Can amitriptyline (tricyclic antidepressant) cause polydipsia (excessive thirst)?

Amitriptyline and Polydipsia: Anticholinergic Side Effect Profile

Amitriptyline can cause polydipsia (excessive thirst) as a result of its anticholinergic properties, which commonly manifest as dry mouth. This side effect is well-documented among tricyclic antidepressants (TCAs).

Mechanism of Action and Side Effects

Amitriptyline works through multiple mechanisms, including:

• Inhibition of serotonin and norepinephrine reuptake
• Blockade of muscarinic-1 receptors (anticholinergic effect)
• Blockade of α1-adrenergic receptors
• Blockade of histamine-1 receptors 1

The anticholinergic effects are particularly relevant to polydipsia, as they include:

1. Dry mouth (xerostomia) - The most common anticholinergic side effect, which can lead to compensatory increased fluid intake (polydipsia)
2. Other anticholinergic effects:
   • Blurred vision
   • Constipation
   • Urinary retention
   • Cognitive dysfunction

Evidence for Anticholinergic Effects

A 2023 systematic review and meta-analysis specifically examining amitriptyline's anticholinergic adverse drug reactions found:

• Anticholinergic side effects were significantly more common with amitriptyline compared to placebo (OR = 7.41; 95% CI, 4.54 to 12.12)
• Dry mouth was among the most frequently reported anticholinergic side effects
• These effects were not clearly dose-dependent 2

Clinical Considerations

Risk Factors for Increased Anticholinergic Burden

• Older age (elderly patients are more susceptible)
• Concurrent use of other medications with anticholinergic properties
• Higher doses of amitriptyline
• Prolonged treatment duration

Management of Amitriptyline-Induced Polydipsia

If a patient develops polydipsia while taking amitriptyline, consider:

1. Dose reduction - Lower doses may reduce anticholinergic side effects while maintaining therapeutic benefit
2. Alternative TCAs - Secondary amines (nortriptyline, desipramine) generally have fewer anticholinergic effects than tertiary amines like amitriptyline 1
3. Alternative drug classes - Consider medications with less anticholinergic burden:
   • For neuropathic pain: pregabalin, gabapentin, duloxetine 3
   • For depression: SSRIs (except paroxetine, which has higher anticholinergic effects) 3

Differential Diagnosis

It's important to rule out other causes of polydipsia when a patient on amitriptyline presents with excessive thirst:

1. Medication-induced polydipsia - Other psychotropic medications, particularly antipsychotics, can cause polydipsia through various mechanisms 4
2. Psychogenic polydipsia - Common in psychiatric patients, characterized by excessive water intake without physiological stimulus 5
3. Diabetes insipidus - Can coexist with psychogenic polydipsia, especially in patients on lithium therapy 5
4. Diabetes mellitus - Hyperglycemia causing osmotic diuresis and compensatory thirst

Conclusion

When prescribing amitriptyline, clinicians should:

• Monitor for signs of anticholinergic side effects, including dry mouth and polydipsia
• Consider alternative medications with lower anticholinergic burden in patients at high risk
• Educate patients about potential side effects and management strategies
• Distinguish between medication-induced polydipsia and other causes of excessive thirst

If polydipsia develops, switching to nortriptyline may be beneficial as it maintains similar efficacy with a better side effect profile 1.