Tricyclic antidepressants (TCAs) are a drug class that were first released to the market in 1959 as a pharmacotherapy for major depressive disorder (MDD). Today, TCAs are Food and Drug Administration (FDA) approved to treat a variety of illnesses, depending on the formulation. TCAs that have FDA approval to treat MDD include amitriptyline, amoxapine, doxepin, desipramine, nortriptyline, protriptyline, imipramine, and trimipramine.[1][2][3][4] Clomipramine is FDA approved for obsessive-compulsive disorder (OCD) in ages ten and older.[5]

In terms of treating major depressive disorder, TCAs display equivocal efficacy with Selective Serotonin Reuptake Inhibitors (SSRIs), but TCAs cause more significant adverse effects due to their anticholinergic activity and a lower threshold for overdose.[6][7] For these reasons, TCAs typically are not used as first-line treatment of MDD.[8] The off-label (non-FDA) uses of TCAs include migraine prophylaxis, OCD, insomnia, anxiety, and chronic pain, especially neuropathic pain conditions such as myofascial pain, diabetic neuropathy, and postherpetic neuralgia.[9][10][11][12][13][14][15] Specifically, for migraine prophylaxis, doxepin and amitriptyline are most commonly used.[16][17] TCAs are also the second-line treatment for fibromyalgia after the failure of preferred treatments, such as pregabalin, duloxetine, and milnacipran.[18][19] Nocturnal enuresis of children is also treatable with TCAs after the failure of first-line therapy desmopressin.[20]

Tricyclic antidepressants act on approximately five different neurotransmitter pathways to achieve their effects. They block the reuptake of serotonin and norepinephrine in presynaptic terminals, which leads to increased concentration of these neurotransmitters in the synaptic cleft. The increased concentration of serotonin in the synapse likely contributes to its anti-depressive effect. Additionally, they act as competitive antagonists on post-synaptic alpha cholinergic (alpha1 and alpha2), muscarinic, and histaminergic receptors (H1).[21][22] Its structure greatly influences the affinity of the TCA for each of these receptors.

The chemical structure of a TCA consists of a three-ringed structure with an attached secondary or tertiary amine. Secondary amines include desipramine, nortriptyline, and protriptyline, while tertiary amines consist of amitryptiline, clomipramine, doxepin, imipramine, and trimipramine. Tertiary amines tend to have greater blockage of serotonin reuptake, while secondary amines have greater blockage of norepinephrine uptake.[23] The combination of different amine structures and variations in chemical composition contribute to the multitude of adverse effects seen with TCA usage as these factors affect TCA-receptor affinity and binding.[24]

TCAs are available in the form of oral tablets, capsules, and solutions. Although intravenous (IV) use of some TCAs, such as clomipramine, has taken place in clinical trials, IV is not a routine route of administration for the administration of TCAs.[25] Topical creams and transdermal patches have been studied for the use of some TCAs, like imipramine and doxepin, as well. However, oral administration (PO) remains the usual route of administration for TCAs.[26] The exact dosages for each of the different TCA tablets vary, however, because TCAs have a high risk of adverse effects, initial dosing is low and is gradually increased based on the level of response.[27] If patients are unresponsive at a low dose, then they may respond at higher doses, especially since TCAs have shown increased efficacy at higher dosages when compared with high dose SSRIs.[27] Blood monitoring of TCA levels is available; however, there is mixed evidence on its effect on treatment outcomes.[7] In general, patients are given an oral dose of a TCA once a day due to the long half-life and sedative effects of the drug class.[24]

TCAs have varying degrees of receptor affinities, leading to several adverse effects. The most common adverse effects include constipation, dizziness, and xerostomia[28]. Due to its blockade of cholinergic receptors, it can lead to blurred vision, constipation, xerostomia, confusion, urinary retention, and tachycardia.[29] Due to the blockade of alpha-1 adrenergic receptors, it can cause orthostatic hypotension and dizziness.[28][29] TCA-induced histamine blockade (H1) may lead to sedation, increased appetite, weight gain, and confusion.[30][28]

TCAs may also cause cardiovascular complications, including arrhythmias, such as QT prolongation, ventricular fibrillation, and sudden cardiac death in patients with preexisting ischemic heart disease.[31] Therefore, the examination of a patient's cardiac health is important before TCA prescription. there is evidence of TCAs increasing the risk of seizures in those with epilepsy, and use requires caution in this population.[32] TCAs may cause mild liver enzyme elevation; however, acute hepatitis rarely has an association with the use of tricyclic antidepressants.[30][33]

TCA use has shown to lead to an increased risk of suicidal ideation and behavior in individuals age 24 or less. Therefore, individuals started on TCAs that are age 24 or less should be followed closely to assess for thoughts and behaviors related to suicide.[33]

The use of TCAs during pregnancy has correlated with congenital eye, ear, face, and neck defects.[34] Specifically, clomipramine has associations with more severe neonatal symptoms such as cardiac defects.[35] Therefore, TCAs are not generally considered safe to use during pregnancy. With regards to breastfeeding, all TCAs, except for doxepin, have not been associated with adverse effects from breastfeeding and therefore are regarded as safe.[36] Nortriptyline appears to be the safest for use during breastfeeding due to its non-sedating profile.[35]

Tricyclic antidepressants are contraindicated in several populations and with the concomitant use of various medications. TCAs should not be prescribed if there is a family history of QT interval prolongation or sudden cardiac death. Hypersensitivity reactions to a TCA drug are considered an absolute contraindication. However, patients with a hypersensitivity reaction to a particular TCA drug may be prescribed a different member of the class with caution. TCAs should not be used concomitantly with monoamine oxidase inhibitors (MAOI) due to the risk of developing serotonin syndrome.[37] Also, patients must have discontinued MAOI for at least 14 days before starting a TCA medication. Combining TCAs with SSRIs is not advised as a combination of these agents has been shown to increase plasma levels of TCAs and risk of serotonin syndrome.[38][39]

TCA use requires caution in individuals with angle-closure glaucoma as its anticholinergic effects may increase the risk of an acute ocular crisis.[40] Additionally, TCAs should be used with caution in patients with a history of seizures, as TCAs may lower the seizure threshold, and in patients with urinary retention, as its anticholinergic properties may worsen this symptom.[29][32] Clinicians should generally avoid TCAs in patients with coronary artery disease (CAD). However, CAD is not an absolute contraindication.[41] Because cytochrome P450 enzymes metabolize tCAs in the liver, caution is necessary when prescribing TCAs to patients with hepatic injury. Specifically, among the TCAs, clomipramine has been shown to have the highest rate of drug-induced liver injury, and so clomipramine is not preferred in patients with non-optimal liver function.[42]