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Up to 90% of TCA suicide deaths occur outside of hospital (5,6). One-half of the in-hospital fatalities have trivial Cyclic antidepressants are pharmacologically dirty drugs: although toxicity on arrival to hospital but develop major toxicity within their primary therapeutic effect is to block presynaptic catechola- 1 hour (5). This reflects the rapid absorption of TCA and onset of mine and serotonin reuptake, most of their adverse effects and tox- cardiac and central nervous system toxicity. Whereas a number icity is mediated by their effects of blocking of cellular ion channels of electrocardiogram (ECG) abnormalities are predictive of seri- as well as α-adrenergic, histaminergic, and muscarinic receptors. ous toxicity, a normal ECG does not exclude serious toxicity. Common adverse effects are sedation and anticholinergic symp- Decontamination, management of airway, and adjustment of toms. The group is dominated by tricyclic antidepressants (TCA) in pH to a mild systemic alkalosis with sodium bicarbonate are the number, clinical experience, and extent of toxicity. mainstays of successful management. Despite changes in antidepressant prescribing patterns, TCA The primary indication for all of these drugs is depression. remain a common cause for admission (1) and death from poi- TCAs have also been used for panic disorder (imipramine), 134: CYCLIC ANTIDEPRESSANT DRUGS 835 Figure 1. Structures of the cyclic anti- depressant drugs. obsessive-compulsive disorders (clomipramine), cataplexy and tetracyclics vary (Table 1). Many TCAs have active metabo- associated with narcolepsy (clomipramine), and attention defi- lites that contribute to their therapeutic effect (Table 2). cit hyperactivity disorder (imipramine, nortriptyline). Medical The ingestion of 15 to 20 mg/kg or more of a TCA is poten- uses include adjunctive treatment in pain management (ami- tially fatal, although there are significant differences in toxicity triptyline, doxepin) and treatment of nocturnal enuresis or urge within the drug class (8–10). Tetracyclics and bicyclics appear to incontinence (amitriptyline, imipramine, nortriptyline) (7). be less toxic in overdose than TCA. Small children can potentially Viloxazine is a bicyclic antidepressant with predominant seroto- develop life-threatening toxicity with ingestion of 1 to 2 tablets. nin reuptake inhibition; no deaths are reported. Mianserin and In a pediatric series of TCA poisonings, all single ingestions of maprotiline are both tetracyclic compounds with similar indica- less than 5 mg remained asymptomatic. Minor toxicity can result tions and mechanism of action to TCAs. from ingestion of more than 5 mg/kg (11). Deaths have been reported rarely with chronic therapeutic doses (desipramine, 3.3 mg/kg per day; imipramine, 6 mg/kg per day) (12). In these TOXIC DOSE cases, other factors such as impaired metabolism due to either genetic variation, drug-induced enzyme inhibition, or preexisting The adult and pediatric therapeutic dose is provided in Table 1. The cardiac conduction defects have been implicated. normal therapeutic dose of most TCAs in both adults and chil- Risk for major toxicity varies within the class. Initially, a dren is 1 to 3 mg/kg given once a day. The doses for the bicyclic number of mortality studies examined the relative risk of death TABLE 1. Physical characteristics and dosage and elimination half-life of the cyclic antidepressants Oral dose Elimination half-lives Molecular formula, molecular weight range of drug and active Compounds included (g/mol), CAS Registry No. Formulation (mg/d) metabolitesa,b (h) Amineptine hydrochloride (Sur- C22H27NO2,HCl; 373.9; 30272-08-3 NR 100–200 1, 2.5 vector) Amitriptyline hydrochloride C20H23N,HCl; 313.9;