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Jan.30.2012

Tricyclic Antidepressants (TCAs)

Summary

  • Tricyclic antidepressants (TCAs) comprise one of the oldest classifications of antidepressant drugs, beginning with the approval of imipramine in 1959.
  • TCAs as a class have a wide range of indications, including major depressive disorder (MDD), dysthymic disorder, neuropathic pain, and migraine or tension-type headache. Individual TCAs may also have additional indications (e.g., imipramine for enuresis, clomipramine for obsessive compulsive disorder).
  • TCAs are generally considered to have similar efficacy to selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) in mild to moderate depression, but may be more effective in severe or treatment-refractory depression.
  • Evidence-based guidelines for the treatment of MDD generally recommend TCAs as second-line treatment because of their inferior safety and tolerability profile compared with SSRIs, SNRIs, and bupropion.
  • In contrast, TCAs are considered first-line treatment for several types of neuropathic pain, including peripheral diabetic neuropathy and postherpetic neuralgia, and for migraine and tension-type headache prophylaxis. When used for these indications, the usual dosage is about 50% less than that required to treat MDD.
  • Antidepressant therapy with TCAs is primarily guided by clinical effectiveness and individual tolerability; however, a correlation has been found between patient response and plasma levels of some nortriptyline and imipramine.

Pharmacology/Mechanism of Action

TCAs are so named because of a common core structure comprising 3 rings. TCAs with a tertiary-amine side chain (amitriptyline, clomipramine, doxepin, imipramine, trimipramine) are characterized by greater inhibition of the reuptake of serotonin (5-HT) than of norepinephrine (NE), whereas those with a secondary-amine side chain (desipramine, nortriptyline, protriptyline) preferentially target the NE transporter.[49961][49959] Although the precise mechanism of action of TCAs is not fully understood, it is thought that interfering with the reuptake of NE and 5-HT results in increased concentrations of these neurotransmitters in the synaptic cleft and, consequently, in increased activity at the postsynaptic receptors. Because 5-HT and NE are known to be involved in the regulation of mood and the basic biological functions associated with mood, such as appetite, cognition, and sleep, their modulation appears to be an important factor in mood regulation. It is now believed that downstream changes in gene expression associated with regulation of adrenoreceptors may be the “final common pathway” responsible for the antidepressant effect. The mechanism of action of TCAs in neuropathic pain and headache is also believed to derive from blockade of NE and 5-HT reuptake.[49960]

 

Receptor Binding Affinity of TCAs and Adverse Effect Profile [49960][49967]

Drug Name

 

 

Amine Classification

NE Reuptake Blockade

5-HT Reuptake Blockade

Anti-cholinergic Effects

Sedation

 

Orthostatic Hypotension

Amitriptyline

tertiary

+

+++

 +++++

+++++

+++++

Clomipramine

tertiary

0

+++++

+++++

++++

++++

Desipramine

secondary

+++++

 +

+

+

+++

Doxepin

tertiary

+

+

+++

+++++

+++++

Imipramine

tertiary

+

+

+++++

+++

+++++

Nortriptyline

secondary

+++

0

+++

+++

+

Protriptyline

secondary

+++++

+

+++++

+

++

Trimipramine

tertiary

0

0

+++++

+++++

++++

0 = no appreciable receptor binding affinity; + = low receptor binding affinity; ++ low to moderate receptor binding affinity; +++ = moderate receptor binding affinity; ++++ = moderate to high receptor binding affinity; +++++ = high receptor binding affinity

Therapeutic Use

  • None of the TCAs are indicated for treatment of MDD in children under age 12;[49961][49959] however, imipramine is indicated in adolescents and children >= 6 years for enuresis.
  • Anticholinergic and antihistaminic adverse events (AEs) are very common; therefore, TCAs are initiated at a low dose and titrated over days to weeks to attain a therapeutic dose. Most patients develop tolerance to these AEs over time.
  • Despite their initial approval as antidepressants, TCAs are more commonly used for neuropathic pain and headache.[49966][49962]
  • In neuropathic pain and headache, efficacy is achieved at lower doses and is not mediated by an antidepressant effect. Therefore, TCAs work well in patients who are not depressed.[49966] Overall, they are most effective in headache prevention[49962]
  • Treatment response generally takes place gradually, often requiring up to 3 weeks of therapy or longer. Adverse effects, in contrast, can be seen within a few hours of the initial dose, but tend to diminish over 2 to 3 weeks at any given dose.
  • Clomipramine is the only TCA indicated for the treatment of obsessive compulsive disorder; meta-analyses suggest it may be more effective than SSRIs, but head-to-head trials have shown equivalent efficacy.[13434]
  • TCAs are typically divided into the tertiary amines (e.g., amitriptyline) and the secondary amines (e.g., nortriptyline). These 2 subgroups have different receptor activity profiles.[49960][49967] 
    • Secondary amines are higher in norepinephrine selectivity than serotonin selectivity. 
    • Some tertiary amines have higher selectivity for serotonin than norepinephrine. 
    • Interchange between a tertiary and secondary amine may be useful in cases of treatment failure with the initial agent. When determining the appropriate tricyclic regimen, it is important to note that desipramine is the major metabolite of imipramine and nortriptyline is the major metabolite of amitriptyline 

 

Dosage Comparison of TCAs in Major Depressive Disorder*

Drug Name

Starting Dose (mg/day)

Dose Range (mg/day)

Titration (mg/day per week)

Maximal Dose in Elderly (mg/day)

Special Notes

Amitriptyline

25-75

150-300

25-50

150

 
Clomipramine

25

100-250

25-50

250

Dosing for obsessive-compulsive disorder is similar

Desipramine

50-75

100-200

25-50

150

May use up to 300 mg in divided doses for inpatients

Doxepin

50-75

75-150

25-50

150

May use up to 300 mg in divided doses for inpatients

Imipramine

25-75

150-300

25-50

150

Therapeutic plasma concentration range for depression is 150-300 ng/ml

Nortriptyline

25-50

75-150

25-50

Up to 150  (if monitored with blood levels)

Therapeutic plasma concentration range for depression is 50-150 ng/mL. Most clearly defined of any TCA

Protriptyline

15-30

30-60

30

15

Only TCA given three times daily

Trimipramine

50-75

100-200

50

150

May use up to 300 mg in divided doses for inpatients

*All TCAs should be used with caution and at lower doses in patients with hepatic impairment.

Comparative Efficacy

  • Given that TCAs have not been used as first-line agents in the treatment of depression  since selective serotonin reuptake inhibitors (SSRIs) became a treatment option beginning in the late 1980s, there are few large, longitudinal, observational studies to provide evidence as to the relative real-world effectiveness of one TCA over another, or of TCAs compared with SSRIs.[49961]
  • Overall, there are few high-quality studies that compare one TCA with another or a TCA with another agent in the treatment of depression, neuropathic pain, or headache.[49964][11687]
  • Comparative efficacy has been addressed by systematic reviews and meta-analyses, but authors acknowledge the need for better evidence.[49964][11687][49968]

Key findings from systematic reviews and meta-analyses are:

  • TCAs were generally found to be of equivalent efficacy to each other for most indications; however, in one meta-analysis assessing the tolerability and efficacy of amitriptyline in the management of depression, the proportion of patients who responded to amitriptyline was 2.4% higher than for comparator tricyclic or heterocyclic antidepressants.[49964]
  • Clomipramine is the only TCA effective for obsessive compulsive disorder (OCD). The effectiveness of clomipramine in treating OCD is likely due to the high serotonin selectivity of the drug.
  • There is no difference in efficacy between TCAs and SSRIs in the treatment of major depression in outpatients, but there may be a slight advantage for TCAs in the treatment of severe major depression in the inpatient setting.[49964][11687]
  • TCAs appear to be more effective than SSRIs in the treatment of neuropathic pain, but they are considered to be generally equivalent in efficacy to SNRIs (venlafaxine and duloxetine) and antiepileptic drugs (gabapentin and pregabalin).[49968]

Adverse Reactions/Toxicities

Adverse effects are the most important determinant of whether or not to prescribe a TCA, and they also help guide drug selection within the class.[49961][49959] Variations in receptor activities (e.g., serotonin, adrenergic, histamine, muscarinic) between tertiary and secondary amines account for differences in the frequency and severity of some side effects. In general, tertiary amines are associated with more sedation, anticholinergic effects, and cardiac effects than secondary amines. Thus, as a group, secondary amines may be better tolerated than tertiary amines.

Anticholinergic adverse reactions

TCAs are associated with high rates of anticholinergic side effects; drugs with greater affinity for muscarinic cholinergic receptors are generally associated with a higher frequency and severity of these adverse events (amitriptyline, clomipramine, trimipramine).[49961][49960] Xerostomia (dry mouth), urinary hesitancy, constipation, and blurred vision are the most common anticholinergic side effects.

Antihistaminic adverse reactions

Antagonism of the histamine H1 receptor is associated primarily with drowsiness and weight gain. Weight gain can be substantial and is thought to be due primarily to increased appetite and food intake. TCAs differ markedly in their relative affinity for the histamine H1 receptor and, therefore, their propensity to cause weight gain and sedation (e.g., amitriptyline > nortriptyline > desipramine). The TCA that is the most potent H1 receptor antagonist is doxepin. For this reason, low-dose doxepin acts as a highly selective H1 receptor antagonist and is used for insomnia.

Orthostatic hypotension

Orthostatic hypotension is the main AE associated with blockade of a-adrenergic receptors; it occurs most frequently with amitriptyline. This is of greatest concern in the elderly.

EKG changes

Alterations in electrocardiogram patterns, arrhythmias, and AV block may occur with the administration of TCAs. Imipramine, and possibly other tricyclic antidepressants, can cause both PR prolongation and QT prolongation. Imipramine and nortriptyline are known to prolong the QRS interval. Other tricyclics would be expected to produce similar ECG changes. Although all tricyclic antidepressants are thought to be proarrhythmic after acute overdoses, at therapeutic doses, their actions on the conducting system of the heart may vary.[23775] Imipramine has been utilized therapeutically for its antiarrhythmic effect.[23776]

Changes in intraocular pressure

TCAs may cause an increase in intraocular pressure.

Psychiatric adverse reactions

TCAs can precipitate a manic episode in patients with underlying bipolar disorder, including those without a previous manic episode. TCAs can also precipitate delirium, particularly in elderly patients with preexisting cognitive impairment. In addition, all antidepressants, including TCAs, carry a black box warning concerning increased risk of suicide (suicidal thoughts, plans, or attempts) in children, adolescents, and young adults. This warning is based on pooled data from clinical trials of antidepressants (mostly SSRIs), which documented a higher rate of suicidality?but not suicide? in these populations receiving active drug.[49959][49961] In contrast, geriatric patients may be at lower risk of suicidal thinking and behavior.[49961]

Seizures

Lowering of seizure threshold is a rare complication of TCA therapy, similar to other marketed antidepressants.[49961] Among the TCA class, clomipramine is generally considered to carry the highest seizure risk, although the incidence appears to be dose-related. One short-term study in patients with obsessive-compulsive disorder found a higher incidence of seizures at clomipramine doses greater than 300 mg/day (2.1%) than with doses less than 250 mg/day (0.48%).[23945]

Drug Interactions

CNS depressants

Because of the risk of sedation, respiratory depression, and hypotension, caution is advised when TCAs are used with other central nervous system depressants, especially alcohol.

Monoamine oxidase inhibitor (MAOI) therapy

TCAs should avoided in patient receiving MAOIs if possible. Concurrent use of MAOIs with TCAs can cause hyperpyrexia, hypertension, or seizures. It is recommended that 14 days elapse between discontinuation of the MAOI and initiation of the TCA.

Class IA and III antiarrhythmics

TCAs should not be coadministered with class IA antiarrhythmics, class III antiarrhythmics, or any other drug known to have similar effects. TCAs share pharmacologic properties that are similar to class IA and III antiarrhythmics and concomitant use may prolong the QT interval.

Drugs that inhibit or induce CYP 450 isozymes

Most TCAs are metabolized, at least partially, by the CYP 450 pathway; coadministration of a drug that either inhibits or induces particular CYP 450 isoenzymes may affect TCA blood levels.

Other pyschotropic medications

Use of TCAs with an SSRI or SNRI may increase the risk of serotonin syndrome, which is characterized by hyperthermia, hypertension, autonomic instability, and mental status changes. Cautious use is also warranted with other serotonergic drugs including linezolid and tramadol.

Safety Issues

Acute myocardial infarction and cardiac conduction defects

TCAs are contraindicated for use in patients in the acute recovery phase of a myocardial infarction. Use of TCA during this time period could cause sudden death due to EKG changes or cardiac rhythm abnormalities. In additoin, TCAs should not be given to patients with QT prolongation or familial histories of long QT syndromes or to patients with cardiac conduction defects (e.g., cardiac arrhythmias, AV block, bundle branch block).[49958]

Glaucoma

TCAs may cause an increase in intraocular pressure, which can exacerbate narrow-angle glaucoma; TCAs should be avoided in patients with known glaucoma.

Geriatric patients

Geriatric patients are at increased risk for falls due to the orthostatic hypotensive and sedative effects of the TCAs. Use with caution and at lower doses than used in adult patients.

Withdrawal syndrome

All TCAs should be tapered gradually over several weeks as abrupt discontinuation has been associated with symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea.

Overdose risk

TCAs are potentially fatal in overdose, and are second only to analgesics in terms of the number of fatalities associated with overdose.[49958] Cardiac arrhythmia leading to cardiac arrest is typically the cause of death. In most cases, cardiac arrest does not occur and patients recover.

[11687]MacGillivray S, Arroll B, Hatcher S, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;326:1014

[13434]Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for obsessive-compulsive disorder. J Clin Psychopharmacol 2002;22:309-17

[23775]Veith RC, Raskind MA, Caldwell JH, et al. Cardiovascular effects of tricyclic antidepressants in depressed patients with chronic heart disease. N Engl J Med 1982;306:954-9.

[23776]Bigger JT Jr, Giardina EGV, Perel JM, et al. Cardiac antiarrhythmic effect of imipramine hydrochloride. N Engl J Med 1977;296:206-8.

[23945]Skowron DM, Stimmel GL. Antidepressants and the risk of seizures. Pharmacotherapy 1992;12:18-22.

[49958]Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001;18:236-241.

[49959]Birmaher B, Brent D, and the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46:1503-1526.

[49960]Hardman JG, Limbird LE. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th International Edition. New York: McGraw Hill; 2001:451-470.

[49961]Practice Guideline for the treatment of patients with major depressive disorder, 3rd Edition. American Psychiatric Association Press. November 2010.

[49962]Jackson JL, Shimeall W, Sessums L, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222.

[49964]Barbui C, Hotopf M. Amitriptyline v the rest: still the leading antidepressant after 40 years of randomised controlled trials. Br J Psychiatry. 2001;178:129-144.

[49966]O’Connor AB, Noyes K, Holloway RG. A cost-effectiveness comparison of desipramine, gabapentin, and pregabalin for treating postherpetic neuralgia. J Am Geriatr Soc. 2007;55:1176–1184.

[49967]Kaplan HI, Sadock BJ.Synopsis of Psychiatry. 8th Edition. Maryland: Williams & Wilkins; 1998:1103.

[49968]Selph S, Carson S, Fu R, Thakurta S, Low A, McDonagh M. Drug Class Review Neuropathic Pain Final Update 1 Report June 2011 Oregon Evidence-based Practice Center Mark Helfand, MD, MPH, Director Oregon Health & Science University, Portland, Oregon 97239. (http://derp.ohsu.edu/about/final-document-display.cfm)

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