Interactions of non-selective monoamine oxidase inhibitors, tranylcypromine and nialamide, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake

J. psychll. Rex, Vol. 18. No. 2, pp. 191-203, Printed in Great Britain.

INTERACTIONS

1984.

0022-3956/84 $3.00 + 0.00 Per@mon Press Ltd.

OF NON-SELECTIVE

MONOAMINE

OXIDASE

INHIBITORS, TRANYLCYPROMINE AND NIALAMIDE, WITH INHIBITORS OF 5HYDROXYTRYPTAMINE, DOPAMINE OR NORADRENALINE RE-UPTAKE E. MARLEYand KRYSTYNA M. WOZNIAK Department of Pharmacology, Institute of Psychiatry, De Crespigny Park, London SE5, U.K. (Received

22 August

1983; revised

19 January

1984)

Summary-Rats pretreated with tranylcypromine and given clomipramine. developed head and body twitches, forelimb flexor-extensor movements and wet dog shakes, phenomena which failed to develop when pretreatment incorporated p-chlorophenylalanine (PCPA) but were unabated when this included a-methyl-p-tyrosine (AMPT). Locomotor activity, itself enhanced by tranylcypromine, was further and significantly elevated compared to saline, by clomipramine or imipramine in grouped rats (n = 3) but not in single or paired rats; desipramine lacked such action. This effect of clomipramine was prevented when PCPA was incorporated into the pretreatment and that of imipramine by including PCPA or AMPT. Brain monoamine oxidase (MAO) A inhibition was 92% and that of MAO B, 80%. Cortical hydroxytryptamine (S-HT) and noradrenaline concentrations as well as hypothalamic S-HT, were significantly elevated by tranylcypromine, as was dopamine in the striatum, nucleus accumbens and tuberculum olfactorium. Hyperthermia developed in tranylcypromine pretreated rats given paroxetine or fluoxetine. Myoclonic phenomena were elicited by paroxetine, fluoxetine, clomipramine or imipramine in nialamide pretreated rats but these were less intense than in rats pretreated with phenelzine or tranylcypromine. Fatalities were fewer than in rats pretreated with tranylcypromine or phenelzine. Brain MAO A inhibition was 92% and that of MAO B, 69%.

INTRODUCTION INTERACTIONS between tranylcypromine, an amine monoamine oxidase (MAO) inhibitor, or between a hydrazide, nialamide and amine re-uptake inhibitors are reported separately as each presented different aspects to those evolving after phenelzine pretreatment. Following tranylcypromine, the S-hydroxytryptamine (5-HT) re-uptake inhibitors evoked not only myoclonic phenomena but significantly augmented locomotor activity, reminiscent of a ‘hyperactivity syndrome’ described in similarly pretreated rats given tryptophan (GREEN and GRAHAME-SMITH, 1974) or L-3,4_dihydroxyphenylalanine (L-DOPA) (GREEN and KELLY,1976). In contrast, after nialamide, the interactions were less intense and there were fewer fatalities, indicative that the hydrazides could be the preferred variety of non-selective MAO inhibitors when used clinically in combination. The results have been reported briefly to the British Pharmacological Society (MARLEYand WOZNIAK, 1983a). METHODS

Male Wistar rats, 180-220 g, were used. As previously, these, in groups of three (MARLEYand WOZNIAK,1984), were placed overnight in a polyethylene cage (dimensions 191

192

E. MARLEY and KRYS~YNA M. WOZNIAK

350 x 230 x 160 mm) on an activity meter (Motron Products, Sweden) and for rats in nialamide experiments, nialamide (200 pmol/kg i.p.) was injected. Food and water were freely available until the following morning (9 a.m.) when they were removed; a period (20-40 min) then elapsed until motor scores stabilized. The three rats were next injected with saline (0.9% w/v NaCl solution) 0.2 ml i.p.; motor scores were recorded for 90 min (control saline). Then either a single dose of tranylcypromine (19.4 pmol/kg i.p.) was injected or for nialamide pretreated rats, a further dose of nialamide (100 pmol/kg i.p.); 90 min later the amine re-uptake inhibitor was injected and myoclonic and motor activity recorded. Classification and scoring of myoclonic phenomena were as previously described. Rats remained in the cage for a further 24 h, to note incidence of fatalities. Methods for measuring brain amines and metabolites (EARLEY and LEONARD, 1978) and amine oxidase inhibition in the brain (TIPTON and YOUDIM, 1976) were those used previously.

Locomotor activity This was recorded with an Animex Activity Meter (Farad Electronics, Sweden) with sensitivity at 30 PA and tuning at 40 PA. Single, paired or rats in groups of three were placed overnight in a larger polyethylene cage (420 x250x 120 mm), on the activity meter, remaining in the cage the subsequent day when saline and drugs were injected as above, and for a further 24 h as in the experiments for myoclonic activity.

Body temperature Body temperature was measured in a small number of rats. Thermistor probes were constructed as described by POOLE and STEPHENSON (1977a), then implanted intrathoracically, under halothane anaesthesia, alongside the trachea so that the tip was adjacent to the pulmonary artery where blood mixes from all regions of the body. The probe was connected via twin microcables (Radiospares Ltd.) taken subcutaneously to gold pins (448-191, Radiospares) which were fixed with dental cement to the cranial vertex. Anaesthesia was terminated and the rat allowed to recover for at least a week before testing. For continuous recording of core temperature, each rat was placed singly into a perspex environmental chamber (333 x 290 x 280 mm) maintained at 23 + 0.5”C, in the thermoneutral range for the rat (POOLE and STEPHENSON, 1977b), through which air flowed at 2 I/min. The two pins on the skull of the rat were then connected via a microcable to a mercury concentric swivel (Camden Instruments, Ltd.) mounted in the roof of the chamber, and in series with a bridge circuit (ALLEN and LANWORN, 1968) and a Devices pen recorder. Rats were allowed 90 min adaptation to the chamber, following which the chamber was opened and tranylcypromine injected; 90 min later the amine re-uptake inhibitor was administered and core temperature recorded for a subsequent 3 h. Statistical analysis of activity meter scores and brain amine concentration were with Students’ t test; myoclonic scores were evaluated with Mann and Whitney’s u-test. DFUgs used Details of drugs used are given in MARLEY and WOZNIAK (1984). Other drugs employed, included nialamide hydrochloride (Pfizer & Co., Sandwich, U.K.) and tranylcypromine (Smith, Kline & French, Welwyn Garden City, U.K.).

MAO1 AND

AMINE

RE-UPTAKE

193

INHIBITORS

Criteria for doses used of tranylcypromine and nialamide Pretreatment with tranylcypromine was limited to a single dose, since a second doseparticularly with grouped rats-evoked substantial locomotor activity, partly obscuring both myoclonic and locomotor effects subsequently induced by certain amine re-uptake inhibitors. Nialamide did not increase motor activity, so two doses were given as with phenelzine, although the total dose exceeded that for the latter. RESULTS

Tranylcypromine Myoclonic phenomena. Similar myoclonic phenomena were elicited by clomipramine (31.6 pmol/kg i.p.) in tranylcypromine pretreated rats (19.4 pmol/kg i.p. 90 min previously) to those in rats pretreated with phenelzine (compare Fig. 1 with Figs. 1 and 2 of MARLEY and WOZNIAK, 1984). Onset of myoclonic features was slower except for head twitches, than in phenelzine pretreated rats and scores for FFEM, head twitches and WDS greater but not significantly so; body twitches were significantly fewer @ < 0.002). Myoclonic phenomena did not develop following tranylcypromine alone.

0

30

60

90

120

150

180

c

b

CIGIT u l

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(;56; 1112’

PCPA

FIG. 1. Totals and time course for the development of FFEM (b), head twitches (c), body twitches (d), WDS (e) and of summed scores for the myoclonic phenomena in 12 rats pretreated with tranylcypromine, 19.4 pmol/kg i.p. and challenged with clomipramine, 31.6 pmol/kg i.p. (@----0). When pretreatment included p-chlorophenylalanine (PCPA, 800 pmol/kg i.p. 24 h prior to clomipramine; l - - - - 0) all scores were drastically reduced, whereas when pretreatment included a-methyl-p-tyrosine (AM-p-T-3doses each of 226 pmol/kg over 24 h prior to clomipramine; 0 - - - - 0). myoclonic phenomena were at most, modestly diminished.

E. MARLEY and KRYSTYNAM. WOZNIAK

194

Paired

Grouped

rats

4oo

,,

11

rate

FIG. 2. Histograms of locomotor activity (over four consecutive 90 min periods) elicited by tranylcypromine followed 90 min later by saline (Sal), clomipramine (Clomip), imipramine (Imip) or desipramine (DMI) in (a) single rats, (b) paired rats or (c) grouped rats (3 in each group); for some grouped rats (d, e), p-chlorophenylalanine (PCPA) or a-methyl-p-tyrosine (AMPT) was included in the pretreatment (for doses see text). Mean scores with tranylcypromine taken at 100%. Vertical bars are SEM. Number of experiments indicated above each histogram sequence. Significance of differences are for mean locomotor scores compared with those following tranylcyprnmine and saline (a, b, c): for (d) and (e) comparisons are with the corresponding experiment< illustrated in (c). *p < 0.05, **p < 0.01, ***p < 0.001.

MAO1

ANDAMINE RE-UPTAKE INHIBITORS

195

When rats were pretreated with p-chlorophenylalanine (PCPA, 800 ,umol/kg i.p. 24 h before clomipramine) as well as tranylcypromine, then myoclonic features induced by clomipramine were virtually abolished (Fig. l), whereas when a-methyl-p-tyrosine (AMPT) (3 doses each of 226 pmol/kg i.p. over 24 h) preceded tranylcypromine, scores for myoclonic phenomena elicited by clomipramine were not significantly altered (Fig. 1).

Locomotor activity This was itself augmented by tranylcypromine (19.4 pmol/kg i.p.) so to normalize scores, locomotor activity evoked by the latter was taken as 100% (see Fig. 2). As in experiments above, amine re-uptake inhibitors (3 1.6 pmol/kg i.p.) or saline were injected 90 min subsequently and locomotor activity over the ensuing 180 min, plotted in successive 90 min epochs (Fig. 2; n = number of experiments). In contrast to single (Fig. 2a) or paired rats (Fig. 2b), for which locomotor activity elicited by tranylcypromine was not significantly increased by clomipramine or imipramine compared to saline, with grouped rats (3 rats) there was a progressively greater and significant increment after clomipramine or imipramine for each 90 min epoch compared to saline (Fig. 2c), larger for clomipramine than for imipramine; after desipramine, locomotor scores differed little from that with saline following tranylcypromine (Fig. 2~). In grouped rats pretreated with PCPA (800 pmol/kg i.p. 24 h previously) locomotor scores were not increased by imipramine or clomipramine after tranylcypromine (Fig. 2d; compare vertically with similar experiments in Fig. 2~); indeed, these were significantly less @ < 0.05 top < 0.001) than in rats not so primed. With tranylcypromine-pretreated grouped rats given AMPT (226 pmol/kg i.p. in 3 spaced doses over previous 24 h), imipramine again lacked effect on locomotor activity (Fig. 2e); however, after clomipramine there was a smaller increase, not significantly different from the control (tranylcypromine plus clomipramine, in Fig. 2~).

Fatalities Deaths with the combined (12/24) and with imipramine

drugs were as follows: (5/45).

tranylcypromine

and clomipramine

Concentrations of brain amines Cortical Shydroxytryptamine (5-HT) and noradrenaline, hypothalamic 5-HT and dopamine in the striatum, n. accumbens and tuberculum olfactorium were significantly increased @ < 0.05 top < 0.001) after tranylcypromine (Table 2, MARLEY and WOZNIAK, 1984; further changes in these concentrations following clomipramine, imipramine or desipramine are also shown in this Table). Concentration of cortical and hypothalamic 5-HT, but neither dopamine nor noradrenaline, were significantly diminished by PCPA (800 pmol/kg i.p. 24 h previously), compared to those for control rats (Table l), given saline 0.2 ml, 3 h previously; the reduction was less in rats subsequently given tranylcypromine (19.4 pmol/kg i.p.) 3 h before sacrifice. For rats pretreated with AMPT (3 doses, each of 226 I.cmol/kg over previous 24 h), dopamine in the striatum, nucleus accumbens and tuberculum olfactorium as well as hypothalamic noradrenaline concentrations, were significantly reduced compared to controls (see Table l), although for those given tranylcypromine (19.4 pmol/kg i.p.) 3 h before sacrifice, the depletion was attenuated.

I.

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PCPA

PCPA + Tran PCPA + Tran + Imip PCPA + Tran + Clomip

Control

AMPT

AMPT AMPT AMPT

7.48 * 1.07 4.9 kO.72 8.21 t 1.17

3.96zO.07

2.92kO.19

1.65~0.26 1.72~ 0.14 1.69kO.37

2.41 k 0.3 p < 0.05 1.31 TO.35

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and

tuberculum olfactorium

N. accum

Dopamine

control

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5

7 3 4

7

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3.64? 0.39 2.52 k 0.2 3.62 + 0.43

5.43 2 0.94 p < 0.05 3.06 zk 0.25

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3.39yO.2

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7

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animals and animals treated with either

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Noradrenaline

(TRAN), OR TRANYL-

DOPAMINE AND NORADRENALINE IN VARIOUS BRAIN REGIONS OF CONTROL

values refer to differences

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Cortex

5-Hydroxytryptamine

Control

+ Tran + Tran + Imip + Tran + Clomip

WET TISSUE) OF 5-HYDROXYTRYPTAMINE,

WITH p-CHLOROPHENYLALANINE

(PCPA) OR O-METHYL-p-TYROSINE (AMPT), THEN GIVEN TRANYL~YPROMINE CYPROMINEFOLLOWEDBY IMIPRAMINE(hlP) OR CLOMIPRAMINE (CLOMIP)

MEAN AND SEM OF CONCENTRATION @g/g

RATS, OF RATS PRETREATED

TABLE

-.-

MAOI AND AMINE RE-UPTAKEINHIBITORS

197

The reductions in brain amines following combination of PCPA or AMPT with tranylcypromine were not significantly amended by injection 90 min later of imipramine or clomipramine (Table 1).

Hyperthermia As shown in Fig. 3, tranylcypromine usually decreased core temperature (Tb). In contrast, Tb was substantially elevated (Fig. 3a, b) by subsequent injection of paroxetine or fluoxetine (n=2 for each) with increases of 4-5°C above control (pre-tranylcypromine) values within 40-80 min, death soon supervening. Hyperthmia developed in one of four rats given clomipramine (Fig. 3c) but not in either of two pretreated rats challenged with imipramine (Fig. 3d).

Nialamide Myoclonicphenomena.

The time course of total scores for myoclonic features elicited by paroxetine, fluoxetine, clomipramine or imipramine in rats pretreated with nialamide are shown in Fig. 4; the corresponding scores for rats pretreated with phenelzine are included for comparison. Total scores for these phenomena were less than in phenelzine pretreated rats, significantly so with paroxetine @ < 0.02) or imipramine @ < 0.002). Total scores for individual myoclonic phenomena are given in Table 2. These scores were smaller than for rats given phenelzine, being significantly so for body twitches with paroxetine, clomipramine (each p < 0.02) and imipramine @ < 0.002); WDS were also substantially less e.g. for paroxetine and clomipramine (each p < 0.05) and fluoxetine @<0.02).

Motor activity Activity scores were augmented compared to controls in rats given paroxetine or fluoxetine combined with nialamide, but only the increase after paroxetine reached significance @ < 0.05); with clomipramine, scores were similar to those for controls while those after imipramine were significantly reduced @ < 0.05).

Fatalities These occurred

only with paroxetine

and nialamide

(l/12).

Brain amines Concentrations of hypothalamic 5-HT and noradrenaline after nialamide (see Table 2, MARLEY and WOZNIAK, 1984).

were significantly

increased

Hypthermia An increment of 3°C in body temperature followed paroxetine pretreated rat (Fig. 3e), with death in the ensuing 24 h; fluoxetine the one rat tested.

given to a nialamide was without effect in

DISCUSSION

Myoclonic phenomena elicited in rats by 5-HT re-uptake inhibitors combined with phenelzine, were reproduced when these compounds were given to animals pretreated

198

E. MARLEY and KRYSTYNAM. WOZNIAK TRANYLCYPROMINE Tranyl.

ParOX.

NIALAMIDE Nlal.

Fluox ,~__~_~7~ -120 -60

0

I

1

60

1

120

160

240

min

FIG. 3. Body temperature response in rats pretreated with tranylcypromine (19.4 pmol/kg i.p. 90 min previously, or nialamide (200 FmoVkg, 18 h and 100 pmol/kg i.p., 90 min previously) to injection of paroxetine (Parox), fluoxetine (Fluox), clomipramine (Clomip), or imipramine (Imip), each given as a 31.6 pmol/kg i.p. dose. Body temperature recorded continuously from intrathoracic thermistor; each record from a single rat.

MAOI

199

ANDAMINE RE-UPTAKEINHIBITORS ” = I2 b

2 a

60

Phenelzlne Paroxetlne

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Nlolomlde + Paroxetine(6421

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Phenelzine + Clomlpramlnei62Ol Nlalamlde + Clomipramlne(373)

0 0 FIG.

4.

60

120 min

180

0

60

I20

180

mln

Totals and time-course for summed scores of the four myoclonic phenomena in rats (each group, 0) compared to those pretreated with phenelzine (0 -0) and challenged with paroxetine (a), fluoxetine (b), clomipramine (c) or imipramine.

n = 12) pretreated with nialamide (O-

instead with tranylcypromine or nialamide, although the series of compounds tested was less extensive. In contrast to experiments using phenelzine, locomotor activity was augmented by tranylcypromine and this was significantly increased again compared to saline by subsequent injection of clomipramine or imipramine but not by desipramine. This feature was obtained only in grouped rats (n = 3) and not in those tested singly or in pairs, suggesting it was contingent on interactions between animals or locomotion. It was thus reminiscent of the enhanced locomotion with amphetamine in grouped compared to single mice (GUNN and GURD, 1940; CHANCE, 1946) and contrasts with the myoclonic phenomena, as intense in single as grouped rats. Genesis of this feature could revolve around the significant increase of dopamine in the nucleus accumbens and tuberculum olfactorium after tranylcypromine and not the other MAO inhibitors, since dopamine applied to these areas of the mesolimbic system provokes locomotion (PIJNENBURG et al., 1976). However, both 5-HT and dopamine appear to be involved, because pretreatment with PCPA prevented its development as did AMPT in the case of imipramine. Noradrenaline was unlikely to be implicated since locomotor activity was not further enhanced by desipramine, a noradrenaline re-uptake inhibitor. This parallels GREEN and GRAHAM-SMITH’S (1974) finding that pretreatment with PCPA or AMPT precluded the emergence of a hyper-activity syndrome in rats given tryptophan and tranylcypromine. ‘Stereotyped activity’ in rats pretreated with tranylcypromine and given 5-HT re-uptake inhibitors was also pre-empted by PCPA administration (HOLMAN et al., 1976).

136

198

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12***

97

Par

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PHENOMENA

162

Clomip

MYOCLONIC

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167 85”

204

Clomip

Body twitches Flu

I2

RE-UPTAKE

IN RATS (n =

23**’

103

Imip

INHIBITORS

275

WITH

189

226

Clomip

55’**

204

Imip

NIALAMIDE

72*

110

Par

AND GIVEN

0

5

Imip

VARIOUS

with nialamide

2*

27

Clomip

WDS

19**

65

Flu

OR PHENELZINE

values are for the extent scores in rats pretreated

198

218

FItI

Head twitches

PRETREATED

290

Par

IN EACH CASE)

Par = paroxetine; Flu = fluoxetine; Clomip = clomipramine; Imip = imipramine. Significance and were less than those given in phenelrine. +p < 0.05; *+p < 0.02; ***p < 0.002.

216

Nialamide

Par

290

~

FFEM

2. TOTAL SCORES FOR ,NDI”lDUAL

~._~ Phenelzine

-,-ABLE

E

3 e 8 Z

2 2

F

!Z

*

;

m

MAO1 AND AMINERE-UPTAKE INHIBITORS

201

Clinical descriptions of interactions with combined antidepressants allude to restlessness as an early feature. In the absence of adequate details, this could be a myoclonic and locomotor composite when tranylcypromine was involved, but with emphasis on the former when other MAO inhibitors were implicated. Fatalities were more frequent in rats following combination of clomipramine with tranylcypromine than phenelzine or nialamide. Of the non-selective MAO inhibitors, tranylcypromine is reputed to pose special hazards in combination when used clinically but the evidence for this has been considered dubious (WHITE and SIMPSON, 1981). Hyperthermia observed in man with combined antidepressants was reproduced in rabbits (LOVELESSand MAXWELL, 1965), elevations of 2.5-3.75”C in rectal temperature being elicited by intravenous imipramine following pretreatment with tranylcypromine, phenelzine or nialamide. Amitryptyline also evoked hyperthermia in rabbits receiving a hydrazide MAO inhibitor (NYMARK and NIELSEN, 1963). In reverse order of administration, intravenous tranylcypromine induced fatal hyperthermia in dogs pretreated with imipramine (HIMWICH, 1962), emphasizing the fortuity that in man the majority of reactions are those in which a tricyclic drug has followed prior administration of an MAO inhibitor. Hyperthermia was also evoked in rats but less consistently except with fluoxetine or paroxetine in tranylcypromine pretreated animals; in the limited number of pretreated rats tested, imipramine did not elevate body temperature and clomipramine was hyperthermic in only one of four. If, as suggested, 5-HT is crucially implicated in the reactions, then it is relevant that in rats-unlike many species, 5-HT lowers body temperature when given intraventricularly (FELDBERG and LOTTI, 1967) or can lower (Cox and LEE, 1980) or elevate it (CRASHAW, 1972) when applied to the anterior hypothalamus. This may account for the relative recalcitrance of pretreated rats to hyperthermic developments after imipramine or clomipramine. Myoclonic phenomena elicited by S-HT re-uptake inhibitors in rats pretreated with nialamide were less intense and shorter-lasting than in those receiving tranylcypromine or phenelzine; fatalities were also fewer but only significantly so with clomipramine for rats primed with tranylcypromine (p < 0.01). Inhibition of brain MAO after nialamide was not significantly less than with the other non-selective MAO inhibitors so the less intense features were not attributable to this. A possible reason for nialamide being less noxious in combination is that unlike tranylcypromine it does not cause efflux of amines from neurones (synaptosomes) (KNOLL and MAGYAR, 1972); additionally, phenelzine and tranylcypromine interfere with neuronal re-uptake of amines (HENDLEY and SNYDER, 1968). Both the above factors would tend to lead to smaller synaptic concentrations of amines after nialamide than with the other MAO inhibitors. There might thus be virtue in preferring the hydrazides to other non-selective MAO inhibitors for use clinically in the context of combined antidepressants, although interactions in man have occurred with hydrazides, WHITE and SIMPSON (1981) alluding to incidents involving iproniazid, isocarboxazid or nialamide. Consequently, non-selective MAO inhibitors do not recommend themselves for use in combined antidepressant therapy, despite enjoying clinical provenance. Acetylenic MAO inhibitors such as pargyline were not tested and while there are theoretical grounds for supposing these could be safer in combination, a non-fatal interaction has nevertheless been reported with it (MCCURDY and KANE, 1964). Instead, relatively selective MAO

202

E. MARLEYand KRYSTYNAM. WOZNIAK

inhibitors would appear more promising, a conclusion as yet based on animal studies. Thus myoclonic features were absent or minimal after clomipramine in rats pretreated with clorgyline (MAO A inhibitor) or deprenyl (MAO B inhibitor); in contrast, intense myoclonic, locomotor and hyperthermic phenomena were evoked by clomipramine in rats pretreated with both clorgyline and deprenyl (MARLEY and WOZNIAK, 1983b), i.e. when MAO A and B were inhibited, as after non-selective MAO inhibitors. Given such potential greater safety of combinations involving a single selective MAO inhibitor, their therapeutic efficacy can be resolved only in the clinical forum.

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