Cardiotoxicity tricyclic antidepressants

Niemann JT, Bessen HA, Rothstein RJ, and Laks MM (1986) Electocardiographic criteria for tricyclic antidepressant cardiotoxicity. American Journal of Cardiology 57 1154-1159. 

Naloxone is effective in reversing the CNS and respiratory depressant actions of propoxyphene but has little effect on the cardiotoxicity. The latter may be treated with NaHCOs to reverse the Na -channel inhibition (a similar therapeutic rationale applies to the treatment of tricyclic antidepressant cardiotoxicity). Because propox)T)hene has a large volume of distribution (10 to 18L/kg) and is highly protein bound (70% to 80%), hemodialysis-is of little value in instances of serious overdose. Forced diuresis likewise is of httle value because only about 1% is eliminated in urine as unchanged propoxyphene. 

The excellent clinical efficacy of the TCAs has been well documented and the pharmacokinetic profiles are favourable. The most serious disadvantage of the TCAs lies in their cardiotoxicity. Thus, with the exception of lofepramine, all the tricyclic antidepressants, including maprotiline, block the fast sodium channels in the heart which can lead to heart block and death. Approximately 15% of all patients with major depression die by suicide and a high proportion of these (up to 25%) do so by taking an overdose of TCAs. Such a dose can be as low as 5-10 times the recommended daily dose. 

Selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants are equally effective. Hov/ever, SSRIs tend to have fewer antimuscarinic side-effects and are less cardiotoxic in case of overdosage. SSRIs tend to cause gastrointestinal side-effects. Both SSRIs and tricylic antidepressants exhibit a time lag before the action of the antidepressants becomes effective. 

Tricyclic antidepressants are cardiotoxic, inducing tachycardias and an increased tendency for ventricular arrhythmias with high doses. This dose dependent cardiotoxicity gives these agents a low therapeutic index. Overdoses are characterized by cardiac conduction disturbances, hyperpyrexia, hypertension, confusion, hallucinations, seizures and coma and there is a high mortality rate in suicide attempts. Depressed patients should therefore not be given more than one week supply of these drugs. 

Agents from this class of antidepressants are selective blockers of the re-uptake of serotonin at presynaptic neurones and have little if any effects on muscarinic, histaminergic, adrenergic or serotonergic receptors. They are as effective as the tricyclic antidepressants in the management of depressive disorders, but have less cardiovascular effects. They have less anticholinergic activity and because of their lower risk of cardiotoxicity in overdose they... 

Maprotiline and amoxapine are selective norepinephrine uptake inhibitors. They share most of the properties of the tricyclic antidepressants. Maprotiline has less sedating effect than mianserin and it is more epileptogenic than any other antidepressant. It shows considerable cardiotoxicity when taken in overdose. 

Bicarbonate, sodium Membrane-depressant cardiotoxic drugs (tricyclic antidepressants, quinidine, etc) 1-2 mEq/kg IV bolus usually reverses cardiotoxic effects (wide QRS, hypotension). Give cautiously in heart failure (avoid sodium overload). 

The side effects and cardiotoxicity of the tricyclic antidepressants have been discussed in detail elsewhere in this volume and, while there is ample evidence of their therapeutic efficacy, it seems difficult to justify their use, particularly in a group of patients who are most vulnerable to their detrimental side effects. Of the newer antidepressants, the reversible inhibitors of monoamine oxidase type A such as moclobemide may also be of value in the elderly depressed patient, particularly in those patients who fail to respond to the amine uptake inhibitor type of antidepressant. 

The selective serotonin-reuptake inhibitors (SSRI) are a new group of chemically unique antidepressant drugs that specifically inhibit serotonin reuptake (see Figure 12.3). This contrasts with the tricyclic antidepressants that nonselectively inhibit the uptake of norepinephrine, and serotonin, and block muscarinic, H histaminic and a -adrenergic receptors. Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity. However, the newer serotonin reuptake inhibitors should be used cautiously until their long-term effects have been evaluated. 

Q12 An SSRI, such as fluoxetine, can be started at a dose of 20 mg per day. Although similar in their efficacy and time course to the tricyclic drugs, the advantage of the SSRIs is their lack of serious side effects, such as cardiotoxicity, sedation, blurred vision, dry mouth and so on, which are associated with tricyclic antidepressants. 

Although pediatric psychopharmacology is much neglected, nocturnal enuresis is an area of extensive research. An earlier review catalogued almost 100 publications on the topic (13). The tricyclic antidepressants have been shown to be effective in well-controlled trials, and over 40 publications had appeared before 1970. At that time adverse effects in children appeared to be minimal and comparable to those in adults. Since then considerable concern has developed over cardiotoxic effects and the risks of accidental overdose in children. The earlier reports have been summarized (SEDA-1,10) managing overdose in children has been reviewed (SEDA-2,10) death in a 16-month-old infant has been reported (SEDA-3, 9). 

Overall, amoxapine appears to have some advantage over other tricyclic antidepressants possible earlier onset of action and relative freedom from serious cardiotoxic effects. Its major drawbacks are the potential for neuroleptic adverse effects, a high incidence of seizures, deaths in overdose (2), and the possibility of long-term neurological damage. 

The major advantages of SSRIs over the tricyclic antidepressants are their less pronounced anticholinergic adverse effects and lack of severe cardiotoxicity. However, some studies have shown some degree of nervousness or agitation, sleep disturbances, gastrointestinal symptoms, and perhaps sexual adverse effects more commonly in patients treated with SSRIs than in those treated with tricyclic antidepressants. SSRIs may also be associated with an increased risk of suicide, particularly in children under 16 (9). 

Based on animal research and restricted experience in overdosage (SEDA-7, 19-21), early attempts to differentiate trazodone from tricyclic antidepressants suggested that it might be relatively free of cardiotoxic effects. However, a preliminary report of a study of the effects of trazodone on the cardiovascular system in 20 subjects mentioned two patients who had ventricular dysrhythmias (7). Others have reported ventricular tachycardia (8-10), atrial fibrillation (11), and complete heart block (12). 

Trazodone is less cardiotoxic than tricyclic antidepressants, although it has rarely been reported to cause ventricular tachycardia. QT interval prolongation has been reported in overdose (34). 

Cardiovascular disease is not a contraindication to lithium, but the risks may be greater, in view of factors such as fluid and electrolyte imbalance and the use of concomitant medications. Close clinical and laboratory monitoring is necessary, and an alternative mood stabilizer may be preferred. While long-term tricyclic antidepressant therapy may be more cardiotoxic than lithium, the newer antidepressants (SSRIs and others) seem to be safe. 

Patients may deteriorate rapidly and progress from no symptoms to life-threatening cardiotoxicity or seizures within 1 hour. Major symptoms of tricyclic antidepressant overdose typically are manifest within 6 hours of ingestion. The principal effects of tricyclic antidepressant poisoning involve the cardiovascular system and the central nervous system and can result in arrhythmias, hypotension, coma, and seizures (see below). 

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