Tricyclics and Tetracyclics

For a more detailed discussion of this topic, see Tricyclics and Tetracyclics, Sec. 31.32, p. 3259, in Comprehensive Textbook of Psychiatry, 9th Edition.

The observation in 1957 that imipramine (Tofranil) had antidepressant effects led to the development of a new class of antidepressant compounds, the tricyclics (TCAs). In turn, the finding that imipramine blocked reuptake of norepinephrine led to research into the role of catecholamines in depression. After the introduction of imipramine, several other antidepressants compounds were developed that shared a basic tricyclic structure and relatively similar secondary or side effects. Later, other heterocyclic compounds were also marketed that were somewhat similar in structure and that had relatively comparable secondary properties. At one time, amitriptyline and imipramine were the two most commonly prescribed antidepressants in the United States, but because of their anticholinergic and antihistaminic side effects, their use declined, and nortriptyline and desipramine became more popular. Nortriptyline has the least effect on orthostatic hypotension, and desipramine is the least anticholinergic. Although introduced as antidepressants, the therapeutic indications for these agents has grown to include panic disorder, generalized anxiety disorder, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and pain syndromes. The introduction of newer antidepressant agents with more selective actions on neurotransmitters or with unique mechanisms of action has sharply reduced the prescribing of tricyclics and tetracyclics. The improved safety profiles of the newer drugs, especially when taken in overdose, also contributed to the decline in use of the older drugs. Nevertheless, the tricyclics and tetracyclics remain unsurpassed in terms of their antidepressant efficacy. Table 32-1 lists TCA and tetracyclic drugs and their available preparations.

Pharmacologic Actions

The absorption of most tricyclic antidepressants (TCAs) is complete after oral administration, and there is significant metabolism from the first-pass effect. Peak plasma concentrations occur within 2 to 8 hours, and the half-lives of the TCAs vary from 10 to 70 hours; nortriptyline (Aventyl, Pamelor), maprotiline (Ludiomil), and particularly protriptyline (Vivactil) can have longer half-lives. The long half-lives allow all the compounds to be given once daily; 5 to 7 days is needed to reach steady-state plasma concentrations. Imipramine pamoate (Tofranil) is a depot form of the drug for intramuscular (IM) administration; indications for the use of this preparation are limited.

The TCAs undergo hepatic metabolism by the cytochrome P450 (CYP) enzyme system. Clinically relevant drug interactions may result from competition for enzyme CYP 2D6 among TCAs and quinidine, cimetidine (Tagamet), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), phenothiazines, carbamazepine (Tegretol), and
the type IC antiarrhythmics propafenone (Rythmol) and flecainide (Tambocor). Concomitant administration of TCAs and these inhibitors may slow the metabolism and raise the plasma concentrations of TCAs. Additionally, genetic variations in the activity of CYP 2D6 may account for up to a 40-fold difference in plasma TCA concentrations in different persons. The dosage of the TCA may need to be adjusted to correct changes in the rate of hepatic TCA metabolism.

Table 32-1 Tricyclic and Tetracyclic Drug Preparations

Drug	Tablets	Capsules	Parenteral	Solution
Imipramine (Tofranil)	10, 25, and 50 mg	75, 100, 125, and 150 mg	12.5 mg/mL	—
Desipramine (Norpramin, Pertofrane)	10, 25, 50, 75, 100, and 150 mg	—	—	—
Trimipramine (Surmontil)	—	25, 50, and 100 mg	—	—
Amitriptyline (Elavil)	10, 25, 50, 75, 100, and 150 mg	—	10 mg/mL	—
Nortriptyline (Aventyl, Pamelor)	—	10, 25, 50, and 75 mg	—	10 mg/5 mL
Protriptyline (Vivactil)	5 and 10 mg	—	—	—
Amoxapine (Asendin)	25, 50, 100, and 150 mg	—	—	—
Doxepin (Sinequan)	—	10, 25, 50, 75, 100, and 150 mg	—	10 mg/mL
Maprotiline (Ludiomil)	25, 50, and 75 mg	—	—	—
Clomipramine (Anafranil)	—	25, 50, and 75 mg	—	—

The TCAs block the transporter site for norepinephrine and serotonin, thus increasing synaptic concentrations of these neurotransmitters. Each drug differs in its affinity for each of these transporters, with clomipramine (Anafranil) being the most serotonin selective and desipramine (Norpramin, Pertofrane) the most norepinephrine selective of the TCAs. Secondary effects of the TCAs include antagonism at the muscarinic acetylcholine, histamine H₁, and α₁-and α₂-adrenergic receptors. The potency of these effects on other receptors largely determines the side effect profile of each drug. Amoxapine (Asendin), nortriptyline, desipramine, and maprotiline have the least anticholinergic activity; doxepin (Adapin, Sinequan) has the most antihistaminergic activity. Although they are more likely to cause constipation, sedation, dry mouth, or lightheadedness than the selective serotonin reuptake inhibitors (SSRIs), the TCAs are less prone to cause sexual dysfunction, significant long-term weight gain, and sleep disturbances than the SSRIs. The half-life and plasma clearance for most TCAs are very similar.

Therapeutic Indications

Each of the following indications is also an indication for the SSRIs, which have widely replaced the TCAs in clinical practice. However, the TCAs represent a reasonable alternative for persons who cannot tolerate the adverse effects of the SSRIs.

Major Depressive Disorder

The treatment of a major depressive episode and the prophylactic treatment of major depressive disorder are the principal indications for using TCAs. Although the TCAs are effective in the treatment of depression in persons with bipolar I disorder, they are more likely to induce mania, hypomania, or cycling than the newer antidepressants, most notably the SSRIs and bupropion. It is thus not advised that TCAs be routinely used to treat depression associated with bipolar I or bipolar II disorder.

Melancholic features, prior major depressive episodes, and a family history of depressive disorders increase the likelihood of a therapeutic response. All of the available TCAs are equally effective in the treatment of depressive disorders. In the case of an individual person, however, one tricyclic or tetracyclic may be effective, and another one may be ineffective. The treatment of a major depressive episode with psychotic features almost always requires the coadministration of an antipsychotic drug and an antidepressant.

Although it is used worldwide as an antidepressant, clomipramine is only approved in the United States for the treatment of OCD.

Panic Disorder with Agoraphobia

Imipramine is the TCA most studied for panic disorder with agoraphobia, but other TCAs are also effective when taken at the usual antidepressant dosages. Because of the potential initial anxiogenic effects of the TCAs, starting dosages should be small, and the dosage should be titrated upward slowly. Small doses of benzodiazepines may be used initially to deal with this side effect.

Generalized Anxiety Disorder

The use of doxepin for the treatment of anxiety disorders is approved by the Food and Drug Administration. Some research data show that imipramine may also be useful. Although rarely used anymore, a chlordiazepoxide–amitriptyline combination (Limbitrol) is available for mixed anxiety and depressive disorders.

Obsessive-Compulsive Disorder

OCD appears to respond specifically to clomipramine, as well as the SSRIs. Some improvement is usually seen in 2 to 4 weeks, but a further reduction in symptoms may continue for the first 4 to 5 months of treatment. None of the other TCAs appears to be nearly as effective as clomipramine for treatment of this disorder. Clomipramine may also be a drug of choice for depressed persons with marked obsessive features.

Pain

The TCAs are widely used to treat chronic neuropathic pain and in prophylaxis of migraine headache. Amitriptyline is the TCA most often used in this role. During treatment of pain, doses are generally lower than those used in depression; for example, 75 mg of amitriptyline may be effective. These effects also appear more rapidly.

Other Disorders

Childhood enuresis is often treated with imipramine. Peptic ulcer disease can be treated with doxepin, which has marked antihistaminergic effects. Other indications for the TCAs are narcolepsy, nightmare disorder, and PTSD. The drugs are sometimes used for treatment of children and adolescents with attention-deficit/hyperactivity disorder, sleepwalking disorder, separation anxiety disorder, and sleep terror disorder. Clomipramine has also been used to treat premature ejaculation, movement disorders, and compulsive behavior in children with autistic disorders; however, because the TCAs have caused sudden death in several children and adolescents, their use is best avoided in this population.

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