Tricyclic Antidepressants (TCA)

Tricyclic Antidepressants (TCAs) are named after their chemical structure, which contains three rings of atoms (“tricyclic ring system”). TCAs are most commonly used as antidepressants, but also have a role in the treatment of neuropathic pain, chronic pain, migraines, and headaches. TCAs are highly protein bound and therefore interact with medications that are also highly protein bound.

Naming Tip

All TCAs end with -iptyline or -ipramine, except for doxepin and amoxepine.
  • Tertiary amine TCAs are molecules made of a 3-ring structure with two methyl groups on the nitrogen atom of the side chain.
  • Tertiary amine TCAs include: amitriptyline, imipramine, clomipramine, trimipramine, and doxepin.
  • Secondary amine TCAs result from the metabolism of tertiary amine TCAs.
    • Metabolism results in loss of one methyl group on the nitrogen side chain.
  • Secondary amine TCAs include: nortriptyline (is a metabolite of amitriptyline), protriptyline, and desipramine (is a metabolite of imipramine).
  • Tertiary amines are generally more potent in blocking reuptake of serotonin, while secondary amines are more potent in blocking the reuptake of norepinephrine.
  • Secondary amines are also usually better tolerated than tertiary amines because of less histaminic, cholinergic, and alpha-1 adrenergic receptor blockade.
    • Thus, they are also considered to be less anticholinergic compared to their tertiary counterparts.[1]
  • Clearance of TCAs is primarily via hepatic metabolism.
    • Renal clearance accounts for only a small portion of elimination.

TCAs have several mechanisms of action:

  • TCAs block the transporter sites for serotonin (SERT) and norepinephrine (NET) and thus reduce uptake of these neurotransmitters into the presynaptic neuron (note: TCAs also block reuptake for dopamine, but less so)
    • Tertiary TCAs (e.g. - clomipramine) primarily indirectly block the uptake of serotonin
      • Aside from clomipramine, which is the most serotonergic TCA, TCAs cause less SSRI-like side effects (e.g. - sexual dysfunction, bleeding risks), as the serotonin reuptake is weaker compared to SSRIs.
    • Secondary TCAs (e.g. - desipramine) primarily indirectly block the uptake of norepinephrine
    • Since tertiary TCAs are also metabolized and become “secondary TCAs,” both serotonergic and noradrenergic effects occur.
  • After the initial serotonin reuptake blockade, concentrations of serotonin rise.
  • In response, the presynaptic somatodendritic serotonin type 1A (5-HT1A) autoreceptors reduces the firing rate of the presynaptic serotonin neuron, and concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin quickly decrease.
  • Over a 2-week period, the presynaptic autoreceptor becomes desensitized, resulting in a normalization of the firing rate. At this point, serotonin transmission is enhanced.
  • Put simply, TCAs sensitize or upregulate postsynaptic 5- HT1A receptors
  • Additionally, TCAs are “dirty”/“sloppy” antidepressants, in that they also:
    • Block muscarinic receptors, producing anticholinergic effects such as dry mouth, blurry vision, constipation, and urinary retention
    • Block histamine-1 (H1) receptors, which causes sedation
    • Block α1- and α2-adrenergic receptors, which causes hypotension and sedation
  • TCAs have a low therapeutic index (TI) (versus SSRIs, which have a high TI, which means toxicity is unlikely even if overdosed on significant amounts of medication).
  • The most common cause of death is from cardiovascular toxicity caused by ECG abnormalities, arrhythmias, and hypotension.
  • In TCA overdose, several mechanisms can occur that can lead to toxicity:[2]
    • TCAs decrease reuptake of biogenic amines (dopamine, norepinephrine, epinephrine, histamine, and serotonin) from neuronal synapses may account for the transient hypertension that precedes hypotension seen in overdose.
    • TCAs are considered type 1A anti-arrhythmic agents and can cause sodium channel blockade of the myocardial fast sodium channels, resulting in QTc prolongation.
    • TCA's anticholinergic effects can results in delirium, mydriasis, tachycardia, dry/flushed skin, urinary retention, and decreased bowel sounds.
    • TCAs also cause peripheral alpha-1 adrenergic blockade, resulting in hypotension
    • Finally, TCAs bind to the picrotoxin binding site on the GABA receptor, causing GABA antagonism, resulting in seizures.[3][4]

Tricyclic Antidepressants Summary and Dosing Recommendations

Adapted from: Richelson, E. et al. (1984). Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. Journal of Pharmacology and Experimental Therapeutics, 230(1), 94-102., and Table 36.34-1 Receptor Affinity or Potency of Cyclic Antidepressants in Human Brain. Sadock, B. J. et al. (2015). Kaplan and Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry (Eleventh edition.). Philadelphia: Wolters Kluwer.
Class Minimum Available Dose Dose Range* Estimated Therapeutic Level (ng/mL) M1 (ACh) Blockade† (i.e. - Anticholinergic Burden) Notes
Amitriptyline Tertiary 10mg 150-300mg Not studied +++ (5.6) -
Clomipramine Tertiary 25mg 130-250mg >150 +++ (2.7) The most serotonergic of the TCAs
Doxepin Tertiary 25mg 150-300mg Not studied +++ (1.2) The most histaminergic, but no anticholinergic effects (i.e. - no muscarinic antagonism)
Imipramine Tertiary 10mg 150-300mg >200 +++ (1.1) -
Nortriptyline Secondary 10mg 50-150mg 50-150 ++ (0.65) Commonly used in geriatric depression
Desipramine Secondary 10mg 150-300mg >115 ++ (0.50) The most noradrenergic of the TCAs

TCAs need to be slowly titrated up because of their side effect profile. The adverse effects of TCAs are also dose-dependent. TCAs have the following actions that can cause side effects:

  1. Alpha-1 adrenergic blockade: postural hypotension, bradycardia, and dizziness.
  2. Histamine (H1) blockade: sedation, postural hypotension, and weight gain
  3. Muscarinic (M1) blockade (i.e. - anticholinergic properties): dry mouth, constipation, urinary retention, blurred vision, cognitive impairment, exacerbation of narrow angle closure glaucoma, and sinus tachycardia

Furthermore, TCAs can cause QTc prolongation in overdose, and have an increased risk of cognitive impairment (due to their anticholingeric effects).

Hypotension is of particular concern for older adults on TCAs. Amitriptyline and imipramine in particular are also associated with high rates of postural hypotension and anticholinergic effects, and should be avoided in geriatric populations. Nortriptyline on the other hand is typically much better tolerated.[5] Generally, TCAs should be avoided in older adults.

  • TCAs are highly protein bound and therefore also interact with medications that are also highly protein bound.

Typically, sodium bicarbonate is given to treat arrhythmia.

  • Doses need to start low, go slowly
  • TCAs require BID or TID dosing to allow it to be tolerable
  • Some TCAs have therapeutic levels established that can be measured
  • Clomipramine is the most serotonergic TCA (with minimal norepinephrine reuptake inhibition)
  • Desipramine is the most noradrenergic TCA (greatest norepinephrine reuptake inhibition)[6]
  • Doxepin is the TCA with the most potent histamine (H1) antagonism, which makes it the most sedating TCA