The TCAs are older antidepressants, derived from the three-ringed chemical (imipramine) shown above. They work by inhibiting reuptake of serotonin (5-HT) and/or norepinephrine (NE). TCAs differ from newer SSRIs and SNRIs in that TCAs are “dirty drugs”, non- selectively affecting several other neurotransmitter systems. Most TCAs are antihistaminic (sedation and weight gain) and anticholinergic (dry mouth, constipation, urinary retention, and confusion). They also block alpha-1 adrenergic (NE) receptors, which may lead to orthostatic hypotension. 

 

Mechanistically, the prototypical TCA is like a combination of venlafaxine (SNRI), diphenhydramine (antihistamine and anticholinergic) and prazosin (alpha-1 blocker). This does not apply to all TCAs, which are a diverse bunch. Amitriptyline and imipramine are prototypical TCAs.

 

TCAs were largely replaced by SSRIs, which are cleaner (selective), without the antihistaminic and anticholinergic baggage. Unlike the diverse TCAs, SSRIs are pretty much homogenous, with similar efficacy and side effects. The main difference between members of the SSRI class are half-life and potential for kinetic interactions. 

 

This chapter highlights the differences between members of the TCA class. Some TCAs are  anxiety-reducing (amitriptyline, doxepin), while others can be energizing (nortriptyline, desipramine). 

​

Clomipramine is highly serotonergic, whereas four TCAs have so little serotonergic activity that they could be safely coadministered with an MAOI— nortriptyline, desipramine, maprotiline, trimipramine = “Non-Disparaged MAOI Tagalongs”.

 

TCAs are deadly in overdose, some more dangerous  than others. Overdose on a ten-day supply of a TCA can be life-threatening owing to disturbance of cardiac conduction. This is seen on EKG as prolongation of the QT interval and other forms of conduction delay. The exception is clomipramine, which is relatively benign in overdose.

 

Compared to SSRIs, TCAs are less likely to contribute to serotonin syndrome, with clomipramine as an exception.

 

Although TCAs are not addictive or abusable, they are reported on the basic urine drug screen (UDS). False positive tricyclic screens can be caused by carbamazepine (Tegretol), oxcarbazepine (Trileptal), cyclobenzaprine (Flexeril), quetiapine (Seroquel),  chlorpromazine (Thorazine), thioridazine (Mellaril), and at toxic doses, diphenhydramine (Benadryl).

 

The muscle relaxant cyclobenzaprine (Flexeril) is a tricyclic by structure. Single-drug overdose on cyclobenzaprine is less dangerous than overdose on a prototypical TCA.