Tricyclic antidepressants and tetracyclic antidepressants

Tricyclic and tetracyclic antidepressants affect brain chemicals to ease depression symptoms. Explore their possible side effects and whether one of these antidepressants may be a good option for you.

By Mayo Clinic Staff

Tricyclic and tetracyclic antidepressants, also called cyclic antidepressants, are among the earliest antidepressants developed. They're effective, but they've generally been replaced by antidepressants that cause fewer side effects. However, cyclic antidepressants may be a good option for some people. In certain cases, they relieve depression when other treatments have failed.

Cyclic antidepressants are designated as tricyclic or tetracyclic, depending on the number of rings in their chemical structure — three (tri) or four (tetra).

How cyclic antidepressants work

Cyclic antidepressants ease depression by affecting chemical messengers (neurotransmitters) used to communicate between brain cells. Like most antidepressants, cyclic antidepressants work by ultimately effecting changes in brain chemistry and communication in brain nerve cell circuitry known to regulate mood, to help relieve depression.

Cyclic antidepressants block the reabsorption (reuptake) of the neurotransmitters serotonin (ser-o-TOE-nin) and norepinephrine (nor-ep-ih-NEF-rin), increasing the levels of these two neurotransmitters in the brain. Cyclic antidepressants also affect other chemical messengers, which can lead to a number of side effects.

Cyclic antidepressants approved to treat depression

The Food and Drug Administration (FDA) approved these tricyclic antidepressants to treat depression:

  • Amitriptyline
  • Amoxapine
  • Desipramine (Norpramin)
  • Doxepin
  • Imipramine (Tofranil)
  • Nortriptyline (Pamelor)
  • Protriptyline
  • Trimipramine

The FDA approved the tetracyclic antidepressant maprotiline to treat depression.

Sometimes cyclic antidepressants are used to treat conditions other than depression, such as obsessive-compulsive disorder, anxiety disorders or nerve-related (neuropathic) pain.

Possible side effects and cautions

Because of the different ways cyclic antidepressants work, side effects vary somewhat from medication to medication. Some side effects may go away after a time, while others may lead you and your doctor to try a different medication. Side effects may also be dependent on the dose, with higher doses often causing more side effects.

Some common possible side effects include:

  • Drowsiness
  • Blurred vision
  • Constipation
  • Dry mouth
  • Drop in blood pressure when moving from sitting to standing, which can cause lightheadedness
  • Urine retention

Other possible side effects include:

  • Weight loss
  • Increased appetite leading to weight gain
  • Excessive sweating
  • Tremor
  • Sexual problems, such as difficulty achieving an erection, delayed orgasm or low sex drive

Generally speaking:

  • Amitriptyline, doxepin, imipramine and trimipramine are more likely to make you sleepy than other tricyclic antidepressants are. Taking these medications at bedtime may help.
  • Amitriptyline, doxepin, imipramine and trimipramine are more likely to cause weight gain than other tricyclic antidepressants are.
  • Nortriptyline and desipramine appear to have better tolerated side effects than other tricyclic antidepressants do.

For antidepressants that cause sleepiness, be careful about doing activities that require you to be alert, such as driving a car, until you know how the medication will affect you.

Which antidepressant is best for you depends on a number of issues, such as your symptoms and any other health conditions you may have. Ask your doctor and pharmacist about the most common possible side effects for your specific antidepressant and read the patient medication guide that comes with the prescription.

Safety issues

Some tricyclic antidepressants are more likely to cause side effects that affect safety, such as:

  • Disorientation or confusion, particularly in older people when the dosage is too high
  • Increased or irregular heart rate
  • More-frequent seizures in people who have seizures

Other issues to discuss with your doctor before you take a cyclic antidepressant:

  • Antidepressants and pregnancy. Talk to your doctor about the risks and benefits of using specific antidepressants. Some antidepressants may harm your baby if you take them during pregnancy or while you're breast-feeding. If you're taking an antidepressant and you're considering getting pregnant, talk to your doctor or mental health professional about the possible risks. Don't stop taking your medication without contacting your doctor first, as stopping might pose risks for you.
  • Drug interactions. When taking an antidepressant, tell your doctor about any other prescription or over-the-counter medications, herbs or other supplements you're taking. Some antidepressants can cause dangerous reactions when combined with certain medications or herbal supplements.
  • Serotonin syndrome. Rarely, an antidepressant can cause high levels of serotonin to accumulate in your body. Serotonin syndrome most often occurs when two medications that raise the level of serotonin are combined. These include other antidepressants, certain pain or headache medications, and the herbal supplement St. John's wort.
    • Signs and symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, lack of coordination, major changes in blood pressure and a rapid heart rate.
    • Seek immediate medical attention if you have any of these signs and symptoms.
  • Safety and blood tests. Your doctor may recommend blood levels to determine the most effective dose. Some side effects and benefits of cyclic antidepressants depend on the dose. Overdose of cyclic antidepressants can be dangerous.
  • Chronic health conditions. Cyclic antidepressants can cause problems in people with certain health conditions. For example, if you have glaucoma, an enlarged prostate, heart problems, diabetes, liver disease or a history of seizures, talk to your doctor about whether a cyclic antidepressant is a safe choice for you.

Suicide risk and antidepressants

Most antidepressants are generally safe, but the FDA requires that all antidepressants carry black box warnings, the strictest warnings for prescriptions. In some cases, children, teenagers and young adults under 25 may have an increase in suicidal thoughts or behavior when taking antidepressants, especially in the first few weeks after starting or when the dose is changed.

Anyone taking an antidepressant should be watched closely for worsening depression or unusual behavior. If you or someone you know has suicidal thoughts when taking an antidepressant, immediately contact your doctor or get emergency help.

Keep in mind that antidepressants are more likely to reduce suicide risk in the long run by improving mood.

Stopping treatment with cyclic antidepressants

Cyclic antidepressants aren't considered addictive. However, stopping antidepressant treatment abruptly or missing several doses can cause withdrawal-like symptoms. Symptoms may vary depending on how the drug works. This is sometimes called discontinuation syndrome. Work with your doctor to gradually and safely decrease your dose.

Withdrawal-like symptoms can include:

  • Agitation, irritability or anxiety
  • Nausea
  • Sweating
  • Flu-like symptoms, such as chills and muscle aches
  • Insomnia
  • Lethargy
  • Headache

Finding the right antidepressant

People may react differently to the same antidepressant. For example, a particular drug may work better — or not as well — for you than for another person. Or you may have more, or fewer, side effects from taking a specific antidepressant than someone else does.

Inherited traits may play a role in how antidepressants affect you. In some cases, where available, results of special blood tests may offer clues about how your body may respond to a specific antidepressant. However, other variables besides genetics can affect your response to medication.

When choosing an antidepressant, your doctor takes into account your symptoms, any health problems, other medications you take, and what's worked for you in the past.

Typically, it may take several weeks or longer before an antidepressant is fully effective and for initial side effects to ease up. Your doctor may recommend dose adjustments or different antidepressants, but with patience, you and your doctor can find a medication that works well for you.

From Mayo Clinic to your inbox

Sign up for free and stay up to date on research advancements, health tips, current health topics, and expertise on managing health. Click here for an email preview.

To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail.

March 30, 2022 See more In-depth

See also

  1. Addison's disease
  2. Adjustment disorders
  3. Adrenal fatigue: What causes it?
  4. Alzheimer's: New treatments
  5. Alzheimer's 101
  6. Understanding the difference between dementia types
  7. Alzheimer's disease
  8. Alzheimer's drugs
  9. Alzheimer's genes
  10. Alzheimer's prevention: Does it exist?
  11. Alzheimer's stages
  12. Ambien: Is dependence a concern?
  13. Antidepressant withdrawal: Is there such a thing?
  14. Antidepressants and alcohol: What's the concern?
  15. Antidepressants and weight gain: What causes it?
  16. Antidepressants: Can they stop working?
  17. Antidepressants: Side effects
  18. Antidepressants: Selecting one that's right for you
  19. Antidepressants: Which cause the fewest sexual side effects?
  20. Antidepressants and pregnancy
  21. Atypical antidepressants
  22. Back pain
  23. Binge-eating disorder
  24. Blood Basics
  25. Borderline personality disorder
  26. Breastfeeding and medications
  27. Dr. Wallace Video
  28. Dr. Mark Truty (surgery, MN) better outcomes with chemo
  29. Can zinc supplements help treat hidradenitis suppurativa?
  30. Hidradenitis suppurativa wound care
  31. Celiac disease
  32. Child abuse
  33. Chronic traumatic encephalopathy
  34. CJD - Creutzfeldt-Jakob Disease
  35. Clinical depression: What does that mean?
  36. Clinical trials for hidradenitis suppurativa
  37. Coconut oil: Can it cure hypothyroidism?
  38. Complete blood count (CBC)
  39. Complicated grief
  40. Compulsive sexual behavior
  41. Concussion
  42. Concussion in children
  43. Concussion Recovery
  44. Concussion Telemedicine
  45. Coping with the emotional ups and downs of psoriatic arthritis
  46. Coping with the stress of hidradenitis suppurativa
  47. COVID-19 and your mental health
  48. Creating a hidradenitis suppurativa care team
  49. Creutzfeldt-Jakob disease
  50. Cushing syndrome
  51. Cyclothymia (cyclothymic disorder)
  52. Delirium
  53. Depression and anxiety: Can I have both?
  54. Depression, anxiety and exercise
  55. What is depression? A Mayo Clinic expert explains.
  56. Depression during pregnancy
  57. Depression in women: Understanding the gender gap
  58. Depression (major depressive disorder)
  59. Depression: Supporting a family member or friend
  60. Diabetes and depression: Coping with the two conditions
  61. Diagnosing Alzheimer's
  62. Did the definition of Alzheimer's disease change?
  63. Dissociative disorders
  64. Vitamin C and mood
  65. Drug addiction (substance use disorder)
  66. Electroconvulsive therapy (ECT)
  67. Fatigue
  68. Fibromyalgia
  69. HABIT program orientation
  70. Hangovers
  71. Hashimoto's disease
  72. Headache
  73. Hidradenitis suppurativa
  74. Hidradenitis suppurativa and biologics: Get the facts
  75. Hidradenitis suppurativa and diet: What's recommended?
  76. Hidradenitis suppurativa and sleep: How to get more zzz's
  77. Hidradenitis suppurativa: Tips for weight-loss success
  78. Hidradenitis suppurativa: What is it?
  79. Hidradenitis suppurativa: When does it appear?
  80. Hidradenitis suppurativa: Where can I find support?
  81. How opioid use disorder occurs
  82. How to tell if a loved one is abusing opioids
  83. Hyperparathyroidism
  84. Hypoparathyroidism
  85. Hypothyroidism: Can calcium supplements interfere with treatment?
  86. Hypothyroidism diet
  87. Hypothyroidism and joint pain?
  88. Hypothyroidism: Should I take iodine supplements?
  89. Hypothyroidism symptoms: Can hypothyroidism cause eye problems?
  90. Hypothyroidism (underactive thyroid)
  91. Insomnia
  92. Insomnia: How do I stay asleep?
  93. Insomnia treatment: Cognitive behavioral therapy instead of sleeping pills
  94. Intervention: Help a loved one overcome addiction
  95. Is depression a factor in rheumatoid arthritis?
  96. Kratom for opioid withdrawal
  97. Lack of sleep: Can it make you sick?
  98. Lecanemab for Alzheimer's disease
  99. Living better with hidradenitis suppurativa
  100. Low blood pressure (hypotension)
  101. Male depression: Understanding the issues
  102. Managing Headaches
  103. Managing hidradenitis suppurativa: Early treatment is crucial
  104. Hidradenitis suppurativa-related health risks
  105. MAOIs and diet: Is it necessary to restrict tyramine?
  106. Marijuana and depression
  107. Mayo Clinic Minute: 3 tips to reduce your risk of Alzheimer's disease
  108. Mayo Clinic Minute: Alzheimer's disease risk and lifestyle
  109. Mayo Clinic Minute New definition of Alzheimer's changes
  110. Mayo Clinic Minute: Prevent migraines with magnetic stimulation
  111. Mayo Clinic Minute: Restless legs syndrome in kids
  112. Mayo Clinic Minute Weathering migraines
  113. Mayo Clinic Minute: Women and Alzheimer's Disease
  114. Medication overuse headaches
  115. Meditation
  116. Memory loss: When to seek help
  117. Mental health: Overcoming the stigma of mental illness
  118. Mental health providers: Tips on finding one
  119. Mental health
  120. Mental illness
  121. Migraine
  122. What is a migraine? A Mayo Clinic expert explains
  123. Migraine medicines and antidepressants
  124. Migraine FAQs
  125. Migraine treatment: Can antidepressants help?
  126. Migraines and gastrointestinal problems: Is there a link?
  127. Migraines and Vertigo
  128. Migraines: Are they triggered by weather changes?
  129. Alleviating migraine pain
  130. Mild cognitive impairment (MCI)
  131. Mindfulness exercises
  132. Monoamine oxidase inhibitors (MAOIs)
  133. Natural remedies for depression: Are they effective?
  134. Nervous breakdown: What does it mean?
  135. New Alzheimers Research
  136. Nicotine dependence
  137. Occipital nerve stimulation: Effective migraine treatment?
  138. Ocular migraine: When to seek help
  139. Opioid stewardship: What is it?
  140. Oppositional defiant disorder (ODD)
  141. Pain and depression: Is there a link?
  142. Pancreatic cancer
  143. Pancreatic Cancer
  144. What is pancreatic cancer? A Mayo Clinic expert explains
  145. Infographic: Pancreatic Cancer: Minimally Invasive Surgery
  146. Pancreatic Cancer Survivor
  147. Infographic: Pancreatic Cancers-Whipple
  148. Perimenopause
  149. Pituitary tumors
  150. Polymyalgia rheumatica
  151. Poppy seed tea: Beneficial or dangerous?
  152. Post COVID syndrome
  153. Premenstrual dysphoric disorder
  154. Premenstrual syndrome (PMS)
  155. Prescription drug abuse
  156. Prescription sleeping pills: What's right for you?
  157. Progressive supranuclear palsy
  158. Psychotherapy
  159. Reducing the discomfort of hidradenitis suppurativa: Self-care tips
  160. Restless legs syndrome
  161. Salt craving: A symptom of Addison's disease?
  162. Schizoaffective disorder
  163. Seasonal affective disorder (SAD)
  164. Seasonal affective disorder treatment: Choosing a light box
  165. Selective serotonin reuptake inhibitors (SSRIs)
  166. Serotonin and norepinephrine reuptake inhibitors (SNRIs)
  167. Sleep disorders
  168. Sleep tips
  169. Soy: Does it worsen hypothyroidism?
  170. Staying active with hidradenitis suppurativa
  171. Stress symptoms
  172. Sundowning: Late-day confusion
  173. Support groups
  174. Surgery for hidradenitis suppurativa
  175. Symptom Checker
  176. Tapering off opioids: When and how
  177. Tinnitus and antidepressants
  178. Transcranial magnetic stimulation
  179. Traumatic brain injury
  180. Treating hidradenitis suppurativa: Explore your options
  181. Treating hidradenitis suppurativa with antibiotics and hormones
  182. Treatment of parathyroid disease at Mayo Clinic
  183. Treatment-resistant depression
  184. Unexplained weight loss
  185. Vagus nerve stimulation
  186. Valerian: A safe and effective herbal sleep aid?
  187. Vascular dementia
  188. Video: Alzheimer's drug shows early promise
  189. Video: Vagus nerve stimulation
  190. Vitamin B-12 and depression
  191. What are opioids and why are they dangerous?
  192. What are the signs and symptoms of hidradenitis suppurativa?
  193. Wilson's disease
  194. Xylazine
  195. Young-onset Alzheimer's