Clomipramine

Clomipramine is unusual among TCAs because it is an exceptionally strong serotonin reuptake inhibitor—as potent as the strongest SSRI, paroxetine (25). This makes it particularly effective for conditions like OCD, but also increases the risk of serotonin-related complications.

Pharmacology and Specificity

Clomipramine works by blocking the reuptake of serotonin and noradrenaline and interacts with several receptor systems, including adrenergic, muscarinic, and histaminic receptors (8, 9).

Like other TCAs, clomipramine also shows anti-inflammatory properties, which may play a role in neuropathic pain and pain sensitisation, and are even under investigation in conditions such as atherosclerosis (16, 1).

Because of this broad pharmacology, clomipramine has both therapeutic benefits and a complex profile of risks, particularly in older adults (8, 9).

Anticholinergic Burden and Brain Health

Clomipramine has anticholinergic effects—it reduces the activity of acetylcholine, a brain chemical important for memory, learning, and coordination. Although weaker than amitriptyline’s, these effects can still accumulate, especially when combined with other medicines.

The overall load is known as the anticholinergic burden (11, 12, 13). This is especially important in older adults, who are more likely to be taking multiple medications.

Factors that make anticholinergic burden more harmful include:

• Multiple drugs adding together, even weak ones (e.g., some treatments for urinary incontinence or IBS)

• Inflammatory stressors such as hospitalisation, frailty, or polypharmacy

• Long-term use, which increases the cumulative impact

• Advanced age and frailty, which make people more sensitive

• Effects being mistaken for “normal ageing,” leading to under-recognition

• The potential for a “prescribing cascade,” where new drugs are added to treat what are actually side effects

Serotonin Syndrome

Because clomipramine is such a strong serotonin reuptake inhibitor, it carries a higher risk of serotonin syndrome than other TCAs (25).

Serotonin syndrome may occur if clomipramine is combined with other serotonergic medications—such as SSRIs, SNRIs, MAO inhibitors, tramadol, or opioids—or with supplements like tryptophan and St John’s Wort (17).

It typically develops quickly: within 1 hour in around 30% of cases, and within 6 hours in about 60% of cases (17). Symptoms can affect the brain, muscles, and autonomic functions (see dedicated section above).

Prolonged QT Interval

Like all TCAs, clomipramine can increase the risk of QT prolongation—a change in the heart’s electrical rhythm that can lead to dangerous arrhythmias. TCAs are more likely to cause this than SSRIs (7).

Risk factors include (15):

• Female sex

• Older age

• Electrolyte imbalances (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)

Because of these risks, doctors may be especially cautious when prescribing clomipramine in people with known heart problems.

Clomipramine Side Effects

Clomipramine’s side effects reflect its complex pharmacology. Some are shared with other TCAs, while others are more pronounced due to its very strong serotonin reuptake inhibition (20, 4, 8).

Most Common Side Effects

• Drowsiness or fatigue

• Constipation

• Dry mouth

• Dizziness

• Headache

• Palpitations (awareness of heartbeats)

Effects from Blocking Alpha-Adrenergic Receptors

Blocking these receptors, which help regulate blood pressure, may cause:

• Low blood pressure when standing (orthostatic hypotension)

• Dizziness

• Sedation

Anticholinergic Side Effects

Although clomipramine blocks muscarinic (acetylcholine) receptors less strongly than amitriptyline, it can still cause:

• 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

Clomipramine is less potent at blocking histamine receptors than amitriptyline, but this effect can still contribute to:

• Sedation

• Increased appetite

• Weight gain

• Confusion

• Delirium

Serotonin-Related Side Effects

Because clomipramine is the most powerful serotonin reuptake inhibitor among TCAs (25):

• Sexual dysfunction (erectile dysfunction, difficulty reaching orgasm)

• Higher seizure risk compared to other TCAs

• Much higher risk of serotonin syndrome than other TCAs (see section above)

Other Reported Side Effects

• Suicidal thoughts or ideation (especially in younger patients)

• Abnormal liver function tests

Because clomipramine relies on both CYP2C19 and CYP2D6, genetic differences in these enzymes can strongly influence treatment response (19, 26).

• Poor metabolisers (CYP2C19 or CYP2D6):
  The drug (and its metabolite) break down more slowly, leading to higher blood levels and greater risk of side effects (such as dizziness, low blood pressure, or heart rhythm changes).
  → Clinical guidance recommends starting at ~50% of the usual starting dose with careful monitoring.

• Ultrarapid metabolisers (especially CYP2D6):
  The drug is cleared too quickly, meaning blood levels may never reach a therapeutic range.
  → In this case, switching to an alternative not primarily metabolised by CYP2D6 or CYP2C19 is often advised.

• Normal metabolisers:
  Standard doses usually work as expected, with adjustments made according to clinical response.

Drug interactions can also mimic genetic effects—for example, taking strong CYP2D6 inhibitors (such as fluoxetine or paroxetine) can make a normal metaboliser behave like a poor metaboliser.

Related Medications:

Pharmacogenetic factors may also be important for other TCAs, including:

• Nortriptyline

• Imipramine

• Amitriptyline

• Doxepin

• Trimipramine

• Protriptyline

• Desipramine