How Do Tricyclic Antidepressants Work?

Tricyclic antidepressants (TCAs) are some of the earliest medications developed to treat depression and other psychiatric conditions. TCAs derive their name from the three rings of atoms in their molecular structure. TCAs alleviate depression by altering the levels of neurotransmitters in the brain and modulating their activity.

Neurotransmitters are chemicals released by nerve cells (neurons) into the space (synapse) between them to communicate nerve signals. Neurotransmitters bind to protein molecules known as receptors on the adjoining cell surfaces to activate them.

Neurotransmitters enable the regulation of physiological functions such as breathing, heart rate and digestion, and are also responsible for learning, memory, sleep, emotions and behavior. Imbalance in certain neurotransmitters can disrupt normal neurotransmission of signals, resulting in depression, anxiety and other disorders.

TCAs increase the levels of serotonin and norepinephrine by preventing their reabsorption (reuptake), a natural process in the brain. The functions of serotonin include regulation of sleep, digestion, cognition, mood and behavior, and increasing their levels helps in relieving depression and anxiety.

TCAs also block histamine receptors and some of them are used to treat chronic itching. Additionally, TCAs block the activity of acetylcholine, a neurotransmitter that makes muscles contract, which is useful for muscle relaxation and sedation.

TCAs have a lower threshold for overdose compared to more advanced antidepressants, and also a higher risk for suicide ideation. With the development of newer classes of antidepressants with better side effect profiles, currently, TCAs are used as second-line treatment for depression.

Tricyclic antidepressants are oral tablets, capsules or solutions approved by the FDA for the treatment of the following conditions:

• Depression
• Depression with anxiety
• Obsessive-compulsive disorder
• Insomnia
• Enuresis (incontinence)

Off-label uses include:

• Postherpetic neuralgia
• Migraine prophylaxis
• Analgesia for chronic pain
• Eating disorder
• Premature ejaculation
• Vulvodynia (chronic pain in the vulva)
• Chronic urticaria (hives)
• Nocturnal pruritus (itching)
• Angioedema (swelling in the tissues under the skin and mucous membranes)
• Nocturnal enuresis (bedwetting in children)
• Smoking cessation
• Attention deficit hyperactivity disorder (ADHD)

Side effects of tricyclic antidepressants may include the following:

• Sedation
• Somnolence (drowsiness)
• Fatigue
• Weakness
• Lethargy
• Dizziness
• Headache
• Ataxia (impaired coordination and balance)
• Extrapyramidal symptoms (drug-induced movement disorders)
• Xerostomia (dry mouth)
• Constipation
• Nausea
• Anorexia (loss of appetite)
• Diarrhea
• Flatulence
• Bloating
• Vomiting
• Dyspepsia (indigestion)
• Blurred vision
• Increased ocular pressure
• Mydriasis (dilation of pupils)
• Agitation
• Anxiety
• Confusion
• Nervousness
• Restlessness
• Insomnia
• Hallucination
• Vivid dreams
• Mania
• Worsening depression
• Suicidal thoughts
• Tremor
• Seizure
• Coma
• Stroke
• EEG abnormalities
• Arrhythmia
• ECG changes
• Tachycardia (rapid heartbeat)
• Brugada syndrome (irregular, rapid heartbeat in the ventricles)
• Hypertension (high blood pressure)
• Myocardial infarction (heart attack)
• Palpitations
• Orthostatic hypotension (blood pressure drop when standing up from sitting or lying down)
• Syncope (fainting)
• Tinnitus (ringing in the ears)
• Paresthesia (prickling sensation)
• Paralytic ileus (blockage of intestines due to paralysis of intestinal muscles), rare
• Edema
• Sweating
• Hypersensitivity reactions such as:
  • Rash
  • Urticaria (hives)
  • Alopecia (hair loss)
  • Photosensitivity
  • Drug rash with eosinophilia and systemic symptoms (DRESS)
• Stomatitis (inflammation in the mouth)
• Nasal congestion
• Fever
• Blood dyscrasias (disorders) such as:
• Agranulocytosis (low granulocytes, immune cells with granules)
• Leukopenia (low levels of leukocytes, a type of immune cell)
• Thrombocytopenia (decrease in platelet count)
• Pancytopenia (decrease in all types of blood cells)
• Hepatotoxicity (toxicity to the liver)
• Elevated liver enzymes
• Hepatic dysfunction
• Jaundice
• Hyperglycemia (increased blood glucose levels)
• Hyponatremia (low sodium in the blood)
• Urinary retention
• Weight change
• Hyperprolactinemia (increased prolactin levels in the blood)
• Galactorrhea (abnormal milk production and leakage)
• Sexual dysfunction
• Ejaculation failure
• Impotence
• Anorgasmia (inability to reach orgasm)
• Libido change
• Menstrual irregularity
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH, a disorder which causes water retention)
• Neuroleptic malignant syndrome (a rare life-threatening drug reaction)

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of tricyclic antidepressant drugs include:

• amitriptyline
• amoxapine
• Anafranil
• chlordiazepoxide/amitriptyline
• clomipramine
• desipramine
• doxepin
• imipramine
• Norpramin
• nortriptyline
• Pamelor
• protriptyline
• Silenor
• Tofranil
• trimipramine