Section 3.2.2.1

TRICYCLICS AND TETRACYCLICS

General Description

The tricyclics are often considered the classic antidepressant drugs; and these drugs share many pharmacokinetic and pharmacodynamic properties. The tricyclics were initially introduced for the treatment of depression. However, the indications for these drugs have been expanded beyond depression to include anxiety disorders, eating disorders, and chronic pain syndromes.

The tricyclics have a three-ring nucleus in their molecular structure. The tertiary amines of this group have two methyl groups on their side chain; and the secondary amines of this group have only one methyl group on their side chain. In the body, the tertiary amines are metabolized into their corresponding secondary amines, making these drugs all structurally similar.

The tertiary amines of the tricyclics include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), trimipramine (Surmontil), and doxepin (Adapin, Sinequan). The secondary amines of the tricyclics include desipramine (Norpramin, Pertofrane), nortriptyline (Pamelor, Aventyl), and protriptyline (Vivactil).

The classification of a tetracyclic drug is somewhat arbitrary, based on a gross count of the number of rings in the molecular structure. This is especially true of amoxapine (Asendin), as this drug is actually a dibenzoxazepine with a cyclic side chain off a three-ring nucleus. Some textbooks refer to amoxapine as a tricyclic; other books consider amoxapine a tetracyclic because of the total of four rings.

The tetracyclic drugs were initially introduced as being significantly different from the tricyclics. Further study and clinical use have demonstrated that the tetracyclic and tricyclic drugs can best be conceptualized as one family. The tetracyclics include, maprotiline (Ludiomil), mianserin, and (depending on the textbook) amoxapine (Asendin). Mianserin is not available in this country.

Indications for Medication

For a major depressive episode, the tricyclics and tetracyclics are equally effective. This antidepressant efficacy occurs both in major depressive disorder patients and in bipolar disorder patients. Symptoms of melancholia and prior episodes of depression may increase the likelihood of a therapeutic response.

For depressions due to a general medical condition, the tricyclics and tetracyclics are also equally effective. These depressions are associated with medical syndromes, such as cerebro-vascular disorders, central nervous system traumas, dementia, movement disorders and acquired immune deficiency syndrome (AIDS).

For panic disorder with agoraphobia, the recommended tricyclic is imipramine. However, the other tricyclics may also be effective. Early literature reports indicated a positive response to low doses (50mg a day) of imipramine, but recent literature reports indicate that the usual antidepressant dosages are usually required.

For generalized anxiety disorder, the FDA has approved doxepin. Some research studies show that imipramine may also be useful. Some clinicians prefer a drug containing chlordiazepoxide and amitriptyline (Limbitrol) for mixed anxiety and depression.

For obsessive-compulsive disorder, clomipramine has been shown to be effective. It does not appear that the other tricyclics or tetracyclics are nearly as effective. Some clinicians prefer the SSRIs (for example fluoxetine and fluvoxamine) for the treatment of this disorder.

For eating disorders and bulimia nervosa, imipramine and desipramine have been shown to be effective. Other tricyclics and tetracyclics may be effective for these conditions, but more research needs to be completed.

For chronic pain syndromes (including headaches, migraines, and peripheral neuropathies), tricyclics and tetracyclics have been shown to be effective.

Other possible syndromes (which may respond to tricyclics and tetracyclics) include narcolepsy, nightmare disorder, and post-traumatic stress disorder.

The tricyclics and tetracyclics are sometimes used with attention deficit, hyperactivity disorder, sleeping walking disorder (somnambulism), separation anxiety and sleep terror disorder.

Clinical Guidelines

The specific choice of which tricyclic or tetracyclic should be based on a collection of data, including the patient's target symptoms, the patient's history of prior responses to drugs, the family's history of responses to drugs, the adverse side effect profile of the drug, and the clinician's own preferences.

All available tricyclics and tetracyclics have been demonstrated to be equally effective in the treatment of depression. In the case of an individual patient, one tricyclic or tetracyclic may be effective, another ineffective. The clinician may need to attempt several medication trials before achieving a successful response.

Researches have demonstrated differences among tricyclics and tetracyclics in their relative ability to block either serotonin reuptake or epinephrine reuptake. If one drug proves ineffective, it is reasonable to switch from a strongly serotonergic drug to a strongly noradrenergic drug.

Tricyclics and tetracyclics have different guidelines for dosage range. The clinician should check the PDR and this manual's recommendations for dosage ranges. All of the tricyclics and tetracyclics should be started at a low dose and titrated toward a more therapeutic dose. Panic disorder patients may be especially sensitive to side effects and these patients may need to begin with very low doses.

Tricyclics and tetracyclics often require 2-4 weeks to achieve a positive response. A full clinical trial may take 6 weeks to assess the drug's efficacy. If a tricyclic or tetracyclic has been prescribed for 4 weeks (at maximum dose) without achieving a therapeutic effect in a depressed patient, lithium or thyroid augmentation may be considered.

Lithium augmentation usually includes a dose range of 900-1200mg a day and a trial duration of 7-14 days. Thyroid augmentation often includes the addition of L-triiodothyronine at 25-50mcg a day for 7-14 days. These adjuvant drugs often convert tricyclic and tetracyclic non-responders into responders. Buspirone has also been reported to convert non-responders into responders.

The length of treatment with tricyclics and tetracyclics varies according to the patient's severity of symptoms, duration of symptoms, and prior episodes of depression. Current research articles support longer treatment courses with acute level dosages for higher risk patients.

Some data suggests that the long-term use of tricyclics and tetracyclics may induce a manic episode or perhaps rapid cycling bipolar disorder in some patients. Lithium prophylaxis may need to be considered in some patients who have frequent, episodic, and serious depressive episodes.

Adverse Effects

The common adverse effects to the tricyclics and tetracyclics include anticholinergic effects, sedation, autonomic effects, cardiac effects, neurological effects, allergic effects, and "other" adverse effects like weight gain, gynecomastia, and amenorrhea.

The anticholinergic effects include dry mouth, constipation, blurred vision and urinary retention. Sugarless gum or candy can alleviate the dry mouth. Bethanechol (urecholine), 25-50mg three or four times a day, can reduce the urinary retention and may be helpful for impotence when taken 30 minutes before sexual intercourse.

Of tricyclics and tetracyclics, amitriptyline, imipramine, trimipramine, and doxepin are the most anticholinergic. Amoxapine, nortriptyline, and maprotiline are less anticholinergic. Desipramine may be the least anticholinergic.

Tricyclics and tetracyclics often cause sedation. This may be welcome if sleeplessness is a problem. Amitriptyline, trimipramine, and doxepin are the most sedating agents. Imipramine, amoxapine, nortriptyline, and maprotiline have some sedating effects. Desipramine and protriptyline are the least sedating agents.

Tricyclics and tetracyclics may cause cardiac effects including tachycardia, flattened T waves, prolonged QT intervals and depressed ST segments in the electrocardiogram. Tricyclics and tetracyclics are contraindicated in patients with bifascicular block, left bundle branch block, or a prolonged QT interval.

In patients with a cardiac history (with no conduction deficit), the tricyclics and tetracyclics can be prescribed but the drugs should be initiated at low doses with gradual increases in dose and careful monitoring.

All tricyclics and tetracyclics may induce seizures in patients who have epilepsy or organic brain lesions. Although tricyclics and tetracyclics can still be used in these patients, the initial doses should be lower and then raised more slowly. Amoxapine and Maprotiline may be more epileptogenic than the other tricyclics and tetracyclics.

Two tricyclics (desipramine and protriptyline) are associated with psychomotor stimulation. Myoclonic twitches and tremors of the tongue and upper extremities are fairly common. Rarer effects include speech blockage, paresthesia, peroneal palsies, and ataxia.

One tetracyclic, amoxapine, is unique in causing neuroleptic-induced parkinsonism, acute akathisia, and even tardive dyskinesia because of the dopaminergic blocking activity of one of its metabolites. It may even cause neuroleptic malignant syndrome in some patients.

Agranulocytosis, leukocytosis, leukopenia and eosinophilia are rare complications of tricyclics and tetracyclics.

Tricyclics and tetracyclics should be avoided during pregnancy. They pass into the breast milk and have the potential to cause serious adverse reactions in the nursing infants.

Drug-Drug Interactions

Tricyclics and tetracyclics block the neuronal activity of guanethidine, reducing its anti-hypertensive effect. Tricyclics and tetracyclics may also block the anti-hypertensive activity of propranolol and clonidine.

The co-administration of tricyclics and tetracyclics with antipsychotics may increase the plasma levels of the tricyclics and tetracyclics. Antipsychotics may add to any anticholinergic and/or sedative effects of the tricyclics and tetracyclics.

Tricyclics and tetracyclics will potentiate the CNS depressant effects of opioids, alcohol, anxiolytics, hypnotics and over-the-counter cold medications. These combinations must be carefully monitored.

Tricyclic and tetracyclics prescribed with the sympathomimetic drugs may cause serious cardiovascular effects.

Tricyclic and tetracyclic plasma levels may be increased by other drugs including acetazolamide, phenytoin, aspirin, cimetidine, thiazide diuretics, fluoxetine, alcohol and sodium bicarbonate.

Tricyclic and tetracyclic plasma levels may be decreased by drugs including ascorbic acid, ammonium chloride, barbiturates, oral contraceptives, smoking, chloral hydrate, lithium and primidone.

MAOIs should be discontinued for two weeks before initiating treatment with a tricyclic. A minimum of a one-week washout is needed when switching from a tricyclic to a MAOI.

Tricyclics can be combined with MAOIs in some treatment resistant depressions. Certain precautions must be taken to avoid hypermetabolic crisis, seizures and strokes. A low dose of a tricyclic should be initiated after at least a one-week washout, then the MAOI may be added. Every few days each medication is alternately increased with close monitoring.

The consent form for these medications is "Antidepressant (Anti-Obsessive-Compulsive Medication / Tricyclics & Similarly Acting Medications)".

Antidepressant Pharmacologic and Pharmacokinetic Parameters

0-none
+ - slight
++ - moderate
+++ - high
++++ - very high
+++++ - highest

Name

Major side effects

Anticholinergic

Major side effects

Sedation

Orthostatic hypotension

Amine uptake and blocking activity

Norepinephrine

Amine uptake and blocking activity

Serotonin

Half-life (hours)

Therapeutic plasma level (ng/ml)

Time to reach steady state (days)

Dose range (mg/day)

Tricyclics- Tertiary amines

Amitriptyline

++++

++++

++

++

++++

31-46

110-250 (1)

4-10

50-300

Clomipramine

+++

+++

++

++

+++++

19-37

80-100

7-14

25-250

Doxepin

++

+++

++

+

++

8-24

100-200

2-8

25-300

Imipramine

++

++

+++

++ (2)

++++

11-25

200-350

2-5

30-300

Trimipramine

++

+++

++

+

+

7-30

180 (1)

2-6

50-300

Tricyclics- Secondary amines

Amoxapine (3)

+++

++

+

+++

++

8 (4)

200-500

2-7

50-600

Desipramine

+

+

+

++++

++

12-24

125-300

2-11

25-300

Nortriptyline

++

++

+

++

+++

18-44

50-150

4-19

30-100

Protriptyline

+++

+

+

++++

++

67-89

100-200

14-19

15-60

Phenethylamine

Venlafaxine

0

0

0

+++

+++

5-11 (1)

-

3-4

75-375

Tetracyclic

Maprotiline

++

++

+

+++

0/+

21-25

200-300

6-10

50-225

Mirtazepine

++

+++

++

+++

+++

20-40

-

5

15-45

Triazolopyridine

Trazodone

+

++++

++

0

+++

4-9

800-1600

3-7

150-600

Aminoketone

Bupropion

++

++

+

0/+

0/+

8-24

-

1.5-8.0

200-450

Selective Serotonin Reuptake Inhibitors

Fluoxetine

0/+

0/+

0/+

0/+

+++++

1-16 days

-

2-4 weeks

20-80

Paroxetine

0

0/+

0

0/+

+++++

10-24

-

7-14

10-50

Sertraline

0

0/+

0

0/+

+++++

1-4 (1)

-

7

50-200

Citalopram

0/+

0/+

0/+

0/+

++++

33

-

7

20-60

Fluvoxamine

0/+

0/+

0

0/+

+++++

15.6

-

~7

50-300

Monoamine Oxidase Inhibitors

Tranylcypromine

+

+

0

-

-

2.4-2.8

-

-

30-60

Phenelzine

+

+

+

-

-

-

-

-

45-90

Phenylpiperazine

Nefazodone

0/+

++

+

0/+

+++++

2-4

-

4-5

200-600

  1. Parent compound plus active metabolite

  2. Via desipramine, the major metabolite

  3. Also blocks dopamine receptors

  4. 30 hours for major metabolite 8-hydroxyamoxapine

  5. Inhibits dopamine reuptake

Reference: Facts and Comparisons Jan. 2000