Tricyclic Antidepressants (TCAs)

• Tricyclic antidepressants (TCAs) comprise one of the oldest classifications of antidepressant drugs, beginning with the approval of imipramine in 1959.
• TCAs as a class have a wide range of indications, including major depressive disorder (MDD), dysthymic disorder, neuropathic pain, and migraine or tension-type headache. Individual TCAs may also have additional indications (e.g., imipramine for enuresis, clomipramine for obsessive compulsive disorder).
• TCAs are generally considered to have similar efficacy to selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) in mild to moderate depression, but may be more effective in severe or treatment-refractory depression.
• Evidence-based guidelines for the treatment of MDD generally recommend TCAs as second-line treatment because of their inferior safety and tolerability profile compared with SSRIs, SNRIs, and bupropion.
• In contrast, TCAs are considered first-line treatment for several types of neuropathic pain, including peripheral diabetic neuropathy and postherpetic neuralgia, and for migraine and tension-type headache prophylaxis. When used for these indications, the usual dosage is about 50% less than that required to treat MDD.
• Antidepressant therapy with TCAs is primarily guided by clinical effectiveness and individual tolerability; however, a correlation has been found between patient response and plasma levels of some nortriptyline and imipramine.

TCAs are so named because of a common core structure comprising 3 rings. TCAs with a tertiary-amine side chain (amitriptyline, clomipramine, doxepin, imipramine, trimipramine) are characterized by greater inhibition of the reuptake of serotonin (5-HT) than of norepinephrine (NE), whereas those with a secondary-amine side chain (desipramine, nortriptyline, protriptyline) preferentially target the NE transporter.[49961][52258] Although the precise mechanism of action of TCAs is not fully understood, it is thought that interfering with the reuptake of NE and 5-HT results in increased concentrations of these neurotransmitters in the synaptic cleft and, consequently, in increased activity at the postsynaptic receptors. Because 5-HT and NE are known to be involved in the regulation of mood and the basic biological functions associated with mood, such as appetite, cognition, and sleep, their modulation appears to be an important factor in mood regulation. It is now believed that downstream changes in gene expression associated with regulation of adrenoreceptors may be the "final common pathway" responsible for the antidepressant effect. The mechanism of action of TCAs in neuropathic pain and headache is also believed to derive from blockade of NE and 5-HT reuptake.[71181][52258]

Receptor Binding Affinity of TCAs and Adverse Effect Profile [49967][52258]

0 = no appreciable receptor binding affinity; + = low receptor binding affinity; ++ low to moderate receptor binding affinity; +++ = moderate receptor binding affinity; ++++ = moderate to high receptor binding affinity; +++++ = high receptor binding affinity

• None of the TCAs are indicated for treatment of MDD in children younger than 12 years; however, imipramine is indicated in adolescents and children 6 years and older for enuresis.[49961][70368]
• Anticholinergic and antihistaminic adverse events (AEs) are very common; therefore, TCAs are initiated at a low dose and titrated over days to weeks to attain a therapeutic dose. Most patients develop tolerance to these AEs over time.
• Despite their initial approval as antidepressants, TCAs are more commonly used for neuropathic pain and headache.[49966][49962]
• In neuropathic pain and headache, efficacy is achieved at lower doses and is not mediated by an antidepressant effect. Therefore, TCAs work well in patients who are not depressed.[49966] Overall, they are most effective in headache prevention.[49962]
• Treatment response generally takes place gradually, often requiring up to 3 weeks of therapy or longer. Adverse effects, in contrast, can be seen within a few hours of the initial dose, but tend to diminish over 2 to 3 weeks at any given dose.
• Clomipramine is the only TCA indicated for the treatment of obsessive compulsive disorder; meta-analyses suggest it may be more effective than SSRIs, but head-to-head trials have shown equivalent efficacy.[13434]
• TCAs are typically divided into the tertiary amines (e.g., amitriptyline) and the secondary amines (e.g., nortriptyline). These 2 subgroups have different receptor activity profiles.[49967][52258][71182]
  • Secondary amines are higher in norepinephrine selectivity than serotonin selectivity.
  • Some tertiary amines have higher selectivity for serotonin than norepinephrine.
  • Interchange between a tertiary and secondary amine may be useful in cases of treatment failure with the initial agent. When determining the appropriate tricyclic regimen, it is important to note that desipramine is the major metabolite of imipramine and nortriptyline is the major metabolite of amitriptyline.

Dosage Comparison of TCAs in Major Depressive Disorder*

*All TCAs should be used with caution and at lower doses in patients with hepatic impairment.

• Given that TCAs have not been used as first-line agents in the treatment of depression  since selective serotonin reuptake inhibitors (SSRIs) became a treatment option beginning in the late 1980s, there are few large, longitudinal, observational studies to provide evidence as to the relative real-world effectiveness of one TCA over another, or of TCAs compared with SSRIs.[49961]
• Overall, there are few high-quality studies that compare one TCA with another or a TCA with another agent in the treatment of depression, neuropathic pain, or headache.[49964][11687]
• Comparative efficacy has been addressed by systematic reviews and meta-analyses, but authors acknowledge the need for better evidence.[49964][11687][49968]

Key findings from systematic reviews and meta-analyses are:

• TCAs were generally found to be of equivalent efficacy to each other for most indications; however, in one meta-analysis assessing the tolerability and efficacy of amitriptyline in the management of depression, the proportion of patients who responded to amitriptyline was 2.4% higher than for comparator tricyclic or heterocyclic antidepressants.[49964]
• Clomipramine is the only TCA effective for obsessive compulsive disorder (OCD). The effectiveness of clomipramine in treating OCD is likely due to the high serotonin selectivity of the drug.
• There is no difference in efficacy between TCAs and SSRIs in the treatment of major depression in outpatients, but there may be a slight advantage for TCAs in the treatment of severe major depression in the inpatient setting.[49964][11687]
• TCAs appear to be more effective than SSRIs in the treatment of neuropathic pain, but they are considered to be generally equivalent in efficacy to SNRIs (venlafaxine and duloxetine) and antiepileptic drugs (gabapentin and pregabalin).[49968]

Adverse effects are the most important determinant of whether or not to prescribe a TCA, and they also help guide drug selection within the class.[49961][52258] Variations in receptor activities (e.g., serotonin, adrenergic, histamine, muscarinic) between tertiary and secondary amines account for differences in the frequency and severity of some side effects. In general, tertiary amines are associated with more sedation, anticholinergic effects, and cardiac effects than secondary amines. Thus, as a group, secondary amines may be better tolerated than tertiary amines.[52258][71182]