Tricyclic Antidepressants (TCAs)

Introduction
Illustrated mechanism of action
Examples of Medication Brand Names (with Images)
Indication
Side Effects
Precautions & Contraindications
Monographs
Reference

History

Tricyclic antidepressants (TCAs) were developed during the rapid expansion of psychopharmacology in the early 1950s. Their story is closely linked to research on antihistamines and antipsychotics. The synthesis of chlorpromazine, an antipsychotic derived from antihistamines, inspired further exploration of related compounds for psychiatric use.

Imipramine, the first TCA, was synthesized by modifying the structure of promethazine, an antihistamine. Swiss psychiatrist Roland Kuhn was pivotal in the discovery of its antidepressant effects. Initially tested as an antipsychotic, imipramine did not help patients with schizophrenia but produced remarkable improvements in patients with severe depression. Kuhn first reported these effects in 1957, and imipramine was approved for depression in 1959 under the brand name Tofranil.

Introduction

Tricyclic antidepressants (TCAs) constitute a class of medications that were initially introduced to the market in 1959 as a pharmacotherapy for major depressive disorder (MDD).TCAs are now regarded as second-line treatment options alongside selective serotonin reuptake inhibitors (SSRIs). They acquired the name "tricyclic" due to the presence of 3 rings in their chemical structure. These medications function by inhibiting the reuptake of neurotransmitters such as serotonin and norepinephrine, which can modulate mood, attention, and pain in individuals.
The first TCA, imipramine, was initially created as an antipsychotic but was later discovered to have potent antidepressant properties. Imipramine's success prompted additional research, leading to the formulation of subsequent TCAs such as amitriptyline, nortriptyline, desipramine, and doxepin.

mechanism of action

TCAs exert their effects by modulating around neurotransmitter pathways. These medications function by inhibiting serotonin and norepinephrine reuptake within the presynaptic terminals, resulting in elevated concentrations of these neurotransmitters within the synaptic cleft. The increased levels of norepinephrine and serotonin in the synapse can contribute to the antidepressant effect. The chemical structure of a TCA comprises a 3-ringed arrangement with an attached secondary or tertiary amine. Desipramine, nortriptyline, and protriptyline are categorized as secondary amines, whereas amitriptyline, clomipramine, doxepin, imipramine, and trimipramine belong to the group of tertiary amines. Tertiary amines typically exhibit significant serotonin reuptake inhibition, whereas secondary amines display heightened inhibition of norepinephrine uptake.

The varied amine structures and chemical compositions observed in TCA usage contribute to the diverse adverse effects observed.

Indication

TCAs are used to treat a variety of conditions, primarily:

Major Depressive Disorder: TCAs are effective for treating major depression, especially in cases where newer antidepressants are not effective or not tolerated.
Anxiety Disorders: TCAs can be prescribed for various anxiety disorders, including generalized anxiety disorder (GAD), panic disorder, and obsessive-compulsive disorder (OCD).
Chronic Pain: Certain TCAs, particularly amitriptyline and nortriptyline, are used to manage chronic pain conditions such as neuropathic pain, fibromyalgia, and chronic tension headaches.
Migraine Prophylaxis: TCAs can be used to prevent migraines, reducing the frequency and severity of attacks.
Nocturnal Enuresis: Imipramine has been used to treat bedwetting in children, although it is generally not a first-line treatment due to potential side effects.
Insomnia: Due to their sedating effects, TCAs like doxepin can be used to treat insomnia, especially in patients who also have depression.

TCAs are typically not first-line treatments due to their side effect profiles.

Side Effects

Precautions & Contraindications

Precautions

Populations Requiring Caution:

Elderly patients: Increased sensitivity to anticholinergic effects (e.g., confusion, urinary retention, falls), orthostatic hypotension, and cardiac arrhythmias.
Cardiovascular disease: TCAs can cause conduction abnormalities, QT prolongation, and arrhythmias, particularly in ischemic heart disease or history of myocardial infarction.
Hepatic impairment: TCAs undergo extensive hepatic metabolism; impaired liver function can increase plasma levels and toxicity risk.
Renal impairment: Although primarily metabolized hepatically, active metabolites may accumulate in renal dysfunction.
Bipolar disorder: Risk of triggering mania or rapid cycling.

Contraindications

Absolute Contraindications:

Recent myocardial infarction (MI)
Known hypersensitivity to TCAs
Concomitant use with MAOIs or within 14 days of discontinuation
Untreated narrow-angle glaucoma (due to anticholinergic effects)
Severe liver disease (depending on agent)

Relative Contraindications:

Angle-closure glaucoma
Prostatic hypertrophy (risk of urinary retention)
Seizure disorders (lowers seizure threshold)
Thyroid disease (enhanced response to catecholamines)
Psychotic disorders (can exacerbate psychosis or mania)
Suicidal risk: TCAs are lethal in overdose; should be prescribed with caution and small quantities.