The tricyclic antidepressants – TCAs
Tricyclic antidepressants continue to be prescribed worldwide (Table Dosing of Tricyclic Antidepressants), although in most countries they are considered second line agents due to their limited safety and tolerability. Among the tertiary amines, amitriptyline, clomipramine and imipramine are the main mixed-uptake blocking agents and have been most extensively investigated. In meta-analyses of tricyclic antidepressants compared to SSRIs, amitriptyline was more effective in hospitalized depressed patients compared to SSRIs, although discontinuation rates were also higher. Amitriptyline, usually at a sub-antidepressant dose, continues to be prescribed for the management of chronic pain, but this may decrease in response to recent reports that several dual-action antidepressants (duloxetine, milnacipran and venlafaxine) effectively treat painful physical symptoms, including diabetic neuropathic pain. While clomipramine is often used to treat hospitalized depressed patients in Europe, it is only indicated for the treatment of obsessive compulsive disorder in the United States. Desipramine and nortriptyline are secondary amines that preferentially block norepinephrine (norepinephrine) reuptake. They respectively display linear and curvilinear dose-response pharmacokinetics. Monitoring of tricyclic antidepressant plasma levels is recommended for therapeutic and safety reasons.
Table Dosing of Tricyclic Antidepressants*
|Drug||Dosage adjustment (mg)|
*These are five examples of tricyclic antidepressants (TCAs); ofher tricyclic antidepressants include doxepin, dosulepin, maprotiline, profripfyline and trimipramine. Maprotiline is a heterocyclic antidepressant.
**Lower starting dose indicated with previous sensitivity to side-effects or with polypharmacy; often
applies to elderly patients.
***Higher doses often exceed recommended upper limits in formularies; these doses should be used with caution.
A major limitation of tricyclic antidepressants is their actions beyond inhibition of norepinephrine or serotonin (5HT) transporters, including effects on cholinergic muscarinic, alpha-adrenergic and histamine H1 receptors (Figure Antidepressant side-effects). Antagonism of these receptors may result in various side-effects: anticholinergic and cardiovascular effects are the most prevalent, especially in elderly patients. Side-effects for the most frequently prescribed tricyclic antidepressants are reviewed in Table Frequently reported side-effects across TCAs.
Table Frequently reported side-effects across TCAs
|Antidepressant||Incidence of side-effects|
|> 30%||> 10%|
|Amitriptyline||Dry mouth; sedation||Disorientation / confusion||Tremor|
|Weight gain||Asthenia; fatigue||Orthostatic|
|Blurred vision||hypotension / dizziness|
|Sexual dysfunction||Blurred vision||hypotension / dizziness|
|Weight gain (over 6 kg)|
|Imipramine||Dry mouth||Drowsiness; sedation||Sweating|
|hypotension / dizziness||Excitement; hypomania||Tremor|
|Desipramine||None||Blurred vision||Delayed micturition|
|Dry mouth||Tachycardia; palpitations|
|Nortriptyline||None||Disorientation / confusion||Constipation|
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