Alternative Applications for Tricyclic Antidepressants

May 20, 2020


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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