazodone labeling contains a boxed warning for liver failure; contraindicated with elevated liver enzymes or liver disease.
  • Trazodone, nefazodone cause drowsiness; may be helpful for patients who have trouble sleeping that is associated with their depression.
  • Trazodone may rarely be associated with priapism, a painful and long-lasting erection considered a medical emergency.
  • Vortioxetine is linked with high rates of nausea (typically highest in the first week of treatment). However, in studies, it had no significant effect on body weight in either short-term or longer-term (6 month) research trials accessing weight gain. Some reports have been received of weight gain since approval, so discuss this side effect further with your doctor.

See also: Miscellaneous Antidepressants

Monoamine Oxidase Inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) work by irreversibly blocking the enzyme monoamine oxidase (both MAO-A and MAO-B when used for depression), and preventing the breaking down of neurotransmitters such as serotonin, norepinephrine, and dopamine. Typically used as a third or fourth line treatment due to severe side effects, diet restrictions, and the possibility of serotonin syndrome. Monoamine oxidase inhibitors (MAOIs) were the first class of antidepressant to be developed.

Table 5: MAOIs Used for Depression

Generic Name Brand Name Examples
isocarboxazid Marplan 
phenelzine Nardil
selegiline transdermal Emsam
tranylcypromine Parnate

Common side effects in this class may include:

  • vomiting
  • constipation
  • dry mouth
  • agitation or anxiety
  • sexual dysfunction
  • urinary hesitancy
  • weight gain

Pros and Cons:

  • May be used for patients with severe depression that does not respond to several other antidepressant treatments first.
  • Not used as initial treatment due to side effects, and serious drug and food interactions (i.e., foods with high amounts of tyramine such as dried fruits, red wine, cheese, pickles, smoked or processed meats, ripe figs, fava beans). The combination may lead to an increase in blood pressure, headache, nausea and vomiting, confusion, seizures, or death. Avoid tyramine for 2 weeks after discontinuation of a MAOI.
  • Phenelzine may cause less insomnia than tranylcypromine.
  • Tranylcypromine causes less weight gain, sedation, and sexual dysfunction than phenelzine.
  • Serious drug-drug and drug-food interactions can occur, consult with your health care provider before using any prescription or over-the-counter medication, vitamin, or herbal product.
  • The 6 mg per 24 hours patch form of selegiline does not result in MAOI-B inhibition in the gastrointestinal tract and tyramine dietary restrictions are not required. Higher selegiline patch doses (9 mg per 24 hours and 12 mg per 24 hours) require tyramine dietary restrictions.
  • Use caution when starting or stopping MAOI treatment to avoid a hypertensive crisis or serotonin syndrome. Continue a low tyramine diet for 2 weeks after stopping a MAOI.
  • Other antidepressants should be stopped before starting treatment with a MAOI (usually for 2 weeks, but for 5 weeks with fluoxetine due to its extended half-life). When stopping MAOI treatment, do not start another antidepressant until at least 2 weeks have elapsed.

See also: Monoamine oxidase inhibitors (MAOIs)

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are an early class of antidepressant from the 1960's and were the first-line drug of choice for depression until the late 1980's. TCAs block the reuptake of both the serotonin and norepinephrine neurotransmitters to exert their antidepressant effect. Alpha-adrenergic receptors and histamine receptors may also be blocked, causing side effects like hypotension and sedation. Most TCAs are available in a lower-cost generic form now, but are infrequently used as a first-line agent due to availability of the SSRIs with a more tolerable side effect profile.

Table 6: TCAs Used for Depression

Generic Name Brand Name Examples
amitriptyline Elavil*, Endep*
amoxapine Asendin
clomipramine Anafranil
desipramine Norpramin
doxepin Adapin*, Sinequan*
imipramine Tofranil
nortriptyline Aventyl*, Pamelor
protriptyline Vivactil
trimipramine Surmontil

*brand discontinued

The tertiary amine TCAs have a greater effect at blocking serotonin (compared to norepinephrine) and include: amitriptyline, clomipramine, doxepin, imipramine, and trimipramine. The secondary amine TCAs preferentially block norepinephrine and include: desipramine, nortriptyline, and protriptyline.

Tertiary amines tend to have more bothersome side effects than secondary amines due to anticholinergic effects (e.g., constipation, dry mouth, blurred vision) and more a more sedating effect.

Related: Anticholinergic Drugs to Avoid in the Elderly

Maprotiline (Ludiomil, brand discontinued) is classified as a tetracyclic antidepressant, but preferentially inhibits norepinephrine. Amoxapine inhibits norepinephrine reuptake and also blocks dopamine receptors. These differences in neurotransmitter inhibition can lead to differences in side effects.

Common side effects in this class may include:

  • blurred vision
  • heart toxicity in those at risk
  • constipation
  • dizziness
  • dry mouth
  • fatigue or drowsiness
  • increased heart rate
  • increased appetite and weight gain
  • orthostatic hypotension
  • urinary retention

Pros and Cons:

  • Lower cost agents that can be used second or third line if newer antidepressants such as SSRIs or SNRIs are not effective.
  • TCAs are first generation (older) antidepressants and are rarely used as initial treatment.
  • Tertiary amines like nortriptyline and desipramine tend to be tolerated best by most patients.
  • TCAs have multiple side effects that often lead to discontinuation, such as drowsiness and anticholinergic side effects (dry mouth, blurred vision, constipation, confusion, trouble urinating).
  • Most TCAs are not recommended for use in the elderly (see the Beers Criteria) or severely depressed patients at risk for suicide due to the risk for overdose with TCAs.
  • Excessive doses of TCAs can lead to cardiac toxicity such as arrhythmias (fast or irregular heart rate), seizures, and orthostatic hypotension, leading to falls and possible injury.

See also: Tricyclic antidepressants (TCAs)

Other Depression Treatments

Atypical Antipsychotics

Atypical antipsychotics are most often used to treat schizophrenia and bipolar disorder. However, some atypical (second generation) antipsychotics are approved as an add-on therapy for patients who do not have an optimal response to first-line depression treatment with a single agent. Although not classified in the drug class of antidepressants, some are approved used for this purpose. They are often combined with SSRI antidepressants. Not all atypical antipsychotics are FDA-approved for use in unipolar major depressive episodes; however, some may be used off-label.

Table 7: Atypical Antipsychotics Used for Depression

Generic Name Brand Name Examples
aripiprazole Abilify, Abilify MyCite
brexpiprazole Rexulti
cariprazine* Vraylar
fluoxetine and olanzapine Symbyax
olanzapine  Zyprexa, Zyprexa Zydis
risperidone* Risperdal
quetiapine Seroquel, Seroquel XR
ziprasidone* Geodon

*off-label use for unipolar major depression

Common side effects in this class may include:

  • difficulty concentrating or speaking
  • changes in blood pressure
  • constipation
  • difficulty sleeping
  • drooling
  • drowsiness or sedation
  • mask-like face
  • restlessness or need to keep moving (akathisia)
  • sexual dysfunction
  • shuffling walk
  • tremor
  • vision problems (blurred or double vision)
  • weight gain.

More serious side effects with this class include: neuroleptic malignant syndrome (NMS) and tardive dyskinesia.

Pros and Cons:

  • The effectiveness appears to be comparable among agents. The selection of an agent will depend upon side effects, possible drug interactions, and affordability,
  • All atypical antipsychotics may lead to weight gain, blood sugar increases, diabetes, metabolic syndrome and lipid changes (high cholesterol). Patients should be monitored for these effects.
  • Lower doses are are often used for unipolar major depression compared to doses for schizophrenia or bipolar depression.
  • Risperidone may have higher rates of extrapyramidal symptoms (EPS), uncontrollable abnormal body movements, than olanzapine.
  • Risperidone and ziprasidone may have higher rates of sexual dysfunction compared with quetiapine.
  • The benefit of using an adjunctive atypical antipsychotic in major depressive disorder typically occurs within the first two weeks of treatment.
  • Boxed warnings
    • All antipsychotics are associated with an increased risk of death when used in elderly people, especially those with dementia-related psychosis, and they are not approved for this use.
    • Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients older than 24 years of age.

The Latest Approvals for Depression

Spravato (esketamine)

In March 2019, the FDA approved Janssen’s Spravato (esketamine), a rapidly-acting non-competitive N-methyl D-aspartate (NMDA) receptor antagonist that is used with an oral antidepressant for adults with treatment-resistant major depressive disorder (MDD).

  • In Phase 3 studies of over 1,700 adults, all patients received an oral antidepressant, and either intranasal placebo or esketamine. In the group that received esketamine, 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.
  • Patients receiving Spravato plus an oral antidepressant were also 51% less likely to relapse as compared to patients on placebo nasal spray plus an oral antidepressant.
  • The most common side effects were disassociation (feeling detached from one’s surroundings), dizziness, nausea, sedation, dizziness, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting and feeling drunk.
  • Esketamine is a Schedule III controlled substance and will only be available through a restricted distribution system (REMS) due to side effects and the potential for abuse.
  • Patients will receive the drug only at a certified doctor's office and cannot take the drug home.

Zulresso (brexanolone)

Zulresso (brexanolone) injection from Sage Therapeutics was approved in March 2019 for the treatment of Postpartum Depression (PPD) in adult women. PPD is a major depressive episode that occurs following childbirth or during pregnancy with symptoms of sadness, loss of interest, inability to feel pleasure, and lack of self-worth. Postpartum depression can also interfere with the maternal-infant bond or lead to suicidality.

  • Zulresso is a gamma-aminobutyric acid A (GABA-A) receptor positive allosteric modulator and is the first approval for PPD.
  • It is given as an intravenous (IV) infusion over 60 hours (2.5 days) in a healthcare facility and is prescribed via a restricted REMS program due to possible loss of consciousness in the patient. A healthcare provider must be available to continuously monitor the patient.
  • In clinical studies, Zulresso demonstrated superiority 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.
  • Commonly reported side effects are sedation or somnolence, dry mouth, loss of consciousness, and flushing.

Less common depression treatments may include:

Important Precautions with Antidepressants

Risk of suicide

Antidepressants are usually safe and may be a life-saving therapy for many patients. However, the U.S. Food and Drug Administration has required labeling on all antidepressants to include a "black boxed warning", the strictest warning for a prescription medication, about increased risks of suicidal thinking and behavior in children, adolescents and young adults under 25 years of age. The risk may be greater in the first few weeks after starting treatment or when the dose is changed. However, it is important to remember that depression and other psychiatric problems are linked to suicide, as well. When depression is not treated, the risk of suicide can go up, too.

Patients who are using antidepressant therapy should be closely monitored by family and healthcare providers for suicidal signs and symptoms. Contact a healthcare provider immediately if changes in depression symptoms or behavior occur, or if signs of a possible suicide emerge. Observe the patient closely within the first few months of treatment and when there is a dose change.

Clinical trial evidence is not sufficient to determine if any one antidepressant is more or less likely to result in suicidal thoughts or action.

Learn MoreDepression, Risk of Suicide, and Treatment Options

Abrupt discontinuation

It is important to speak with a physician prior to stopping an antidepressant medication. Abruptly stopping an antidepressant can lead to a host of antidepressant withdrawal symptoms. Paroxetine (Paxil, Paxil CR) and venlafaxine (Effexor, Effexor XR) are especially prone to cause these symptoms if they are abruptly stopped; fluoxetine (Prozac, Prozac Weekly) is less likely to cause this problem. A health care provider may recommend that the antidepressant be slowly tapered to help prevent withdrawal side effects, which may include:

  • anxiety
  • feelings of depression or sadness
  • moodiness and irritability
  • fatigue
  • headaches and dizziness
  • nausea and vomiting
  • diarrhea

If an antidepressant is causing an unpleasant side effect that does not subside, the physician may lower the antidepressant dose or prescribe a different class of antidepressant if treatment should not be discontinued.

Serotonin syndrome

Many antidepressants, such as SSRIs and SNRIs, raise the levels of serotonin in the brain. Serotonin is a neurotransmitter that helps to facilitate chemical messages in the brain and it is thought this helps with the symptoms of depression. However, too much serotonin can lead to symptoms such as:

  • confusion
  • hallucinations
  • loss of coordination
  • fever
  • fast heart rate (tachycardia)
  • nausea and vomiting

Serotonin syndrome is a rare reaction but may occur when two drugs that elevate serotonin in the brain are taken at the same time. It is important that a drug interaction screen is performed by a physician or pharmacist any time a new medication (prescription or over-the-counter drug, vitamin, or herbal product) is taken while also taking antidepressant therapy. Examples of drugs that may cause serotonin syndrome include:

Use in Pregnancy and Breastfeeding

Many antidepressants can be continued during pregnancy or breastfeeding, but this decision is made with your doctor case-by-case looking at the risks and benefits of treatment. The risks of birth defects are low; however some antidepressants may be discouraged in pregnancy.

Other information: Antidepressants

Specific drug interactions of antidepressants with other medications may be viewed by using the Drugs.com Drug Interactions Checker. To fully review the product label and common and serious side effects, including warnings, search for your specific drug at Drugs.com Drug Index.

Learn MoreAntidepressants and Alcohol Interactions

More resources

  • U.S. Suicide Hotline: Call 1-800-273-TALK (1-800-273-8255) 24/7, free and confidential, nationwide network of crisis centers.

Sources

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.