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Alternative Applications for Tricyclic Antidepressants

Written byDesiree Smith

Tricyclic Medications

Were first introduced in 1957 for the treatment of depression. Imipramine was the first tricyclic medication shown to be efficacious for the treatment of depression. Not long after, clomipramine, doxepin,nortriptyline, and others were subsequently introduced to the United States market. For the next 30 years, tricyclics were first-line pharmacotherapy for treatment of depression. However, in 1987, Selective Serotonin Reuptake Inhibitors (SSRIs) were introduced and quickly became first-line treatment over tricyclics due to their reduced side effect profile.

Although tricyclics have become secondary to SSRIs for the treatment of depression, they are still essential medications for the management of treatment-resistant depression, panic attacks, generalized anxiety disorder, posttraumatic stress disorder, bulimia nervosa, and smoking cessation. Furthermore, tricyclic medications have been shown beneficial in the treatment of more nuanced conditions like enuresis, cyclic vomiting syndrome, and trichotillomania.

Enuresis is defined by the DSM-5 as repeated voiding of urine into bed or clothes, whether involuntary or intentional, at the age of 5 or older. The behavior is clinically significant as manifested either by a frequency of at least twice a week for at least 3 consecutive months or by the presence of clinically significant distress in social, academic, or other important areas of functioning.

Enuresis affects up to 20% of five-year old children and 2% of adults. In a Cochrane study of 64 trials and 4,071 children, tricyclic medications, specifically imipramine, were found to be effective in reducing the number of wet nights during treatment. Imipramine is thought to relax the bladder muscle and potentially cause the patient to have a lighter sleep and wake more readily to void, if necessary. Following cessation of imipramine, patients do not experience a sustained effect, which ultimately results in most children relapsing. However, imipramine can be extremely helpful in treating enuresis as children conjunctively work on bladder training and other behavioral therapies.

Cyclic vomiting syndrome is defined as a disorder that causes recurrent episodes of nausea, vomiting, and lethargy. While it is more common in children, cyclic vomiting syndrome can affect people of any age. A person with cyclic vomiting syndrome can experience episodes of nausea, vomiting, and lethargy that last between 1 hour and 10 days. Additionally, dehydration, pallor, abdominal pain, diarrhea, headache, fever, and photophobia are associated symptoms of cyclic vomiting syndrome.

Cyclic vomiting syndrome is thought to be a variant of migraines and is specifically associated with a condition known as abdominal migraine that manifests as attacks of stomach pain and cramping. As children age, attacks of nausea, vomiting, or abdominal pain may be replaced by migraine headaches.Treatment of cyclic vomiting syndrome is based on the patient’s needs and response. Cyclic vomiting syndrome can be treated with anti-migraine medications, anti-vomiting medications, and sedation.

Other treatment options are symptomatic and address pain and IV hydration, while psychological approaches employ cognitive behavioral therapy. While there is not currently significant data, amitriptyline is widely used for refractory IBS in children and has shown some efficacy in cyclic vomiting syndrome. Trichotillomania is defined by the DSM-5 as recurrent pulling out of one’s hair, resulting in hair loss, with repeated attempts to decrease or stop hair pulling. Additionally, the hair pulling causes significant distress or impairment in social, occupational, or other important areas of functioning.

While trichotillomania is best treated with habit reversal therapy, evidence suggests that clomipramine is more efficacious than placebo in the treatment of trichotillomania and aids patients in the cessation of this behavior. Additionally, it is of note that glutamatergic agents such as N-acetyl cysteine have also shown efficacy in treating behavioral addictions like trichotillomania. In summation, while tricyclic medications have become less prevalent with the advent of SSRIs, they still have a relevant place in pharmacotherapy for symptom reduction across many disorder processes.


American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th Edition). Arlington, VA: American Psychiatric Publishing.

Caldwell, P.H.Y., Sureshkumar, P., Wong, W.C.F. Tricyclic and Related Drugs for Nocturnal Enuresis in Children. Cochrane Database of Systematic Reviews 2016, Issue 1. Article No.: CD002117. DOI: 10.1002/14651858.CD002117.pub2

Chamberlain, S.R., Odlaug, B.L., Boulougouris, V., Fineberg, N.A., & Grant, J.E. (2009). Trichotillomania: Neurobiology and Treatment. Neuroscience & Behavioral Reviews, 33(6), Pages 831-842.

Condition, Gene, or Chromosome Summary: National Library of Medicine (US). Genetics Home Reference. Bethesda (MD): The Library; 2020. Cyclic Vomiting Syndrome.

Hirsch, M. Birnbaum, R.J. Tricyclic and Tetracyclic Drugs: Pharmacology, Administration, and Side Effects. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on May 20, 2020.)

Li, B.U. Cyclic Vomiting Syndrome. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on May 20, 2020.)

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