Toxicology of Antidepressant Drugs

2015

As many pharmacodynamic effects carry over from animals to man, many toxic effects may also be predicted from observations made in animals. However, some important toxic effects are not predictable from animal studies (WHO, 1966) and this limitation may apply particularly to drugs acting on the central nervous system, such as the antidepressants. Nevertheless, the recognition of species differences and similarities in responses is considered as an important means of predicting toxic effects in man. In the following, some degree of correlation is attempted by the comparison, whenever feasible, between toxicity in laboratory animals and adverse effects described in man, particularly in cases of acute intoxication. However, due to the differing amount of data that was available on various drugs and the widely varying experimental conditions employed, such a comparison may not always prove to be reliable.

The following review has been restricted to antidepressants in clinical use and, as far as evidence was available from the literature, concentrated on two main categories of antidepressants, the monoamine oxidase (MAO) inhibitors and the tricyclics. The lithium salts are considered in a separate chapter of this volume. Emphasis is placed on the systemic toxicity and on adverse effects on particular organs or tissues. Attention has also been directed to problems of possible adverse reactions arising from the concurrent application of several drugs and the attempt has been made to re-assess the sometimes controversial issue of effects on reproduction and embryonal-fetal development.

Monoamine Oxidase Inhibitor

Animal Toxicity

General Toxicology

The acute i.p. LD 50 of nialamide, phenelzine sulfate, and iproniazide in mice was reported to be 820, 640, and 135 mg/kg, respectively (). In the rat, i. p. administration of tranylcypromine was found to be associated with high mortality, multifocal cardiac necrosis with inflammatory reaction, and mononuclear cell infiltration. If the animals survived, myocardial fibrosis ensued. The injury was found to resemble that due to isoproterenol (). Panisset et al. () reported species differences for intravenously administered tranylcypromine in dogs on the one hand and in cats and rabbits on the other hand. In dogs, the blood pressure increased while in cats and rabbits tranylcypromine caused an elevation followed by a fall in blood pressure.

The continuous lifetime administration of phenelzine sulfate (0.015 % in drinking water) to Swiss mice gave rise to an increased incidence of adenoma and adenocarcinoma of the lungs and to angioma and angiosarcoma of blood vessels in female mice. The treatment had no statistically significant effect on the development of tumors in males. The sex difference was explained by the increased mortality due to toxic effect in the males, before tumors had arisen ().

Some of the MAO inhibitors used as antidepressants were reported to cause em-bryotoxicity, but when given to pregnant animals, at high doses well exceeding the maximum recommended human dose, no congenital malformations were produced in the surviving offspring (). Nialamide, at oral doses of 60-80 mg/kg, markedly diminished fertility in the rat and caused fetal resorptions. The treatment caused marked changes in the estrus cycle. This still prevailed at 10 mg/kg, a dose level that reduced fertility but had no fetotoxic action (). Similar to nialamide, other amine oxidase inhibitors (including iproniazid, tranylcypromine, and phenelzine) have also been reported to prevent embryonic development in mice when administered in early pregnancy (). This effect was neither dependent on the amine oxidase inhibitory activity nor on the chemical structure. Hydrazines, for instance, claimed to interact with bacterial DNA (), appeared no more embryotoxic than other compounds. In the case of phenelzine it was suggested that the antifertility effect, brought about in mice at a daily subcutaneous dose of 25 mg/kg, was due to partial depression of pituitary gonadotropin activity ().

Interaction Experiments

The combined administration of ethanol and phenelzine to mice increased the duration of coma and loss of righting reflex due to alcohol (). The acute toxicity of isocarboxazid to mice increased when the mice were kept under crowded conditions (). Tranylcypromine caused fetal hyperpyrexia in rats pretreated with lithium chloride for 4 consecutive days (). In rabbits pretreated with MAO inhibitors, in contrast to nonpretreated rabbits, ethoheptazine consistently produced substantial hyperpyrexia, motor restlessness, hyperexcitability, tremors and tachypnea and, eventually, death (). The acute toxicity of morphine, pethidine, and phenazocine in mice was increased by pre-treatment with iproniazid or tranylcypromine. The reaction was related to an increased concentration of 5-hydroxytryptamine in the brain (). Nialamide, iproniazid, and tranylcypromine potentiated the actions of histamine on cat blood pressure and on the tracheobronchial muscle of guinea pigs. It was concluded that side effects occurring with MAO inhibitors may be due to increased sensitivity to histamine (). All MAO inhibitors, regardless of chemical type or biologic potency, increased the toxicity of amphetamine in mice (). While parachlorphenylalanine had no protective effect on early mortality following tranylcypromine administration, it appeared to have protected the mice from late tranylcypromine toxicity (). Anesthesia may protect mice against the potentiation of toxic effects resulting from MAO inhibition and concurrent L-Dopa administration by preventing an increase in central dopamine concentration and by reducing hyperthermia. Halothane had the most consistent beneficial effect (). In mice, the LD 50 of meperidine was markedly reduced by tranylcypromine pretreatment (). Chlorpromazine, parachlorphenylalanine, and cooling decreased the lethal effect of the combined treatment of tranylcypromine and meperidine in mice ().

Intoxication in Man

Effects of Acute Overdose

In parallel to the more limited use of MAO inhibitors when compared to tricyclic antidepressants, new publications have become rare and relatively few cases of attempted suicide are reported. Fatalities after tranylcypromine overdosage have occurred at doses as low as 170 mg though most cases involve a dose range above 300 mg. With phenelzine, lethal outcome may be encountered in the range of 375-1500 mg. Doses up to 1,500 mg nialamide have been treated successfully but 5,000 mg have been fatal ().

While a MAO inhibitor alone can result in death if taken at a high enough dose it should be mentioned here that a number of fatalities have occurred due to interaction of MAO inhibitors with other drugs or certain types of food. MAO inhibitors not only block the deamination of biogenic amines thus inducing pharmacodynamic changes, but also interfere with various other enzymes and are able to prolong and intensify the effects of other drugs and to interfere with the metabolism of naturally occurring substances. Interference occurs with central depressant agents such as barbiturates, alcohol, and potent analgesics; with anticholinergic agents and tricyclic antidepressants; with meperidine and with precursors of biogenic amines. The action of sympathomimetic amines are potentiated following treatment with MAO inhibitors and this is of considerable practical importance when food containing higher amounts of tyramine (cheese – especially aged cheese, beer, wine, pickled herring, chicken liver, yeast extracts such as Marmite or Bovril, cream, coffee, broad beans, etc.) are ingested by patients under treatment ().

Switching a patient from one MAO inhibitor to another or to a tricyclic antidepressant requires a rest period of 10-14 days (). A combined tricyclic-MAO inhibitor therapy for refractory depression, if carefully initiated, is, however, possible ().

The clinical symptoms of acute overdosage appear after a lag period of several hours starting with motor uneasiness, agitation, violent motor activity with moaning and grimacing, profuse sweating and hallucinations. Temperature increases steadily well over 42 ° C within 24 h. The full clinical picture is characterized by coma with hyperthermia, tachypnea, tachycardia, dilated pupils, and hyperactive deep tendon reflexes. Convulsions and renal complications may also occur ().

Treatment of Acute MAO Inhibitor Overdose

Since various types of supra-additive effects from possible antidotes in clinical use may be expected, caution must be exercised in their use. In most reported cases, conservative treatment aimed at maintaining normal temperature and at supporting respiration, blood pressure, fluid and electrolyte balance has proven successful. The lag period between ingestion and the appearance of severe symptoms and hyperthermia should be used for therapeutic intervention. Osmotic diuresis, forced fluids, acidification of urine and in severe cases, hemodialysis, have been successful for elimination of the drug.

Chlorpromazine is a useful drug and in a hypertensive crisis phentolamine may be helpful, their actions being related to the α-adrenergic blocking properties.

Patients who took overdoses of MAO inhibitors should be observed in the hospital for at least a week after poisoning as late toxic effects may appear. Their diet should be controlled ().

Chronic Toxicity of MAO Inhibitors

MAO inhibitors possess a considerable potential for chronic toxic effects. Though the incidence of hepatotoxicity with currently used MAO inhibitors is low, hepatic effects are among the most dangerous. Liver involvement does not seem to be related to dosage or duration of therapy. Excessive central stimulation is observed covering the range from tremors and insomnia over agitation and, on rare occasions, hallucinations or confusion to convulsions. Finally, orthostatic hypotension occurs with all currently used MAO inhibitors ().

Toxicology of Antidepressant Drugs: Tricyclic Antidepressants

Conclusions

Toxic reactions occurring in man with tricyclic antidepressants are most commonly associated with their pharmacodynamic properties, antichohnergic responses and neurological symptoms; the effects associated with their aminergic actions being prominent. Moreover, adverse effects on the cardiovascular system are observed. Toxic reactions of this type, although occasionally seen at therapeutic doses, usually form part of the toxicity due to acute overdosage. Since these effects are related to the action spectrum of this type of drug, there is a close correlation between animal and human studies.

MAO inhibitors may produce serious acute and chronic toxicity, involving the central nervous system, blood pressure, and hepatotoxicity. There is a considerable danger of potentiation of the actions of endogenous biogenic amines and of interaction with other drugs, in particular with tricyclic antidepressants. A number of these toxic effects including conditioning factors can also be studied in laboratory animals.

Less reliance can be placed upon animal reproduction data as a predictive method of assessing the teratogenicity of antidepressants. At present, there is no evidence of interference with human reproduction when these drugs are used at the recommended dosages.

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