Antidepressant Drugs

Sedating antidepressants have been used to induce sleep in doses lower than those generally used for depression in an attempt to avoid the benzodiazepines’ liabilities of dependence, rebound insomnia, and withdrawal effects. Low-dose tricyclic antidepressants (TCAs), such as amitriptyline or doxepin, were once the most commonly used antidepressants for insomnia. Trazodone in doses of 50–200 mg at bedtime has more recently become the preferred antidepressant for insomnia. Trazodone’s hypnotic efficacy has not been directly compared to that of the benzodiazepines. It has been studied only in populations of depressed patients with insomnia, and usually the insomnia was secondary to SSRI use.Trazodone offers prominent sedation with little anticholinergic effect, but a slow onset and noticeable orthostatic hypotensive effect. There is no concern regarding dependence or withdrawal after as long as four months of use. Compared to TCAs, trazodone offers better safety in overdose. Priapism, a rare but serious adverse effect, can occur with daily doses of trazodone as low as 50–200 mg. Male patients must be counseled about the possibility of this adverse effect.

Benzodiazepines

Pharmacokinetic Differences: Flurazepam, the first benzodiazepine hypnotic drug, available in the United States since 1974, offers a rapid onset of effect but a long duration of effect. Flurazepam has an active metabolite with an elimination half-life of up to five days. Such a long elimination half-life minimizes the risk of rebound insomnia, but makes morning hangover, or daytime sedation, more likely. Doses of 15 mg of flurazepam or 20 mg of temazepam have been shown to impair coordination skills necessary for driving on the morning after use. Subsequently, benzodiazepines with shorter elimination half-lives were marketed as hypnotics. Temazepam has an elimination half-life of 8–20 hours, and triazolam 2–6 hours. Temazepam has the disadvantage of a slow onset of effect compared to flurazepam and triazolam. More recently, estazolam and quazepam were marketed in the United States. Estazolam is most similar to temazepam; it has a slow onset of effect of 1–2 hours and an elimination half-life of 8–24 hours. (The pharmacokinetic profiles of estazolam and other selected hypnotic agents are outlined in TABLE 2.) Quazepam is very similar to flurazepam in that it has a fast onset of effect, an intermediate to long elimination half-life, but overall, a long duration of effect due to an active metabolite whose half-life is 2–5 days. Quazepam was the first hypnotic drug to offer specificity for the omega-1 benzodiazepine receptor. However, this unique mechanism is quickly lost because the active metabolite of quazepam is N-desalkyl-flurazepam, the same active metabolite as flurazepam. Temazepam, estazolam, and triazolam do not have clinically important active metabolites.

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