Nortriptyline

Nortriptyline is part of the tricyclic antidepressant (TCA) family—an older class of medications first introduced in 1959 (9). It works by increasing the levels of certain brain chemicals, including serotonin and noradrenaline, which influence both mood and how the body processes pain (9).

Although TCAs are generally as effective as newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), they are linked to more side effects and a higher likelihood of patients stopping treatment. This is why SSRIs—like fluoxetine (Prozac) and citalopram—are usually preferred as first-line treatments for depression (9, 8).

That said, nortriptyline has a somewhat different side-effect profile to its close relative amitriptyline, and is often considered to be better tolerated with fewer risks (4, 23). Because of this, nortriptyline is sometimes chosen in cases where patients have not responded well to other options.

Pharmacological Profile

Nortriptyline has multiple actions in the body (4, 20, 24, 8, 9):

• It prevents the reuptake of noradrenaline more strongly than amitriptyline, boosting its levels in the brain.

• It also affects serotonin, contributing to its antidepressant effect.

• It blocks several types of receptors, including adrenergic (involved in blood pressure and alertness), muscarinic (linked to memory and digestion), and histaminic (linked to allergy and sleep).

• Like other TCAs, it shows anti-inflammatory effects, which are being studied for their role in conditions such as neuropathic pain, pain sensitisation, and even atherosclerosis (16, 1).

This broad pharmacology is part of why nortriptyline has both benefits and risks. Its side effects are generally less tied to heart problems than amitriptyline, but they can still be significant, especially in older adults (20, 9).

Anticholinergic Effects and Brain Health

One important effect of nortriptyline is its anticholinergic activity. This means it reduces the action of a brain chemical called acetylcholine, which plays a role in memory, attention, and coordination.

Although nortriptyline’s anticholinergic effects are weaker than those of amitriptyline, they can still lead to problems such as:

• Memory loss

• Confusion

• Delirium (sudden confusion and disorientation)

• Increased risk of falls

• A higher chance of triggering or worsening dementia

The overall impact of these effects across all the medications a person takes is called the anticholinergic burden (11, 12, 13).

Anticholinergic Burden in Older Adults

Anticholinergic burden is particularly important in older adults, many of whom are prescribed multiple medications. Even drugs with mild anticholinergic activity—such as those for urinary incontinence or irritable bowel syndrome—can add to the total burden.

Healthcare professionals are especially mindful of this risk in older patients because:

• Multiple medicines can add together to create a stronger effect.

• Stress, hospital stays, frailty, or polypharmacy (taking many medicines) can make symptoms worse.

• The longer a person is exposed, the greater the impact.

• Symptoms can be mistaken for “normal ageing,” delaying the real cause being recognised.

• Anticholinergic effects interfere with the brain’s natural protective mechanisms, possibly accelerating inflammation and neurodegeneration.

• Misdiagnosis can lead to a “prescribing cascade,” where extra drugs are added to treat side effects rather than stopping the cause.

Nortriptyline contributes less to anticholinergic burden than amitriptyline but is still considered a moderate-to-high risk drug, often classed as Category 2–3 on the Anticholinergic Burden Scale (10).

Serotonin Syndrome Risk

Nortriptyline is less likely than amitriptyline to cause serotonin syndrome, but the risk is not zero. Because it increases serotonin, nortriptyline can interact with:

• Other antidepressants (SSRIs, MAO inhibitors)

• Painkillers such as tramadol and certain opioids

• Supplements such as St John’s Wort or tryptophan

Serotonin syndrome is a rapid-onset condition that can occur within 1 hour in about 30% of cases, or within 6 hours in about 60% of cases (17).

Symptoms include:

• Mental changes: agitation, anxiety, confusion, seizures, coma

• Muscle symptoms: tremors, poor coordination, rhythmic jerks (myoclonus)

• Autonomic symptoms: sweating, diarrhoea, fever, very high temperature (>40°C), rapid heart rate (tachycardia)

Not all symptoms need to be present for diagnosis. Serotonin syndrome can be mild but is sometimes life-threatening—urgent medical attention is required.

Prolonged QT Interval

All TCAs, including nortriptyline, can increase the risk of QT prolongation—a change in the heart’s electrical rhythm that can lead to dangerous arrhythmias. This risk is generally higher for TCAs than SSRIs, and among TCAs, amitriptyline is the most strongly associated (7).

Symptoms (15):

• Palpitations

• Light-headedness or fainting

• Weakness

• Seizures (in some cases)

Risk factors (15):

• Female sex

• Older age

• Use of multiple QT-prolonging drugs

• Electrolyte imbalances (low potassium, magnesium, or calcium)

• Heart disease, heart failure, or recent heart attack

• Liver or kidney dysfunction

• Genetic predisposition (e.g., Long QT Syndrome)

If you experience these symptoms, seek immediate medical attention.

Overdose and Toxicity

Nortriptyline is toxic in overdose, though generally considered slightly less so than amitriptyline (24, 17). Symptoms may include:

• Dry mouth

• Low blood pressure (hypotension)

• Seizures

• Serious heart arrhythmias

• Dilated pupils

• Urinary retention

• Coma (mild to severe)

Nortriptyline Side Effects

Nortriptyline’s side effects reflect its pharmacology, but compared to amitriptyline, they are generally milder in terms of sedation and anticholinergic load (20, 4, 8).

Most Common Side Effects

• Drowsiness or fatigue

• Constipation

• Dry mouth

• Dizziness

• Headache

• Palpitations

Effects from Blocking Alpha-Adrenergic Receptors

Nortriptyline can block alpha-adrenergic receptors, which influence blood pressure and alertness. This can cause:

• Low blood pressure when standing (orthostatic hypotension)

• Dizziness

• Sedation

Anticholinergic Side Effects

Nortriptyline has about half the anticholinergic activity of amitriptyline. Anticholinergic means reducing the action of acetylcholine, a brain chemical important for memory, attention, and coordination. This can lead to:

• Blurred vision

• Dry mouth

• Difficulty passing urine (urinary retention)

• Fast heart rate (tachycardia)

• Acute angle-closure glaucoma (a serious eye condition)

• Confusion

• Delirium

Histamine Receptor Blockade

Nortriptyline is much less potent than amitriptyline at blocking histamine receptors—about 25 times less. Even so, this action may still cause:

• Sedation

• Increased appetite

• Weight gain

• Confusion

• Delirium

Other Reported Side Effects

• Suicidal thoughts or ideation (especially in younger patients)

• Increased risk of seizures

• Abnormal liver function tests

Nortriptyline is mainly broken down by an enzyme called CYP2D6. Your genes affect how active this enzyme is, which can change how well the medicine works and whether side effects appear (19, 8, 20).

• Slow metabolisers (poor CYP2D6 function): The drug stays in the body longer, increasing the risk of side effects. Doctors may recommend starting at a lower dose.

• Fast metabolisers (ultrarapid CYP2D6 function): The drug is cleared too quickly, so it may not reach effective levels. In these cases, an alternative medicine may be a better choice.

• Most people (normal metabolisers): Standard doses usually work as expected.

Drug interactions can also mimic genetic effects—for example, some antidepressants block CYP2D6 and raise nortriptyline levels.

Related Medications:

Pharmacogenetic factors may also be important for other TCAs:

• Clomipramine

• Imipramine

• Amitriptyline

• Doxepin

• Trimipramine

• Protriptyline

• Desipramine

(CYP2D6 is key across the class; CYP2C19 matters more for the tertiary-amine TCAs listed above.)