Developed in the 1950s, tricyclic antidepressants, or TCAs, have a strong history of anxiety and depression treatment. The name "tricyclic" comes from the atomic structure of these medications, which consists of three molecular ring shapes. TCAs were first developed when scientists began working on a series of compounds to improve antihistamines, sedatives, analgesics, and anti-Parkinson’s drugs. Imipramine, the first tricyclic antidepressant developed in the late ‘50s, showed positive effects when it was first tested on a group of participants diagnosed with depressive psychosis. Modifications to TCA formulas led to the discovery of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs).  

Commonly Prescribed TCAs

Until 1988, TCAs were commonly prescribed by physicians. However, with the discovery of many SSRIs, TCAs lost their significance due to a harsher profile of side effects. Today, many TCAs are used when other prescription antidepressant medications fail to produce positive treatment results. The TCAs most commonly prescribed today include:

Conditions Treated with TCAs

TCAs may be used in the treatment of a variety of conditions including, but not limited to:

Norpramin (desipramine), Aventyl (nortriptyline), Tofranil (imipramine), and Silenor (doxepin) are among the tricyclic drugs approved to treat depression. Research shows that newer antidepressant medications are no more effective at treating depression than the older tricyclics. However, tricyclics have much more pronounced and unpredictable side effects than many newer medications.

Tricyclic antidepressants have received new interest by some physicians for their potential to alleviate conditions involving chronic pain. For the treatment of a chronic condition, such as diabetic neuropathy, doctors usually prescribe a lower dose of these medications. Lower dosages help prevent many of the unwanted side effects of tricyclic antidepressants.

Mechanism of Action of TCAs

TCAs increase the quantity of neurotransmitters, such as serotonin and norepinephrine, in the central nervous system. They block specific serotonin (SERT or 5-HTT) and norepinephrine transporters (NET). When affected, these transporters cannot play their part in the reuptake of neurotransmitters, which increases the concentration and ultimately has an effect on mood. Some TCAs bind with SERT and some bind with NET. Clomipramine, for example, is a potent binder of SERT, but it is a weak binder of NET. Desipramine, on the other hand, is a strong binder of NET.

Additionally, it should be noted that antidepressant medications, when used for anxiety, depression, or other mental health issues, tend to be more effective when combined with some type of therapy. Medication can help treat symptoms of mental health conditions, but pills do not address the underlying emotions, behaviors, and root causes of mental health issues. If you are prescribed an antidepressant or other psychotropic medication, consider finding a qualified therapist to better understand and help treat your condition.

Side Effects and Adverse Drug Reactions

The potential side effects of these medications depend largely on which tricyclic antidepressant a person takes. Drowsiness, dry mouth, and sexual problems are possible with any of these medications. Silenor, in particular, has been associated with a greater risk of weight gain. Potentially severe side effects of these medications include low blood pressure and seizures. Other effects can include:

  • Anticholinergic effects: TCAs are notorious for causing anticholinergic effects (usually related to the parasympathetic nervous system) such as dry mouth, dry mucous membrane, mydriasis (dilation of the pupils), dilation of the urinary tract, hyperthermia, tachycardia, cycloplegia, and blurred vision. Constipation is also frequently reported.
  • Effects on the central nervous system: Confusion, delirium, irritability, loss of concentration, agitation, anger, anxiety, drowsiness, and insomnia are commonly reported side effects of TCAs. Suicidal ideation and worsening of depression may occur at the start of treatment with TCAs, and should be monitored carefully. Involuntary motor movements, dystonia, muscle breakdown, and seizures are minor effects that were reported by people using TCAs.
  • Effects on the cardiovascular system: Postural hypotension—the medical name for the dizzy or fuzzy feeling you get when standing up or stretching too quickly—is common. Alteration in electrocardiogram patterns (electrical activity of the heart), palpitation, arrhythmias, tachycardia, ventricular fibrillation, atrioventricular block, and bradycardia also occur. TCAs are not recommended for a person with a cardiac condition unless there is no other therapy available.
  • Liver effects: Asymptomatic increase in serum aminotransferase, changes in serum alkaline phosphatase concentration, obstructive type jaundice, and hepatitis have been reported when using TCAs. Hepatitis and jaundice can be treated with the discontinuation of medication. Monitoring of liver function tests is highly advised for people using this category of antidepressant.
  • Gastrointestinal effects: Constipation, dry mouth, anorexia, weight gain, increase in pancreatic enzymes, epigastric distress, abdominal cramps, and nausea are some common adverse effects of TCAs.
  • Possible effects on the urinary and reproductive systems: Impotence, delayed or premature ejaculation, testicular swelling, increased or decreased libido, breast engorgement, galactorrhea, and anorgasmia have been reported. Inappropriate secretion of antidiuretic hormone, irregular urinary frequency, and nocturia are also noted side effects of some TCAs.
  • TCAs and pregnancy: TCAs can be harmful to a developing fetus. Their use in pregnancy and for nursing mothers is not recommended based on animal studies.

Tricyclic Antidepressant Drug Interactions

It is important to discuss with your doctor any additional medications you are taking prior to starting treatment with a tricyclic drug. TCAs may have dangerous interactions with certain medications, drugs, or substances.

  • Monoamine oxidase inhibitors (MAOIs) combined with TCAs may produce tachycardia, hypertension, mania, confusion, and seizure.
  • Hypotensive agents (drugs used to treat blood pressure) such as clonidine cannot perform properly when combined with TCAs.
  • TCAs with central nervous system depressants such as alcohol, sedatives or hypnotics, and barbiturates may cause respiratory depression.
  • Antipsychotic agents should be avoided because they increase the blood concentration of TCAs.
  • Cimetidine (Tagamet), SSRIs, SNRIs, levodopa (Dopar), anticoagulants, thyroid agents, methylphenidate (Ritalin), cisapride (Propulsid), antidiabetic agents, anticholinergic agents, and sympathomimetics should be used with caution while taking a TCA.

FDA Recommendations

The FDA urges that the lowest dose should be used to start the treatment. Monitoring of the person in treatment is necessary and dose should be adjusted based on the results.

Withdrawal and TCAs

Withdrawal symptoms are possible when people suddenly stop taking tricyclic antidepressants or miss several doses. Nausea, headache, depression, anxiety, insomnia, and dizziness are common symptoms of withdrawal. Consult your doctor if you experience unwanted withdrawal symptoms.


  1. National Library of Medicine - National Institutes of Health. (n.d.). Antidepressive Agents, Tricyclic. Retrieved from
  2. Mayo Clinic. (n.d.). Depression (Major Depression). Retrieved from
  3. WebMD. (n.d.). Tricyclic Antidepressants for Pain Treatment. Retrieved from

Page content reviewed by James Pendleton, ND.