properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect. Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively. The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity. It may also be involved in their efficacy as analgesics, however. In summary, tricyclic antidepressants can act through NMDA antagonism, opioidergic effects, sodium, potassium and calcium channel blocking, through interfering with the reuptake of serotonin and acting as antagonists to SHAM (serotonin, histamine, alpha, muscarinic) receptors. Thus their dangerous side effect profile limits their use in daily practice. Binding profiles The binding profiles of various TCAs and some metabolites in terms of their affinities (, ) for various receptors and transporters are as follows: With the exception of the sigma receptors, the TCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters. Tianeptine is included in this list due to it technically being a TCA, but with a vastly different pharmacology. Therapeutic levels of TCAs are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM. Plasma protein binding is generally 90% or greater. Chemistry There are two major groups of TCAs in terms of chemical structure, which most, but not all, TCAs fall into. The groupings are based on the tricyclic ring system. They are the dibenzazepines (imipramine, desipramine, clomipramine, trimipramine, lofepramine) and the dibenzocycloheptadienes (amitriptyline, nortriptyline, protriptyline, butriptyline). Minor TCA groups based on ring system include the dibenzoxepins (doxepin), the dibenzothiepines (dosulepin), and the dibenzoxazepines (amoxapine). In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of substitutions of the side chain amine. These groups include the tertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and the secondary amines (desipramine, nortriptyline, protriptyline). Lofepramine is technically a tertiary amine, but acts largely as a prodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines. Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them. In 2021, a new method was