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6.3 Antidepressants

Antidepressants are commonly used to treat depression and are also used to treat other conditions, such as anxiety, chronic pain, and insomnia. According to a research review by the Agency for Healthcare Research and Quality, antidepressant medications work relatively well in improving symptoms of depression and to keep depression symptoms from coming back.[1] For reasons not yet well understood, some people respond better to certain antidepressant medications than to others, so an individual may have to try different types of antidepressants before finding one that effectively treats their symptoms.[2] Additionally, it may take antidepressants two or more weeks to achieve peak effect.

There are several classes and types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), serotonin antagonist and reuptake inhibitors, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). TCAs and MAOIs are often referred to as first-generation antidepressants because they were first marketed in the 1950s. They have many side effects and are not prescribed as frequently to treat depression as are SSRIs, SNRIs, and NDRI that have fewer side effects.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) prevent the uptake of serotonin at the synapse, causing the serotonin neurotransmitter to stay in the synapse longer and overall raise the level of serotonin in the brain. SSRIs are primarily used to treat depression but are also used to treat bipolar disorder, obsessive-compulsive disorder, bulimia, panic disorder, post-traumatic stress disorder, anxiety, premenstrual syndrome, and migraines. Examples of common SSRIs include fluoxetine, citalopram, sertraline, paroxetine, and escitalopram.[3]

Serotonin Norepinephrine Reuptake Inhibitor (SNRI)

Serotonin norepinephrine reuptake inhibitors (SNRI) prevent the reuptake of serotonin and norepinephrine, with weak inhibition of dopamine reuptake. Examples of SNRIs are venlafaxine and duloxetine.[4]

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion is an example of a norepinephrine and dopamine reuptake inhibitor. It therefore leads to increased levels of norepinephrine and dopamine. It is used to treat depressive disorders, seasonal affective disorder, attention deficit disorder and to help people stop smoking. It is also important to note that this medication does decrease seizure threshold.[5]

Serotonin Antagonist and Reuptake Inhibitor

Trazodone is an example of a serotonin antagonist and reuptake inhibitor. It is an antidepressant but most commonly prescribed off-label for anxiety or as a hypnotic. Trazodone reduces levels of the neurotransmitters associated with arousal effects, such as serotonin, noradrenaline, dopamine, acetylcholine, and histamine. Low-dose trazodone use exerts a sedative effect for sleep, so is typically administered in the evening.[6]

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are older first-generation antidepressants that block the reuptake of serotonin and norepinephrine in the synapse, which leads to increased concentration of these neurotransmitters in the brain. They are now more commonly used to treat neuropathic pain and insomnia. An example of a TCA is amitriptyline.[7]

TCAs are often administered at bedtime due to sedating effects. Older adults are particularly sensitive to the anticholinergic side effects of tricyclic antidepressants (e.g., tachycardia, urinary retention, constipation, dry mouth, blurred vision, confusion, psychomotor slowing, sedation, and delirium). Elderly clients should be started on low doses of amitriptyline and observed closely because they are at increased risk for falls. Blockage of adrenergic receptors can cause cardiac conduction disturbances and hypotension.[8]

Death may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. If overdose occurs, call 911 in an outpatient setting or rapid response in an inpatient setting. Responders can consult with a Certified Poison Control Center (1-800-222-1222) or go to https://www.poisonhelp.org/help for the latest treatment recommendations.[9]

Monoamine Oxidase Inhibitors (MAOI)

Monoamine oxidase inhibitors (MAOIs) are an older first-generation antidepressant. MAOIs are contraindicated with all other classes of antidepressants. Monoamine oxidase is an enzyme that removes the neurotransmitters norepinephrine, serotonin, and dopamine from the brain. By inhibiting this enzyme, MAOIs cause the levels of these transmitters to increase. Tranylcypromine is an example of an MAOI.[10]

A significant disadvantage to MAOIs is their potential to cause a hypertensive crisis when taken with stimulant medications or foods or beverages containing tyramine. Examples of foods containing tyramine are aged cheese, cured or smoked meats, alcoholic beverages, and soy sauce. Older adults are at increased risk for postural hypotension and serious adverse effects.[11]

Classes of antidepressant medications and their mechanisms of action are outlined in Table 6.3a.

Table 6.3. Antidepressants

Medication Class Mechanism of Action
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Common examples:

Venlafaxine

Duloxetine

Block the uptake of both serotonin and norepinephrine from the cell synapse. Similar to SSRIs but with two neurotransmitters.
Selective Serotonin Reuptake Inhibitors (SSRIs)

Common examples:

Fluoxetine

Sertraline

Citalopram

Impact the receptors of the cell synapse to inhibit or prevent the uptake of serotonin, making the neurotransmitter serotonin stay in the synapse longer.
Tricyclic Antidepressants (TCAs)

Common examples:

Amitriptyline

Nortriptyline

Block the presynaptic receptor for norepinephrine and partially serotonin. This makes the neurotransmitter norepinephrine level increase in the synapse.
Monoamine Oxidase Inhibitors (MAOIs)

Common examples:

Phenelzine

Tranylcypromine

Block the enzyme that breaks down monoamine, which causes an increase in the level of neurotransmitters serotonin and norepinephrine.
Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Example: Bupropion

Block the uptake of both norepinephrine and dopamine from the cell synapse.
Serotonin Antagonist and Reuptake Inhibitor

Example: Trazodone

Reduces levels of the neurotransmitters associated with arousal effects, such as serotonin, noradrenaline, dopamine, acetylcholine, and histamine.

Antidepressants commonly take four to eight weeks for noticeable effects on mood symptoms.  Clients should also be counseled that if they do not feel better with the first antidepressant prescribed, the provider may need to try several different classes of medications to find one that works best for them. If a person’s symptoms do not improve after trying at least two antidepressants, esketamine may be prescribed for treatment-resistant depression. Esketamine is delivered as a nasal spray in a health care provider’s office, clinic, or hospital and acts rapidly within a few hours, to relieve depression symptoms. People usually continue to take an oral antidepressant(s) to manage their symptoms.[12]

Clients should be instructed to never suddenly stop taking antidepressant medications or they may experience withdrawal symptoms.

Withdrawal Symptoms

To safely stop or change antidepressants, clients must have prescribed dosage reductions with  2-6 weeks between dose reductions. Withdrawal syndrome may occur if antidepressants are stopped abruptly due to the rapid changes in levels of neurotransmitters in the brain. Withdrawal symptoms can include the following[13]:

  • Flu-like symptoms, such as fatigue, headache, muscle aches, and sweating
  • Fatigue
  • Flushing
  • Heart racing
  • Trouble sleeping
  • Vivid dreams or nightmares
  • Nausea, diarrhea, and possibly vomiting
  • Loss of appetite
  • Dizziness, lightheadedness, or feeling unsteady on your feet
  • Burning, tingling, or shock-like sensations
  • Mood changes, such as anxiety, irritability, agitation, and aggression
  • Brief shock-like feelings in the brain, short periods of blacking out, or a shock-like feeling with a buzzing sound

Side Effects

Nurses monitor clients receiving antidepressants for side effects and report concerns to the prescribing provider. Common side effects of SSRIs and SNRIs are as follows:

  • Nausea
  • Diarrhea
  • Weight gain
  • Insomnia
  • Feeling agitated, shaky or anxious
  • Sexual dysfunction (reduced sex drive, difficulties achieving orgasm, or difficulties obtaining or maintaining an erection)

Side effects generally improve within a few weeks, although some can occasionally persist and require tapering or switching to a different class of antidepressant.

Black Box Warning

A Black Box Warning is a significant warning from the Food and Drug Administration (FDA) that alerts the public and health care providers to serious side effects, such as injury or death. Black Box Warnings are in place for all classes of antidepressants used with children, adolescents, and young adults under age 25 due to a higher risk of suicide. All clients receiving antidepressants should be monitored for signs of worsening depression or changing behavior, especially when the medication is started or dosages changed. Clients should be instructed to immediately call their provider if they have any of the following symptoms:

  • Thoughts about suicide or dying or attempts to commit suicide
  • Worsening symptoms of depression
  • Anxiety or feelings of mania
  • Aggression, anger, or violence

Serotonin Syndrome

Serotonin Syndrome is a potentially life-threatening condition resulting from excessive serotonergic activity in the central nervous system, often triggered by the use or interaction of certain psychiatric medications. It most commonly occurs when two or more drugs that increase serotonin levels—such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or certain over-the-counter supplements—are combined. Symptoms typically include altered mental status (e.g., agitation, confusion), autonomic instability (e.g., hyperthermia, tachycardia), and neuromuscular abnormalities (e.g., tremors, hyperreflexia, clonus). Nurses play an important role in early recognition and prompt intervention, including immediate discontinuation of serotonergic agents and supportive care.

A mnemonic commonly used to remember the symptoms of serotonin syndrome is SHIVERS:

  • S: Shivering: A neuromuscular symptom similar to tremors specific to serotonin syndrome
  • H: Hyperreflexia (and myoclonus): Hyperactive reflexes most prominent in the lower extremities.
  • I: Increased Temperature
  • V: Vital Sign Abnormalities: Tachycardia, tachypnea, and labile blood pressure
  • E: Encephalopathy: Mental status changes such as agitation, delirium, and confusion
  • R: Restlessness
  • S: Sweating

People may get slowly worse and can become severely ill if not quickly treated. Untreated, serotonin syndrome can be deadly. With treatment, symptoms usually go away within 24 hours, but permanent kidney damage may result even with treatment. Uncontrolled muscle spasms can cause severe muscle breakdown called rhabdomyolysis. Myoglobin is released into the blood with muscle breakdown and clogs renal tubules, which can cause severe kidney damage if serotonin syndrome isn’t recognized promptly and treated.

Treatment of serotonin syndrome may include the following[14],[15]:

  • Stopping all serotonergic medications.
  • Providing supportive care to normalize vital signs such as IV fluids, cooling measures, and medications to control heart rate and blood pressure.
  • Sedating with benzodiazepines, such as diazepam or lorazepam, to decrease agitation, seizure-like movements, and muscle stiffness.
  • If symptoms persist, administering cyproheptadine to block serotonin production.
  • For clients with severe symptoms such as hyperthermia and muscle rigidity, more aggressive measures are required. These include sedation, intubation, neuromuscular paralysis, and active cooling techniques.[16]

Clients with moderate to severe serotonin syndrome should be hospitalized for close monitoring and management. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome (NMS) caused by antipsychotic medications. However, NMS develops over a period of days to weeks.  Neuroleptic malignant syndrome (NMS) will be discussed further in Chapter 11.

Hypertensive Crisis

Hypertensive crisis can occur when clients taking monoamine oxidase inhibitors (MAOIs) also take medications containing pseudoephedrine or eat foods containing tyramine (aged foods; fermented foods; cured meats; alcoholic beverages such as beer or red wine; or overripe fruits such as raisins, prunes, or bananas). MAOIs inhibit the breakdown of tyramine, causing elevated tyramine levels in the body that can lead to hypertensive crisis.  Hypertensive crisis is a medical emergency defined as severe hypertension (blood pressure over 180/120 mm Hg) with acute end-organ damage such as stroke, myocardial infarction, or acute kidney damage. Symptoms may include a severe headache accompanied with confusion and blurred vision. Tachycardia or bradycardia may be present and associated with constricting chest pain. Other symptoms include neck stiffness or soreness, nausea or vomiting, sweating, dilated pupils, photophobia, shortness of breath, severe anxiety, and unresponsiveness. Seizures may occur, as well as intracranial bleeding in association with the increased blood pressure. Hypertensive crisis treatment involves discontinuation of the offending agent, administration of appropriate intravenous antihypertensive medications such as phentolamine or labetalol, and supportive care.. In severe cases, treatment in the intensive care unit may be required.[17][/footnote],[18]

Client Education

Clients should be instructed it may take 4 to 8 weeks for antidepressants to achieve their full effectiveness. They should not suddenly stop taking antidepressants or they may experience withdrawal symptoms. When it is time to stop the medication, the provider will slowly and safely decrease the dose. If clients stop taking the medication before the provider advises, the depression may return. They may not feel better with the first antidepressant they try, and they may need to try several different classes of medications to find one that works best for them.  Education related to potential side effects and when to contact the provider, clinical worsening, avoiding alcohol, interference with cognitive or motor functioning, and potential drug interactions should also be provided.

Review additional information in the “Antidepressants” section of the “Central Nervous System” chapter of Open RN Nursing Pharmacology, 2e.


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  2. National Institute of Mental Health. (2023). Mental health medications. U.S. Department of Health & Human Services. https://www.nimh.nih.gov/health/topics/mental-health-medications
  3. National Institute of Mental Health. (2016). Mental health medications. U.S. Department of Health & Human Services. https://www.nimh.nih.gov/health/topics/mental-health-medications
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  15. Tanen, D. (2021). Serotonin syndrome. Merck Manual Professional Version. https://www.merckmanuals.com/professional/injuries-poisoning/heat-illness/serotonin-syndrome
  16. Spadaro, A., Scott, K. R., Koyfman, A., & Long, B. (2022). High risk and low prevalence diseases: Serotonin syndrome. The American Journal of Emergency Medicine, 61, 90-97. doi: 10.1016/j.ajem.2022.08.030.
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