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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. 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.
Receptor Binding Affinity of TCAs and Adverse Effect Profile 
NE Reuptake Blockade
5-HT Reuptake Blockade
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
Dosage Comparison of TCAs in Major Depressive Disorder*
Starting Dose (mg/day)
Dose Range (mg/day)
Titration (mg/day per week)
Maximal Dose in Elderly (mg/day)
Dosing for obsessive-compulsive disorder is similar
May use up to 300 mg in divided doses for inpatients
Therapeutic plasma concentration range for depression is 150-300 ng/ml
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
Only TCA given three times daily
*All TCAs should be used with caution and at lower doses in patients with hepatic impairment.
Key findings from systematic reviews and meta-analyses are:
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. 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.
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). Xerostomia (dry mouth), urinary hesitancy, constipation, and blurred vision are the most common anticholinergic side effects.
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 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.
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. Imipramine has been utilized therapeutically for its antiarrhythmic effect.
TCAs may cause an increase in intraocular pressure.
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. In contrast, geriatric patients may be at lower risk of suicidal thinking and behavior.
Lowering of seizure threshold is a rare complication of TCA therapy, similar to other marketed antidepressants. 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%).
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.
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.
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.
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.
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.
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).
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 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.
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.
TCAs are potentially fatal in overdose, and are second only to analgesics in terms of the number of fatalities associated with overdose. Cardiac arrhythmia leading to cardiac arrest is typically the cause of death. In most cases, cardiac arrest does not occur and patients recover.
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