Current Medical Research and Opinion Vol. 6, Suppl. 7, 1980

Relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in acute experiments in rabbits

I. E. Hughes, B.Sc., Ph.D., and Salwa Radwan, D.Msc., M.B., B.Ch.

Department of Pharmacology, The University of Leeds, Leeds, England

Curr. Med. Res. Opin., (1980), 6, Suppl. 7, 13. Paper read: 17th September 1979

Summary In conscious rabbits, a slow intravenous infusion of amitriptyline, imipramine, mapro- tiline or mianserin produced death preceded by convulsions. Amitriptyline produced these efects at the lowest dose, imipramine and maprotiline were intermediate and much higher doses of mianserin were required. Cardiac dysrhythmias in the form of missing QRS complexes were evident in 6 out of 6 animals receiving amitriptyline, 616 with maprotiline and 216 with imipramine but were not seen in aninials receiving mianserin. All four drugs lengthened the P-R interval and widened the QRS complex, though these efects were smallest with mianserin. The convulsive episodes greatly modified cardiovascular parameters and therefore complicated an assessment of cardiovascular toxicity. No convulsive episodes developed in barbiturate-anaesthetized rabbits infused with the antidepressants and heart rate and bloodpressure were lowered by all four drugs. The P-R interval was lengthened and the QRS complex increased in width; these efects were greatest with amitriptyline and least with mianserin, which was up to 30-times less egective than amitriptyline in causing cardiovascular disturb- ances. Dysrhythmias were seen with all four drugs, but only at very high doses with mianserin. In these models it is concluded that the relative cardiovascular toxicity of these antidepressants is in the order amitriptyline > imipramine > maprotiline % mianserin .

Key words: Amitriptyline - imipramine - maprotiline - mianserin - antidepressive agents - antidepressive agents, tricyclic

Introduction The availability of tricyclic antidepressants has undoubtedly been of great benefit to the depressed patient but in recent years there has been an alarming increase in the misuse of these drugs. The U.K. Registrar General’s figuresl8 show clearly that deaths from poisoning involving a tricyclic antidepressant have formed a steadily increasing proportion of total deaths from poisoning (Figure 1). In 1976, as many as 13 % of all deaths from poisoning in England and Wales involved a tricyclic anti- depressant and it is relevant to note that in the same yea: prescriptions for all types of antidepressant formed only 3% of the total number of prescriptions issued in England.’

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Relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in acute experiments in rabbits

Figure 1. to 1976) expressed as a percentage of the total number of fatal poisonings each year’ *

Number of fatal poisonings involving a tricyclic antidepressant in England and Wales (1961

12 1

0 J

I

I I I I I I I I I

Year

1963 I967 1971 1975

Two major groups of symptoms are seen in tricyclic antidepressant overdose. Firstly, those arising from the central nervous system toxicity, e.g. coma, convulsions, and secondly those arising from the cardiotoxicity, e.g. changes in the ECG, dys- rhythmias. 4 ~ 2 2 A considerable proportion of patients may show cardiac changes. Thorstrand,22 for example, found that 49 % of 153 unselected patients admitted to hospital because of tricyclic antidepressant overdose showed changes in the QT interval, and Freeman,’ in similar patients, found that 10 out of 10 admissions showed a prolonged QT time. More seriously, major dysrhythmias also occur and the cardiotoxicity of the tricyclic antidepressants may be difficult to correct and require continuous cardiac monitoring of the patient for several days because sudden death, possibly associated with cardiac problems, has been reported as long as 4 to 6 days after the ingestion of an overdose.’ , 1

For these reasons, the relative acute toxicity of antidepressants is of particular interest and we have previously reported an assessment of the relative toxicity of amitriptyline, maprotiline and mianserin in perfused rabbit hearts.1 O Although mianserin was found to be less cardiotoxic than the other two drugs, the perfused heart is performing in a non-physiological environment and is isolated from the normal neuronal and hormonal control mechanisms whxh operate in the in vivo situation. We have re-examined, therefore, the relative toxicity of four antidepress- ants, amitriptyline, imipramine, maprotiline and mianserin, in conscious and in anaesthetized rabbits where cardiac function will be modulated by normal control mechanisms.

Some of the results in this paper have previously been communicated to the International Workshop on Mianserin held in Amsterdam in October, 1977 and published elsewhere.’ *,’

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I. E. Hughes and Salwa Radwan

Methods and materials The methods used have been fully described elsewhere.’ Briefly, experiments were performed in conscious and in anaesthetized New Zealand White rabbits. For the experiments in conscious rabbits, a carotid arterial cannula and a cardiac electrode (inserted through the jugular vein a.nd located in or near the right atrium) were chronically implanted under phenobarbitone anaesthesia 24 hours before the experiment. For the experiments on anaesthetized animals, the above operative procedure was carried out acutely under anaesthesia with a mixture of pheno- barbitone and pentobarbitnne and the animals were artificially respired through- out the experiment.

In both the conscious and the anaesthetized animals, blood pressure, heart rate (derived from the pulsatile pressure wave) and ECG records were taken as required and antidepressants were administered by slow intravenous infusion through the ear vein for 5 hours or until the death of the animal, whichever was sooner. In the conscious animals, changes in behaviour, especially the appearance of convulsions were noted. Where appropriate, results are expressed as mean f standard error of the mean. Student’s t-test was used in the analysis of statistical significance unless otherwise stated.

Results Choice of the dose and control experiments Preliminary experiments were performed in conscious rabbits in order to discover the dose rates of the antidepressants which would be lethal to the rabbits within the period 2 to 4 hours after the start of the infusion. In most cases, the rate of infusion was held constant at 12 ml/hour and the concentration of the antidepressants in the solution was altered in successive experiments. In this way the additional fluid load placed on the animal was constant with time for the different drugs and never exceeded 60 ml over the duration of the experiment. From these preliminary experi- ments satisfactory dose rates were found to be 10 mg amitriptyline/kg per hour, 18 mg imipramine/kg per hour, 25 mg maprotiline/kg per hour and 35 mg mian- serin/kg per hour. In the anaesthetized rabbits, these same dose rates were used and proved satisfactory except in the case of mianserin. All 5 animals in an experimental group survived the whole of a 5-hour infusion with mianserin a t a rate of 35 mg/kg per hour and the dose rate was increased, therefore, to 45 mg/kg per hour in the anaesthetized animals.

Because of the high concentrations of antidepressant required in the infusion solutions, two different vehicles were needed to dissolve the antidepressants in the limited volumes of fluid available for use. Control experiments were carried out, therefore, in whch 3 conscious and 3 anaesthetized rabbits were infused with each of the vehicles at a rate of 12 ml/hour for 5 hours. Conscious animals receiving either vehicle remained alert and interested in their surroundings for the duration of the infusion. Small changes in heart rate, blood pressure, P-R interval and width of the QRS complex occurred which were not statistically significantly different with the

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Relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in acute experiments in rabbits

two vehicles (p > 0.3). The observations in the control animals have been pooled, therefore, to give a single control group of 6 conscious rabbits and a single control group of 6 anaesthetized rabbits. All tests for statistical significance between the treated and the control groups refer to the appropriate pooled control group.

Imipramine was soluble in both hot saline and in saline plus 3 % propylene glycol (the two vehicles used) and was infused at 20 mg/kg per hour in each vehicle into a matched pair of rabbits. In hot saline and in saline plus 3 % propylene glycol, the doses of imipramine required to produce the first convulsive episode (18 and 15 mg/kg respectively), the doses administered when convulsions became repeated and severe (20 and 23 mg/kg), and the doses which produced death in the rabbits (20 and 25 mg/kg) were not very different under the two sets of conditions.

Experiments in conscious animals The lethal doses of the antidepressants in the conscious animals are shown in Table 1. Clearly, amitriptyline was most toxic (p < 0.02) while mianserin was least toxic, though the difference between mianserin and imipramine was not statistically significant probably because of the disproportionately large standard errors associated with the imipramine result which reflect the somewhat more variable effects of this drug in different an-imals. With regard to the production of convulsions by the antidepressants, all animals, except controls, developed convulsions at some time during the infusion.

Table I. Doses (mg/kg) of antidepressants required to produce convulsions and death in conscious rabbits: mean (lS.E.M.) values for 6 animals

First convulsive Repeated and Death episode severe convulsions

~ ~ ~~~~ ~~~

Amitriptyline 18.0S4.4 34.012.4 36.9S3.8

Imipramine 22.7f3.2 69.45 11.3 72.9 f 10.8 Maprotiline 34.0S2.8 52.0&6.5* 57.4S6.0

Mianserin 81.2f5.0 86.21 4.8 92.7 14 .0

(n =5)

(n =4)

*Two animals died before developing repeated and severe convulsions

The doses required for amitriptyline and imipramine (Table I) were not statistically significantly different, while maprotiline was required in higher dose than amitriptyl- ine (p < 0.05) and mianserin was required in higher dose again (p < 0.001). Most animals developed repeated and severe convulsions and the detection of this rather subjective end-point was not difficult once some experience had been obtained. A considerable additional dose of antidepressant was usually needed to induce repeated and severe convulsions, and the ratio of the two doses was 1 .%fold for amitriptyline, 3.0-fold for imipramine and 1.5-fold for maprotiline. With mianserin, the ratio of the two doses was very close to unity (1.06-fold) and animals often progressed straight into repeated and severe convulsions without any preceding minor convulsive episode.

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These convulsive episodes produced massive changes in both heart rate and blood pressure. The resting values for these parameters (heart rate 25317 beatslmin; systolic blood pressure 81.3f2.3 and diastolic blood pressure 61.9h2.5 mmHg; n=30) seemed rather low but are apparently within the normal range for New Zealand White rabbits. It was impossible to separate the changes in cardiovascular parameters caused by the convulsions from those caused directly by the anti- depressants and, therefore, these parameters are not discussed further. The con- vulsions also interfered with the ECG recording and large movement artifacts were apparent. Before readings became too distorted, however, changes in the P-R interval and in the width of the QRS complex were noted (Table 11).

Table II. Maximum change (% of initial value) observed in the P-R interval and the width of the QRS complex during the infusion of antidepressants: mean (* S.E.M.) values in 6 conscious animals

D w P-R interval QRS width

Control + 4.450.4 + 7.753.0 Amitriptyline +49.7&5.8 + 75.7 5 18.0 Imipramine $41.8 k4.3 +57.0+ 10.7 Maprotiline +49.9*8.3 + 40.9+ 6.5 Mianserin + 25.6 8.2 +24.9&6.8

All four antidepressants produced a statistically significant increase in the P-R interval and in the width of the QRS complex compared to the changes which took place in control animals. Mianserin produced the smallest changes, though these were statistically significantly different only from those produced by amitriptyline (p < 0.05) and imipramine (QRS only; p < 0.05). Dysrhythmias developed in many animals but movement artifacts associated with the convulsive episodes made detailed analysis difficult. Missing QRS complexes (sinus arrest or heart block, for example) were easy to identify and were seen in 6 out of 6 animals with amitriptyline, in 616 with maprotiline, in 216 with imipramine and were not seen in the mianserin- treated animals. The dose levels at which missing QRS complexes were first apparent averaged 22.3 mg/kg for amitriptyline, 23.6 mg/kg for maprotiline and 70.6 mg/kg for imipramine.

In addition to convulsions, other behavioural changes were noted. The control animals were alert, responsive and maintained an interest in their surroundings for the duration of the infusion but, in animals given antidepressants, sedation was apparent 0.5 to 1 .O hour after the start of the infusion and the rabbits often lay down and become flaccid and relaxed. In all cases, just before convulsions developed, the animals became restless and irritable and showed a sharp increase in respiration. With mianserin alone, the majority of animals showed an increase in salivation, which was very marked in some cases.

Experiments in anaesthetized animals The lethal doses of the antidepressants in the anaesthetized animals are shown in Table 111. One animal in the amitriptyline group and 2 animals in the mianserin group survived the duration of the infusion and, therefore, received 50 and 225

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Relative toxicity of amitriptyline, imipramine, maprotiline a.nd rnianserin in acute experiments in rabbits

Table 111. Doses (mg/kg) of the antidepressants required to produce a variety of effects in barbiturate-anaesthetized rabbits: mean (+S.E.ILI.) values

Heart rate Arterial blood P-R interval QRS complex width Death reduced by pressure reduced increased 30 beatslmin by IS mmHg by 20%

Drug 50% increase

20% increase

Arnitriptyline 12.2 k 3.1 15.0 f4.0 12.2 f 2.5 2.6 0.8 7.4 *2.0 25.7 & 3.6 (n =7) (n =6) Irnipramine 12.8h3.7 29.0+10.5 18.717.6 11.2k6.0 19.9h5.8 40.3h10.4 (n =7) (n =6) Maprotiline 33.9k7.5 33.9f6.5 21.413.0 7.1 +1.0 18.0&3.0 78.6k6.6 (n =6) Mianserin 41.9h6.9 144.02~30.8 161.4i24.2 80.0+11.7 165.1 +18.4 168.9k25.8 (n =6) (n =4) (n =2) (n =4) (n =4)

Note: the required responses were not seen in every member of each experimental group

mg/kg, respectively, and have been excluded from the mean values. The lethal doses of amitriptyline and imipramine were not significantly different f p > 0.2), while maprotiline was less toxic than imipramine or amitriptyline (p < 0.02), and mianserin was least toxic of all (p < 0.02).

In anaesthetized control rabbits, the resting heart rate before the start of the infusion was 228 & 5 beats/min and the resting systolic and diastolic blood pressure were 73 .613 .8 and 52.8h3.7 mmHg, respectively, (n -6 ) and remained remarkably stable during the course of the 5-hour infusion with vehicle alone. At the end of this time, a paired t-test showed that both the systolic and diastolic blood pressures had risen significantly (+12.7 and +9.5 mmHg, respectively; p < 0.02), while the small rise in heart rate (+5 beats/min) which was observed was not statistically significant (p > 0.2). Infusion of the antidepressants had variable effects on the blood pressure and heart rate initially but later on the infusion consistently reduced these parameters. For each animal, a graph was plotted of the change in heart rate or mean arterial blood pressure (calculated from the formula : mean arterial blood pressure =diastolic pressure + 1/3 pulse pressure; see2) against the dose of antidepressant administered and a value was obtained for the dose required to lower heart rate by 30 beats/min and blood pressure by 15 mmHg. Average values are shown in Table I11 and it can be seen that the doses required to lower heart rate by 30 beats/min were not significantly different for amitriptyline and imipramine (p > 0.9) but both these were significantly lower than the doses required with maprotiline (p < 0.05) or mianserin (p < 0.001). With regard to the effect or, blood pressure, the order of potency of the antidepressants in lowering the blood pressure by 15 mmHg was amitriptyline 3 imipramine 2 maprotiline 9 mianserin. The difference in potency between ami- triptyline and imipramine and between imipramine and maprotiline was not statistically significant (p > 0.2), although a significantly larger dose of maprotiline than of amitriptyline was needed (p < 0.05) and mianserin was required in much larger dose than any of the other drugs (p < 0.01).

The initial values for the P-R interval and for the width of the QRS complex in the anaesthetized control animals were 67.3f2.8 and 35.0& 1.5 msec, respectively, (n = 6). There was little change during the infusion and even at the end of this period

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the P-R interval and the width of the QRS complex showed mean changes of only -1.3 and -0.4 msec, respectively, which were not significantly different from zero (paired t-test ; p > 0.4). Infusion of the antidepressants increased the P-R interval and the width of the QRS complex, and values were calculated, as above, in each animal for the dose required to increase the P-R interval by 20 % of the initial value and the width of the QRS complex by 20 % and 50 % of the initial value, The group means of these calculated doses are shown in Table 111. Amitriptyline and maprotiline were not significantly different from imipramine (p > 0.05) with regard to the doses required to increase on the P-R interval, while 7 to 13-times more mianserin had to be administered to produce a similar effect (p < 0.001) which was seen in only 2 of the 6 animals. With regard to effects on the QRS interval, amitriptyline and imi- pramine showed no significant difference in the dose required to produce either level of effect (p > 0.05), while a higher dose of maprotiline was required than of ami- triptyline (p < 0.02). At least 7-times more mianserin was required than with any of the other drugs, and this difference was highly significant statistically at both levels of effect (p < 0.001).

In these anaesthetized animals, a great variety of dysrhythmias were seen and frequently more than one type of dysrhythmia was seen in a single animal. The small number of animals makes a meaningful analysis of the incidence of different types of dysrhythmia impossible but, overall, some type of dysrhythmia was seen in 7 out of 7 animals with amitriptyline, 6/6 with maprotiline, 6/7 with imipramine, and 4/6 with mianserin. Ectopic ventricular beats were seen least frequently with mianserin, which was also required in higher dose than any of the other drugs before any type of dysrhythmia occurred.

Discussion A phenobarbitone-pentobarbitone mixture was chosen as the anaesthetic agent because some of the halogenated hydrocarbons are known to sensitize the heart to the dysrhythmogenic action of catecholamines’ 5 which may interact with anti- depressants in the production of dysrhythmias.’ O An alternative anaesthetic, urethane, was not used because it is claimed to reduce the signs of cardiotoxicity produced in dogs by treatment with imipramine.6 With the barbiturate anaesthesia used, the resting cardiovascular parameters in the anaesthetized animals corres- ponded reasonably closely to the resting values in the conscious animals, whereas with urethane or urethane-chloralose mixtures grossly disturbed resting cardio- vascular readings were obtained. Since barbiturates may increase the respiratory depressant action of the tricyclic antidepressants,21 all anaesthetized animals were artificially respired to remove this complication.

The antidepressants were administered by slow intravenous infusion since this is a parenteral route which circumvents. therefore, the uncertainties of gastro- intestinal absorption, and which most closely mimics the steadily rising plasma levels likely to be seen in man after oral overdose. Little information is available on the plasma concentration-time relationship in man during the few hours immediately

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Relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in acute experiments in rabbits

after an oral overdose has been consumed but, after therapeutic oral doses, plasma levels appear to peak at 2 to 8 hours, depending on the particular antidepressant.3.5. 16.19 For this reason, dose rates were chosen which produced severe toxic signs in 2 to 4 hours.

The relative insolubility of the antidepressants made it necessary to use two vehicles (hot saline and saline plus 3 % propylene glycol) for the infusion. In control animals receiving either vehicle alone, there were no significant differences in the changes in the parameters recorded over the 5-hour infusion period and with imipramine, at least, the quantitative toxicity appears to be independent of the vehicle used.

The overall results of this investigation are summarized in Table IV.

Table IV. Order of toxicity among the antidepressants investigated on the various parameters measured in conscious and anaesthetized rabbits

Effect Order of toxicity

Conscious rabbits Death Convulsions Cardiac conduction Dysrhythmias

Amitriptyline > Maprotiline3 Imipramine > Mianserin Amitriptyline3 Irniprarnine > Maprotiline% Mianserin Amitriptyline3 Imipramine3 Maprotiline > Mianserin Amitriptyline = Maprotiline > Imipramine > Mianserin

Anaestherized rabbits Death Blood pressure Heart rate P-R interval QRS width Dysrhythrnias

Arnitriptyline z Imipramine > Maprotiline% Mianserin Arnitriptyline 3 Imiprarnine 3 Maprotiline% Mianserin Amitriptyline = hipramine > Maprotiline% Mianserin Arnitriptyline 3 Imiprarnine3 Maprotiline% Mianserin Amitriptylinea Maprotiline 3 Imipramine% Mianserin Arnitriptyline = Maprotiline> Irnipramine > Mianserin

Clearly, from all the aspects investigated, the toxicity of mianserin is less than that of the other three drugs. The finding that the dose rate of mianserin which was lethal in the conscious animals had to be increased to produce death in the anaesthetized animals is compatible with a relatively minor cardiovascular component in the toxicity of mianserin. Thus, when anaesthesia is used to eliminate the convulsions caused by mianserin, a much larger dose was needed to produce death from the low level cardiotoxicity.

When maprotiline was administered to a group of 4 rabbits at 15 mg/kg per hour, 1 animal died after 66.75 mg/kg while the other 3 survived the 5-hour infusion period and thus received 75 mg/kg. These lethal doses are all in excess of the mean lethal dose (57.4 mg/kg) found during administration of maprotiline at a rate of 25 mg/kg, though they are all within 2 standard deviations of this latter figure. A Mann-Whitney rank test,20 however, indicates that there is a significant difference between these groups (p < 0.05) and some pharmacokinetic factor, therefore, may be influencing the results.

The relative doses of the antidepressants required to produce similar effects on heart rate and on blood pressure suggest that the cardiovascular toxicity of mianserin is low, and analysis of the ECG records suggests that cardiotoxicity is likely to be low

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also. Some degree of cardiotoxicity is evident, however, since the P-R interval and the width of the QRS complex showed minimal changes in control animals but were significantly altered by all four drugs. Since all four drugs also lowered heart rate, it is possible that this action contributed to the effect on the P-R interval because these two parameters are related in man.9 Changes in the P-R interval in response to heart rate are usually small, however, and in these experiments maprotiline, for example, produced a 70 % to 90 % lengthening of this interval. In addition, the ratio between the doses of maprotiline and mianserin which were equi-effective in lowering heart rate was I :2 whereas the ratio between the doses which were equi-effective in lengthening the P-R interval was 7:5. It would seem unlikely, therefore, that the change in heart rate can account for the change in P-R interval.

A considerable increase in the width of the QRS complex was also produced by the antidepressants, amitriptyline being most toxic in this respect and mianserin least toxic. Because the width of the QRS complex is thought to be independent of heart rate, the effects on this parameter must be due to an action of the antidepressants themselves and not a consequence of a change in heart rate. In conjunction with the effects on the P-R interval, this suggests that the antidepressants slow conduction in cardiac tissue, though the doses required to produce this effect are very different with the different antidepressants.

The variety of dysrhythmias seen in these experiments is consistent with the find- ings in man after antidepressant overdose and, taking all these factors into account, it would appear that the relative cardiotoxicity of these antidepressants is in the order of amitriptyline > imipramine z maprotiline9 mianserin. A single numerical value for relative cardiotoxicity cannot be established because of the several different aspects to the cardiotoxic efects.

Sedation was the behavioural effect noted which was common to all four anti- depressants and quantitation was not attempted. The apparent salivary stimulation which was seen with mianserin alone in the conscious animals is interesting, though again this effect was not quantitated. Mianserin does not give rise to the dry mouth usually found during treatment of depressive patients with tricyclic antidepressants. A negative correlation has been reported in fact between the incidence of dry mouth and treatment with mianserin in depressed patients4-8 and a direct stimulant effect of mianserin on salivary output seems possible.

The clinically utilized dose range for amitriptyline, imipramine and maprotiline is usually 75 to 200 mg per day, while that for mianserin is somewhat lower (60 to 100 mg per day). This will tend to reinforce the toxicity difference seen in these experi- ments. While direct extrapolation from animals to man always carries a degree of uncertainty, it appears that the safety margin with mianserin may well be greater than with the other antidepressants, especially in the acute overdose situation and, if there is a risk of an acute overdose being taken, then mianserin may well be a safer alternative.

Acknowledgements We would like to express our thanks to Ciba Laboratories Ltd., to Geigy Pharmaceuticals Ltd. and to Roche Products Ltd. for gifts of antidepressants, to Organon International Ltd. for financial support, and to the Egyptian Government for a scholarship (S.R.).

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Relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in acute experiments in rabbits

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