Which tricyclic antidepressants (TCAs) have the lowest side effect profiles?

Tricyclic Antidepressants with the Lowest Side Effect Profiles

Secondary amine tricyclic antidepressants (TCAs), specifically nortriptyline and desipramine, have the lowest side effect profiles among TCAs due to their lower anticholinergic effects and better tolerability. 1, 2

Comparison of TCAs by Side Effect Profile

Secondary Amine TCAs (Preferred)

• Nortriptyline has the most favorable side effect profile among TCAs, with low anticholinergic activity, relatively few cardiac side effects (even in patients with preexisting cardiac disease), and less orthostatic hypotension 1
• Desipramine also has a less toxic side effect profile, especially with respect to anticholinergic effects, making it more suitable for patients who are sensitive to these effects 1, 3
• Secondary-amine TCAs are considered safer because of their lower affinity for muscarinic receptor antagonism 2
• Both nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs) and have fewer interactions with other medications 3

Tertiary Amine TCAs (Higher Side Effect Burden)

• Amitriptyline and imipramine (tertiary amine TCAs) have higher rates of anticholinergic effects, orthostatic hypotension, sedation, and impaired cardiac conduction 2, 4
• Tertiary-amine TCAs are associated with significant adverse anticholinergic effects and are considered potentially inappropriate medications in the American Geriatric Society's Beers Criteria 2
• Common side effects of tertiary amine TCAs include drowsiness, dry mouth, blurred vision, constipation, urinary retention, and cardiovascular effects 4

Side Effect Comparison Between TCAs and Other Antidepressants

• A meta-analysis comparing SSRIs with TCAs showed that patients receiving TCAs were more likely to withdraw from studies and discontinue drug therapy because of adverse reactions 2
• The overall odds ratio of discontinuation on tricyclic/heterocyclic antidepressants compared with SSRIs was 0.86 (95% CI 0.78-0.94), indicating higher discontinuation rates with TCAs 5
• However, when comparing newer TCAs with SSRIs, the difference in discontinuation rates was not statistically significant (odds ratio 0.89,95% CI 0.74-1.06) 5

Specific Side Effects of Concern with TCAs

Cardiovascular Effects

• TCAs can cause hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, and heart block 6
• Data from a large retrospective study showed an increased risk of sudden cardiac death associated with TCA doses >100 mg/day 2
• Caution should be taken in any patient with a history of cardiovascular disease, and some authorities recommend an electrocardiogram before starting treatment 2

Anticholinergic Effects

• Common anticholinergic side effects include dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment 6, 2
• Secondary amine TCAs (nortriptyline, desipramine) have significantly fewer anticholinergic effects than tertiary amine TCAs (amitriptyline, imipramine) 1, 2

Central Nervous System Effects

• Neurologic effects include numbness, tingling, paresthesias, incoordination, ataxia, tremors, and seizures 6
• Psychiatric effects include confusional states (especially in the elderly), hallucinations, disorientation, anxiety, agitation, and insomnia 6

Clinical Applications and Recommendations

• For painful diabetic peripheral neuropathy, amitriptyline and imipramine are commonly prescribed at doses of 25-75 mg/day, but secondary amine TCAs like nortriptyline and desipramine are better tolerated 2
• For irritable bowel syndrome, TCAs have shown efficacy for global symptoms and abdominal pain, with secondary amine TCAs being preferred for IBS-C due to their lower anticholinergic effects 2
• For chronic low back pain, tricyclic antidepressants were slightly to moderately more effective than placebo for pain relief 2

Practical Prescribing Considerations

• Start at a low dose, especially in older adults (approximately 50% of the adult starting dose) 2
• Carefully titrate the dose to minimize side effects, using small increments at intervals that allow an adequate period of observation (usually at least a week at each dose level) 2
• The analgesic dose is potentially lower than the antidepressant dose for TCAs 2
• If treatment must be stopped, dose tapering is advisable to reduce the risk of a discontinuation syndrome 2

In conclusion, when a TCA is indicated, secondary amine TCAs (nortriptyline and desipramine) should be preferred over tertiary amine TCAs (amitriptyline and imipramine) due to their more favorable side effect profiles, particularly regarding anticholinergic effects, cardiovascular effects, and overall tolerability.