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Day # 35: Tricyclic Antidepressants (TCAs)

Today we will be discussing the heterocyclic antidepressant medications which include tricyclic and tetracyclic antidepressants. We will discuss mechanism of action, side effects, and unique characteristics to specific medications within this class.

Today's Content Level: Beginner, Intermediate


•TCAs = Tricyclic and Tetracyclic Antidepressants

•TCAs are heterocyclic compounds that inhibit the reuptake of norepinephrine and serotonin which increases the availability of these neurotransmitters in the synapse.

The term tricyclic or tetracyclic refers to the three or four ringed chemical structure of these medications. They are subdivided into tertiary and secondary amines.

  • Tertiary amines: high affinity for blocking serotonin reuptake. Highly anticholinergic, antihistaminergic, and antiadrenergic. This makes these medications have a higher side effect profile particularly being more sedating and having a higher lethality in overdose.

  • Secondary amines: high affinity for blocking norepinephrine reuptake. Less anticholinergic, antihistaminergic, and antiadrenergic.

•History: The first TCA, imipramine, was originally designed to treat schizophrenia (structurally related to chlorpromazine). After realize that it exacerbated mania in those with Bipolar/Schizoaffective disorder it was rebranded as an antidepressant in the 1950s. Many TCAs are structurally related to imipramine as well as other antihistamines.

•They are not frequently used as first-line agents due to a higher incidence of side effects and lethality in overdose.


Similar to other antidepressants, TCAs are not only used in the treatment of major depressive disorder. They are used for a variety of conditions:

  • Major Depressive Disorder (MDD): used as second-line for depressive disorders. More likely to induce mania than SSRIs. Amitriptyline and its metabolite nortriptyline are most used.

  • Panic Disorder with Agoraphobia: imipramine is best.

  • Generalized Anxiety Disorder: especially imipramine and doxepin.

  • OCD: clomipramine is FDA approved.

  • Chronic pain and migraine: amitriptyline is used most for this but others also used.

  • Diabetic neuropathy: pregabalin and gabapentin may be more frequently used.

  • Childhood enuresis: imipramine can be used to treat childhood enuresis but due to reports of sudden death in children and adolescents, TCAs should be avoided in this population if possible.

  • Insomnia: doxepin.

  • PTSD: imipramine has a weak recommendation although SSRIs are first line.

  • Cataplexy syndrome: climipramine and protriptyline used in the prevention of loss of voluntary muscle tone in syndromes such as narcolepsy.


•The side effects of TCAs are mostly due to their lack of specificity and interaction with many other receptors.

In addition to inhibiting the reuptake of serotonin and norepinephrine, TCAs can block muscarinic acetylcholine, histamine, and alpha 1 and 2 receptors. They can also block sodium and calcium channels. This leads to:

  • Anticholinergic: dry mouth, blurred vision, urinary retention, constipation (mnemonic-> hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter).

  • Antihistamine: sedation, weight gain.

  • Antiadrenergic: orthostatic hypotension, dizziness, reflex tachycardia.

  • Sodium/Calcium: cardiac side effects to include ECG changes (widens QRS, QT, and PR intervals) and arrhythmias. TCAs are relatively contraindicated in patients with cardiac disease or conduction abnormalities. Screening ECG should be performed in patients with cardiac risk factors or who are older than 40 years of age prior to initiating TCA therapy.

Other Side Effects

  • GI upset

  • Sexual dysfunction: occurs but less likely to cause sexual side effects and sleep disturbance than SSRIs.

  • Seizures: occur at a rate of about 0.4%, more common at higher plasma levels and with clomipramine (2%) and tetracyclics.

  • Delirium: increases risk for delirium due to andcholinergic and andhistamine effects, especially with amitriptyline.

  • Avoid in narrow-angle glaucoma.

  • Hepatic dysfunction: increased LFTs are associated with imipramine and desipramine. Typically AST>>ALT. Acute hepatitis is rare but fatal and may be seen in 0.1%.

  • Lethal in overdose -> See below.


•TCAs are lethal in overdose. A one week supply is all that is necessary for lethality (as little as 1-2 grams). TCAs are the second most lethal cause of overdose in the United states (after acetaminophen).

•Carefully assess suicide risk before prescribing these medications.

Major complications of TCA overdose (whether intentional or not) include the three C's.

  • Cardiotoxicity

  • Convulsions (seizures)

  • Coma / altered mental status

•Symptoms of overdose include agitation, tremors, ataxia, arrhythmias, delirium, respiratory depression (CNS depression), myoclonus, hyperreflexia, seizures, and coma. Death typically occurs as the result of cardiac arrhythmia.

Treatment of TCA overdose.

  • Attempt to reduce absorption with gastric lavage if <1hr after ingestion +/- activated charcoal.

  • Sodium bicarbonate-> primary treatment for the cardiotoxicity of TCAs. Administer if the patient is hypotensive, has a QRS interval > 100 ms, or a ventricular arrhythmia.

  • The mechanism of sodium bicarbonate increases sodium outside of the cell which increases the sodium gradient across cardiac cells. This leads to reduced inhibition of the sodium channels by the TCAs.

  • Supportive care-> IV fluids +/- vasopressor support (may have severe hypotension), replete electrolytes such as Mg and K (stabilize cardiac membrane), intubate for airway compromise.

  • Treat seizures with benzodiazepines.


Imipramine (Tofranil)

  • Tertiary amine.

  • Used more often in anxiety disorders (GAD and panic disorder).

  • Can also be used as a treatment for enuresis (bed wetting) in children older than 6 years old. It does this by causing contraction of the internal sphincter of the bladder and stimulation of ADH secretion. However, as mentioned above, due to reports of sudden death in children and adolescents, TCAs should be avoided in this population if possible.

Amitriptyline (Elavil)

  • Tertiary amine.

  • Most anticholinergic and antiadrenergic.

  • Useful in chronic pain, migraines, and insomnia.

Clomipramine (Anafranil)

  • Tertiary amine.

  • Most serotonergic.

  • Can be used in OCD, however, SSRI's are 1st line.

  • Higher risk of seizures.

Doxepin (Sinequan)

  • Tertiary amine.

  • Useful in GAD, chronic pain, and emerging use as a sleep aid in low doses.

Desipramine (Norpramin)

  • Secondary amine.

  • Less sedating than other TCAs (more activating).

  • Least anticholinergic and most noradrenergic.

Nortriptyline (Pamelor, Aventyl)

  • Secondary amine.

  • Low anticholinergic effects.

  • Least likely to cause orthostatic hypotension.

  • Useful in treating chronic pain.

Amoxapine (Ascendin)

  • This is a tetracyclic antidepressant (4 rings).

  • It is derived from a mid-potency antipsychotic (loxapine), thus it is the only TCA with both antidepressant and antipsychotic properties.

  • Two active metabolites that 1) block serotonin and norepinephrine reuptake and 2) block dopamine receptors.

  • Associated with extrapyramidal symptoms (EPS) due to its dopamine receptor blockade.

  • Higher risk of seizures.


I hope you found this post helpful. In the next lesson we will discuss monoamine oxidase inhibitors (MAOIs).

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