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Imipramine


A classic antidepressant with fewer sedating effects.

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Introduction to Imipramine

Imipramine belongs to the tricyclic antidepressant (TCA) family, one of the earliest classes of antidepressants introduced in the 1950s (27).

Although TCAs are generally as effective as newer selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac) or citalopram, they tend to cause more side effects and have higher dropout rates (8, 9).

Imipramine is not usually a first-line treatment today. Instead, it is sometimes prescribed for more severe or melancholic depression, where its more stimulating (activating) profile may be beneficial (27, 4).

Imipramine

Considerations for Patients Taking Imipramine

Imipramine works by blocking the reuptake of serotonin and noradrenaline, increasing their levels in the brain. It also blocks several receptor systems, including adrenergic, muscarinic, and histaminic receptors (8, 9).

Like other TCAs, imipramine also shows anti-inflammatory effects, which are being studied for potential roles in neuropathic pain, pain sensitisation, and even conditions such as atherosclerosis (16, 1).

This wide-ranging activity makes imipramine effective but also responsible for a broad profile of possible side effects, especially in older adults (8, 9).

Anticholinergic Burden and Brain Health

Imipramine has strong anticholinergic effects—meaning it reduces the activity of acetylcholine, a neurotransmitter vital for memory, learning, and coordination.

These effects can lead to:

  • Memory loss

  • Confusion

  • Delirium

  • Increased risk of falls

  • A higher chance of triggering or worsening dementia

The total impact of these effects is called the anticholinergic burden (11, 12, 13).

Older adults are especially vulnerable, because many already take multiple medications that contribute to this burden (for example, some drugs used for urinary incontinence or IBS). Over time, the cumulative effect can mimic “normal ageing,” leading to misdiagnosis and unnecessary prescribing cascades.


Serotonin Syndrome

By increasing serotonin levels, imipramine can interact with other serotonin-boosting drugs such as SSRIs, MAO inhibitors, tramadol, opioids, or supplements like tryptophan and St John’s Wort (17).

This can trigger serotonin syndrome, a potentially life-threatening condition. Symptoms usually appear quickly—within 1 hour in around 30% of cases, and within 6 hours in about 60% of cases (17)—and may include agitation, tremors, diarrhoea, fever, or seizures. Immediate medical help is required.


Prolonged QT Interval

Like most TCAs, imipramine can prolong the QT interval—a change in the heart’s electrical rhythm that increases the risk of arrhythmias (7).

Symptoms may include (15):

  • Palpitations

  • Dizziness or fainting

  • Weakness

  • Seizures (in some cases)

Risk factors include (15):

  • Female sex

  • Older age

  • Electrolyte imbalances (e.g., low potassium, magnesium, calcium)

  • Use of multiple QT-prolonging drugs

  • Heart disease or recent heart attack

  • Liver or kidney dysfunction

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


Overdose and Toxicity

Imipramine overdose can be dangerous, with symptoms including (27):

  • Dry mouth

  • Severe drowsiness or coma

  • Low blood pressure

  • Convulsions

  • Serious heart arrhythmias

  • Dilated pupils

  • Urinary retention


Imipramine vs Other TCAs

Imipramine is often described as a “well-behaved” TCA:

  • It has an activating profile, which may suit melancholic depression.

  • Its anticholinergic burden is significant—though generally less severe than amitriptyline.

  • It carries a toxic cardiac risk profile similar to other TCAs (27, 4).

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Why Have I Been Prescribed Imipramine?

An alternative to other antidepressants

An alternative to other antidepressants


Imipramine is generally not used as a first-choice antidepressant. However, it may be prescribed when other treatments are not effective, particularly in melancholic depression (27).

Imipramine Does

How and when to take it

How and when to take it


Depressive Illness

  • Adults: Start at up to 75 mg daily in divided doses, then gradually increase to 150–200 mg daily. Up to 150 mg may be given as a single bedtime dose.

  • Older adults: Start at 10 mg daily, increasing gradually to 30–50 mg daily.

Imipramine Side Effects

Imipramine can cause a broad range of side effects. Like other tricyclic antidepressants, it affects several different brain and body systems at once. Compared to amitriptyline, its side effects are generally a little less intense, but they still include:

  • Anticholinergic effects such as dry mouth, constipation, blurred vision, or difficulty passing urine. These can also affect thinking and memory, especially in older adults.

  • Sedation and dizziness, though usually milder than with amitriptyline.

  • Weight gain and increased appetite, due to its effect on histamine receptors.

  • Heart-related risks, such as palpitations or changes in heart rhythm, which is why regular monitoring is important.

  • Other possible effects include headaches, mood swings, or in rare cases, seizures.

Because of these risks, imipramine is usually prescribed only when other antidepressants haven’t worked well enough, or when its particular profile is thought to suit a patient’s needs (27, 4).

Most Common Side Effects

  • Weight gain

  • Constipation

  • Dry mouth

  • Dizziness

  • Headache

  • Drowsiness (somnolence)


Effects from Blocking Alpha-Adrenergic Receptors

  • Low blood pressure when standing (orthostatic hypotension)

  • Dizziness

  • Sedation


Anticholinergic Side Effects

  • Blurred vision

  • Dry mouth

  • Difficulty passing urine (urinary retention)

  • Fast heart rate (tachycardia)

  • Acute angle-closure glaucoma

  • Confusion

  • Delirium


Histamine Receptor Blockade

  • Sedation (less pronounced than amitriptyline)

  • Increased appetite

  • Weight gain

  • Confusion

  • Delirium


Other Reported Side Effects

  • Suicidal thoughts or ideation

  • Increased risk of seizures

  • Abnormal liver function tests

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How Your Body and Genes Process Imipramine

How your body breaks down imipramine—and the way your genes influence this process—can affect how well the medicine works for you and whether you are more likely to experience side effects (28, 19). Like other TCAs, imipramine goes through several steps in the body before reaching its active form and then being cleared away. Understanding these steps helps explain why dosing may need to be adjusted for different people.

AbsorptionAbsorption

  • Bioavailability: ~50% (range 20–70%), due to extensive first-pass metabolism in the liver.

  • Peak concentrations: Reached within 2–8 hours.

MetabolismMetabolism

  • CYP2C19: Converts imipramine into its active metabolite desipramine, which primarily inhibits noradrenaline reuptake.

  • CYP2D6: Breaks down both imipramine and desipramine into inactive metabolites.

Personalising Imipramine with Pharmacogenetics

Because imipramine depends on both CYP2C19 and CYP2D6, genetic differences in these enzymes can affect how well the drug works and how likely side effects are.

  • Poor metabolisers (CYP2C19 or CYP2D6):
    Higher drug levels, with increased risk of side effects such as dizziness, drowsiness, or heart rhythm problems.
    → Recommendation: Start at 50% of the usual dose with close monitoring.

  • Ultrarapid metabolisers (especially CYP2D6):
    Drug is broken down too quickly, leading to lower blood levels and reduced effectiveness.
    → Recommendation: Consider switching to another antidepressant not dependent on CYP2D6.

  • Normal metabolisers:
    Standard dosing usually applies, adjusted according to clinical response.

Pharmacogenomic testing can help clarify whether imipramine is the right choice, although in practice, dose adjustments are often guided by side effects and clinical benefit.

Related Medications:

Other TCAs with similar genetic considerations include:

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References

(1) https://www.mdpi.com/1424-8247/18/2/197 (2) https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2017.00307/full (3) https://www.mdpi.com/2227-9059/5/2/24 (4) https://pmc.ncbi.nlm.nih.gov/articles/PMC2014120/ (5) https://www.nature.com/articles/s41392-024-01738-y (6) https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-020-01296-8 (7) https://pmc.ncbi.nlm.nih.gov/articles/PMC5972123/ (8) https://www.ncbi.nlm.nih.gov/books/NBK537225/ (9) https://www.ncbi.nlm.nih.gov/books/NBK557791/ (10) https://pmc.ncbi.nlm.nih.gov/articles/PMC9427617/ (11) https://journals.sagepub.com/doi/10.1177/20451253231195264 (12) https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2019.01309/full (13) https://onlinelibrary.wiley.com/doi/10.1111/jnc.15244 (14) https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15261 (15) https://pmc.ncbi.nlm.nih.gov/articles/PMC4110870/ (16) https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1072629/full (17) https://pmc.ncbi.nlm.nih.gov/articles/PMC6539562/ (18) https://www.nice.org.uk/about/what-we-do/evidence-and-best-practice-resources/british-national-formulary--bn (19) https://pmc.ncbi.nlm.nih.gov/articles/PMC5478479/ (20) https://www.ncbi.nlm.nih.gov/books/NBK482214/ (21) https://pmc.ncbi.nlm.nih.gov/articles/PMC6493872/ (22) https://pmc.ncbi.nlm.nih.gov/articles/PMC9048453/?utm_source=chatgpt.com (23) https://pubmed.ncbi.nlm.nih.gov/7395525/ (24) https://pmc.ncbi.nlm.nih.gov/articles/PMC11141239/ (25) https://pubmed.ncbi.nlm.nih.gov/9537821/ (26) https://www.ncbi.nlm.nih.gov/books/NBK541006/ (27) https://www.ncbi.nlm.nih.gov/books/NBK557656/ (28) https://www.researchgate.net/publication/372475601_Therapeutic_drug_monitoring_of_imipramine_correlation_with_a_case_study (29) https://www.ncbi.nlm.nih.gov/books/NBK542306/ (30) https://pmc.ncbi.nlm.nih.gov/articles/PMC4027305/ (31) https://pubmed.ncbi.nlm.nih.gov/39202/ (32) https://www.sciencedirect.com/science/article/abs/pii/002839089190160D (33) https://link.springer.com/article/10.1007/BF02190274 (34) https://pubmed.ncbi.nlm.nih.gov/2693055/ (35) https://pmc.ncbi.nlm.nih.gov/articles/PMC3555062/