Tricyclics: Still solid performers for the savvy psychiatrist

Imipramine is the only TCA indicated for nocturnal enuresis, but its exact mechanism of action is not known. The benefit may be secondary to imipramine’s anticholinergic effect or to changes in sleep architecture. Recommended bedtime doses for children with enuresis are:

• 25 to 50 mg under age 12;
• up to 75 mg age 12 and older.

TCAs are an option for children with ADHD, especially if ADHD is present with comorbid depression or anxiety disorder. However, because at least four cases of sudden cardiac death have been reported in children taking desipramine, it is prudent to monitor cardiac function when children are started on TCAs. AACAP guidelines recommend obtaining a baseline ECG, resting blood pressure, and pulse (supine or sitting, then standing), with regular monitoring of the child’s weight during TCA therapy.

Combination therapy Few controlled studies have tested TCAs as combination therapy. Trazodone can be used as an adjunct to SSRIs and monoamine oxidase inhibitors (MAOIs) for patients with insomnia. TCAs are used as an adjunct to treat resistant depression and OCD^13,14 (e.g., clomipramine added to fluvoxamine to treat OCD).¹⁵ Serum level monitoring is recommended when TCAs are used as adjuncts.

Other uses TCAs play a role in the prophylactic treatment of premature ejaculation and migraine headaches, probably because of their serotonergic (5HT2) effect. In patients with migraine and depression, a trial of a TCA such as amitriptyline may be warranted.

TCAs are widely used to manage neuropathic pain,¹⁶ although the exact mechanism of action is unknown. Because depression is commonly associated with pain, the effect may result from the agents’ action on depression, or TCAs may possess direct analgesic action.

Trazodone, 25 to 100 mg at bedtime, is widely used for insomnia, alone or as an adjunct with other classes of antidepressants—even in combination with MAOIs. Nortriptyline has been shown to be safe and effective for post-stroke and geriatric types of depression.¹⁷

TCAs are also used for a host of other medical, psychiatric, and neurologic problems, such as social phobia, PTSD, GAD, substance abuse disorders, and eating disorders.¹⁸ Only a few controlled studies have tested TCAs for these indications.

Side effects

Although TCAs have shown efficacy in many clinical situations, their use is associated with potentially serious side effects, which may include anticholinergic effects, sedation, weight gain, CNS toxicity, orthostatic hypotension, cardiovascular toxicity, delirium, and risk of suicide by overdose. The risk of side effects can be reduced with careful prescribing practices (Box 2).

Anticholinergic effects, sedation TCAs vary in their anticholinergic activity (Table 2). Tertiary amine TCAs such as amitriptyline and protriptyline may cause dry mouth, constipation, urinary hesitancy, and blurred vision in some patients, and confusion in elderly or demented patients. Secondary amine TCAs such as nortriptyline or desipramine are less anticholinergic and less likely to cause these side effects.

Peripheral anticholinergic side effects can be managed with bethanacol—a cholinergic drug—in dosages of 25 to 50 mg tid or qid. Dry mouth can be treated with pilocarpine, 5 mg bid to qid, or oral bethanacol (5- to 10-mg tablets sublingually), artificial saliva drops, sugarless candy/gum, or mouthwash.

Box 2

Table 2

BIOCHEMICAL EFFECTS OF TRICYCLICS AND OTHER ANTIDEPRESSANTS

Table 3

APPROXIMATE THERAPEUTIC PLASMA LEVEL RANGES

Sedation is a common side effect caused by the antihistaminic properties of some TCAs (Table 2). Agents with this effect (e.g., doxepin), when given once daily at bedtime, can benefit patients with concomitant sleep disturbance.