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Depression and Tricyclics

For many years, tricyclic antidepressants (TCAs) and heterocyclics were the main depression medications used in the treatment of severe depression. The tricyclics are considered "dirty" drugs because they react with a number of receptors besides the one responsible for their therapeutic effect, resulting in a host of side effects. In terms of chemical structure, secondary amine drugs such as amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline are preferred to tertiary amine drugs because they have fewer side effects.

Effect of Tricyclics on Depression

The majority of the TCAs are thought to act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET) which results in an elevation in concentration of these neurotransmitters and therefore an enhancement of neurotransmission.1 In addition to their SNRI function, many TCAs also have a tendency to act as an antagonist at various receptors in the brain (5-HT2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, and NMDA receptors) and as agonists at the sigma receptors, some of which may contribute to their therapeutic efficacy, as well as their side effects.7

It is important to note, however, that these drugs do not act rapidly. It generally requires 10 to 21 days of treatment for symptoms to start to improve.

Read more details about Tricyclics.

Research Evidence on Tricyclics

Prior to the discovery of SSRIs and other newer antidepressants, TCAs were a first choice for pharmacological treatment of clinical depression. Newer antidepressants are thought to have fewer and less intense side effects and are also thought to be less lethal if used in a suicide attempt as the doses required for clinical treatment and potentially lethal overdose are far wider in comparison to TCAs. Nonetheless, TCAs are still occasionally used for treatment-resistant depression that has failed to respond to newer antidepressants.2

How to Use Tricyclics

A psychiatrist will typically prescribe these brands of drugs for patients with certain types of depression.3

Drug name and brand name Starting dose Therapeutic dose
Amitriptyline (Elavil) 25-50 mg 150-300
Doxepin (Sinequan, Adapin) 25-50 mg 150-300 mg
*Imipramine (Tofranil) 25-50 mg 150-300 mg
Trimipramine (Surmontil) 25-50 mg 100-300 mg
Clomipramine (Anafranil) 25-50mg 150-200 mg
Amoxapine (Asendin) 25-50 mg 150-400 mg
Desipramine (Norpramin) 25-50 mg 150-300 mg
Maprotiline (Ludiomil) 25-50 mg 150-225 mg
Nortriptyline (Aventyl, Pamelor) 10-25 mg 75-125 mg
Protriptyline (Vivactil) 5-15 mg 15-40 mg
**Trazodone (Desyrel) 25-50 mg 150-400 mg

*One of the first TCAs, Gold standard TCA antidepressant

** Of the existing tricyclics, trazodone appears to have the lowest degree of cardiotoxicity

TCAs have also been linked to sudden death syndrome in children. For this reason, many clinicians put them at the bottom of the list of ADHD medications for children. TCAs can also be risky for substance abusers. Before starting TCA treatment for children, doctors recommend getting a baseline EKG in addition to monitoring side effects.

Side effects

The side effect associated with Tricyclic antidepressants are usually mild. These may include:

  • Dry mouth
  • Drowsiness
  • Constipation
  • Weight gain
  • Difficulty with urination
  • Blood pressure changes
  • Risk of severe mood and behavior changes, including suicidal thoughts (Young adults may be at a higher risk for this side effect.)

To reduce the risk of side effects, your doctor will prescribe a low starting dose and slowly increase the amount. Tricyclics are generally well-tolerated especially in low doses. The doses needed to induce pain relief are typically lower than the doses recommended for treating depression

All of the Tricyclics have the same side effects, but in varying degrees. To fully understand these potential side effects, they are grouped as follows:

  • Anticholinergic- These side effects range from unpleasant (dry mouth, dry skin, blurred vision, and constipation) to serious (paralytic ileus, cessation of the movement of the intestine, which can lead to intestinal rupture and death; and urinary retention, inability to urinate, which in serious cases can lead to rupture of the bladder).
  • Adrenergic- Side effects can include sweating, sexual dysfunction, and orthostatic hypotension-- sudden drop in blood pressure upon rising and a sensation of lightheadedness. This condition can lead to a fall and, in turn, to fractures, which can have serious medical consequences, particularly in the elderly.
  • Antihistaminic- Side effects include sedation and weight gain.
  • Miscellaneous- Other side effects include lowered seizure threshold, cardiac arrhythmia, hepatitis, rashes, sweating, anxiety, and elevated heart rate.

Other Uses

Imipramine (Tofranil) is also often used as a sleep medication and is not addictive like most sleep medications, although one's tolerance can be built up quickly. It is also used for eneuresis (bed-wetting) off-label. Trazodone (Desyrel) is more commonly used as sleep medication. Clomipramine (Anafranil) has also been approved as anti-obsessional medication. The TCAs also show efficacy in the clinical treatment of a number of different types of chronic pain, most notably neuralgia or neuropathic pain and fibromyalgia.6

Tricyclics and Children

Early case reports and clinical practice have shown that very severely depressed, hospitalized children and adolescents did often respond to treatment with TCAs. However, TCAs are plagued by significant side effects, they are very toxic in overdoses, and there have been 6 cases of sudden death in children (due to cardiac effects with the tricyclic, Desipramine (Norpramin). Additionally, in the small number of recent, well-controlled studies, tricyclics have been found to be no more effective than placebos (recall that in such studies severely ill children are not included).4 To date, the double-blind, placebo-controlled studies of antidepressants in the treatment of major depressive disorder in children and adolescents have been limited to SSRIs. The limited studies in this area reveal that SSRIs are much better tolerated than tricyclics.5


1 Gillman, P. K. (2007). Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology, 151(6), 737-48.

2 Broquet, K. (1999). Status of treatment of depression. Southern Medical Journal, 92(9), 846-56.

3 Preston, J. & Johnson, J. (1994). Clinical psychopharmacology made ridiculously simple. Miami, FL: MedMaster, Inc.

4 Preston, J. D., O'Neal, J. H., & Talaga, M. C. (2005). Handbook of clinical psychopharmacology for therapists. Oakland, CA: New Harbinger Publications, Inc.

5 Emslie, G. J., & Mayes, T. C. (2001). Mood disorders in children and adolescents: Psychopharmacological treatment. Biological Psychiatry, 49, 1082-1090.

6 McQuay, H., Tramer, M., Nye, B., Carroll, D., Wiffen, P., & Moore, R. (1996). A systematic review of antidepressants in neuropathic pain. Pain, 68(2-3), 217-27.

7 Musselman, D. L., DeBattista, C., Nathan, K. I., Kilts, C. D., Schatzberg, A. F., & Nemeroff, C. B. (1998). Biology of mood disorders. In A. F. Schatzberg and C. B. Nemeroff's (Eds.), Textbook of Psychopharmacology, 2nd ed., 549-588.

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