British Journal of Psychiatry (1985), 146, 576—584 Review Article

The Present Status of Monoamine Oxidase Inhibitors

C.M.B.PARE
Summary: Thepresentstatusof monoamineoxidaseinhibitorsin thetreatment
of depressionis reviewed.With adequatedosesthey are effective antidepres
sants, but dosages have in the past been too low. Provided proper dietary
precautionsare taken,the incidenceof fatality from dietary interactionsis very
small and should not deter doctorsfrom using thesedrugs, especiallyin those
depressedpatients who do not respond to tricyclic-type antidepressants.The
present status of combining monoamine oxidase inhibitors with tricyclics is
discussed,asarethe newerspecificinhibitorsparticularlyclorgylineanddeprenyl.
The story of the discovery of tyramine oxidase and an early study of human brain, showed that 100—125
the subsequent history of monoamine oxidase mg of iproniazid was necessary to produce such a
(MAO) and its inhibitors has been excellently told degree of inhibition. The work of Nies, Robinson,
by Kety (1976). I reviewed the clinical status of the and Ravaris has shown that doses of phenelzine
monoamine oxidase inhibitors (MAOIs) in 1977, sufficient to produce a greater than 80% inhibition
and this paper sets out to update the position. In any of platelet MAO result in a good antidepressant
reassessment, it is important to keep an open mind, effect, but if the inhibition is less, and certainly if
especially so with the MAOIs which have errone less than 60%, the antidepressant effect is poor
ously been thought to be either ineffective or only (Robinson eta!, 1978a, 1978b; Davidson eta!, 1978;
weak antidepressants and at the same time to carry Nies & Robinson, 1982; Georgotas et a!, 1981,
high risks. In this respect, we should ignore many of 1983). For practical purposes, a dose of phenelzine
the early trials which either used inadequate doses of 60 to 75 mg a day is usually sufficient, although
or patients who were probably not suitable, for individual patients may need more.
instance the much quoted Medical Research Coun Thus, there is substantial pharmacological evi
cil trial of 1965, where the patients were in-patients dence to suggest that the usually recommended
and chosen because of their suitability for E@T. dose of phenelzine (45 mg) is definitely too low.
Table I sets out the recent controlled trials of this
Dosage drug which are acceptable as far as methodology
There is considerable pharmacological evidence to and patient numbers are concerned; provided the
suggest that the dosages of MAOIs originally dose is adequate, the results are all positive. Very
recommended for clinical use were too small. In the similar findings have been shown with isocarboxa
early 1960s, the brains of 76 elderly patients who zid: doses of about 50 mg a day will usually result in
had died while receiving MAOIs for terminal de a greater than 80% inhibition of platelet MAO
pression were studied (Maclean et a!, 1965; Bevan (Davidson et a!, 1981a; Giller et a!, 1982) and
Jones et a!, 1972; Pare 1976). These investigations clinical trials using doses of 40—60mg a day show a
showed that the patients varied considerably in good antidepressant effect (Davidson et a!, 1981a;
their pharmacological response, that 60 mg of Giller et a!, 1982; Davidson & Turnbull, 1983;
isocarboxazid was frequently required to obtain a Zisook, 1983).
good response, and that this was roughly equivalent In the absence of laboratory tests, a dose of 60—75
to 20—30mg of tranylcypromine. In the clinical mg phenelzine or 40—50 mg isocarboxazid a day is
setting, Oswald among others has shown that usually adequate for an effective antidepressant
clinical improvement in depression only occurs action. A mild degree of orthostatic hypotension
when REM sleep is abolished, and again this may usually occurs after 10—14days on an adequate
need a dose of phenelzine substantially above the dose, and may correlate with clinical response
usual daily one of 45 mg (Akindele et a!, 1970). (Murphy et a!, 1981); in the absence of orthostatic
There is in fact an abundance of MAO in the brain, hypotension, if there is a lack of clinical improve
and Green & Youdim (1976) showed that in rats, it ment, the clinician should certainly consider in
was necessary to inhibit at least 80% of brain MAO creasing the dose.
to produce a behavioural effect. Such a reduction is
frequently not attained in man with standard Acetylatorstatus
dosage (Youdim et a!, 1972); Ganrot eta! (1962) in Phenelzine is a hydrazine MAO! and is thought to
576
 THE PRESENT STATUS OF MONOAMINE OXIDASE INHIBITORS 577
TABLE I
Controlled trials of pheneizinein affectivedisorders
SourceComparison of
drug (s)Dose phenelzine drug treatment
(wk)OutcomeRobinson (mg/day)Duration
(1973Placebo606+Johnstone
ci al
(1973)Placebo45—903+Tyrer
& Marsh
(1973)Placebo45—908+Solyom
etal
Rx4512+Raskin
et al(1973)Placebo, behavioural
diazepam454—70Ravarisetal(1976)Placebo606+Mountjoy
ci a! (1974)Placebo,

(1977)Placebo45—703+Sheehan
et al
imipramine45—6012+Rowan
ci al(1980)Placebo,
etal(1982).
amitriptyline60—756+Liebowitz Placebo,

ci al(1984)Placebo, imipramine60—904—6+

be metabolised by acetylation (Tilstone eta!, 1979), period; they concluded that acetylation is not a
though Marshall (1976) has suggested that other factor in phenelzine metabolism.
pathways may be more relevant. Acetylator status
is genetically determined, and if acetylation was Type of patient
important for the metabolism of phenelzine, slow Depression: Cross-over studies suggest that there
acetylators might be expected to show a ‘¿better may be some patients who respond to tricyclic
clinical response than fast acetylators, in whom the antidepressants and some others who only respond
drug would be expected to be destroyed mOre to MAOIs; thus, patients responding to one MAO!
rapidly. Three studies did indeed show a greater on the whole respond to another, but not to a
improvement in slow acetylators (Johnstone & tricyclic, and vice versa (DaIly 1960; Dally & Rhode
Marsh, 1973; Johnstone, 1976; Paykel eta!, 1982), 1961; Pare 1965). Somewhat differently, Hamilton
but five other trials failed to show any difference in (1974) showed that the response to ECT was quite
clinical response (Evans et a!, 1965; Davidson et a!, different between those patients failing to respond
1978; Marshall et a!, 1978; Tyrer et a!, 1980, 1981; to phenelzine and those failing to respond to
Nies & Robinson, 1982). Three groups of workers imipramine. In other words, pheneizine and
also failed to show any difference in the degree of imipramine were curing different types of depres
inhibition of platelet MAO (Davidson ci a!, 1978; sion. Perhaps more convincing to the clinician is his
Marshall ci a!, 1978; Nies & Robinson, 1982)@ personal experience of a severely depressed patient
Discussing these contradictory findings, Paykel eta! who is unresponsive to tricyclic antidepressants and
(1982) suggested that a weak acetylator effect ECT, who responds dramatically to an MAO!,
would not be expected to show in all trials, but relapses when the drug is withdrawn, and responds
would be most evident in the earlier weeks of the again to the reintroduction of the drug.
study and in patients on a lower dose of phenelzine. Some workers in the course of trials have
Certainly, these were the findings in Paykel's own concluded that MAOIs are best for classical severe
investigation, and the suggestion is supported by depressions with well marked psychomotor retar
two other studies of MAO inhibition: Johnstone dation (Murphy et a!, 1981); using high doses of
(1976), using urinary tyramine as an estimate of phenelzine, Davidson ci a!, (1981b), have shown
MAO inhibition, and Yates & Loudon (1979), this drug to be effective in severley depressed in
estimating platelet MAO, both found MAO was patients, provided they were not deluded. Other
inhibited earlier in the slow acetylators but that this investigators, while confirming that MAOIs have a
difference disappeared with continued treatment. true antidepressant effect, have been unable to
The crucial question is whether phenelzine is identify a subgroup of depressed patients who will
indeed metabolised to a significant degree by respond to MAOIs, as distinct from those who will
acetylation; ordinary measurement of acetylated respond to tricyclic antidepressants (Rowan Ct a!,
compounds is not sufficient, as such compounds can 1982; Bhat eta!, 1984). The general view, originally
arise from endogenous substances such as put forward by West & DaIly (1959), is that
phenylacetic acid. Cooper et a! (1984) have been although MAO!s can be effective in any type of
able to synthesise isotope labelled analogues of depression, they are most effective in those cases
pheneizine, and using these, have been unable to which are not of the classical endogenous type. This
detect any ‘¿3C-N-acetylphenelzine in any urine or has been strongly supported by Nies, Robinson, &
plasma samples during the 24 hours' post-drug Ravaris in a series of more systematic studies
578 C. M. B. PARE
T',BLEII
Typical symptom profile of MAOJ-responsive patients (from Nies
& Robinson 1982)
symptomsmood
PsychopathologicalsymptomsVegetative
insomniairritabilityhypersomniapanic
reactivity retainedinitial
gainagoraphobiahyperphagiasocial
episodesweight
sweetshypochondriasislethargy
fearscraving
fatigueobsessive and
preoccupationstremulousnessInterpersonal
featuresself-pity/blaming
reactionsHistorical
otherspersonal loss before
intensificationcommunicative
responserejectionsuicidal actionspoor ECI'
amphetaminesvanity/applause-seekingdysphoric
sensitiveliking
responseshistrionic tricyclic
personalityalcohol/sedative abuse
(Robinson eta!, 1973; Nies eta!, 1974; Ravaris eta!,
1976, 1980; Nies & Robinson, 1982) (Table II). In
these non-classical depressions, ECT often does
more harm than good and patients tend to react
badly to the tricyclic group of antidepressants, often
complaining that they produce a light-headed, ‘¿not
with it', almost depersonalised feeling. In addition
to feelings of depression, anxiety and apprehension
are the rule in such illnesses. The patient lacks
confidence in himself, there is a constant irrational
feeling of apprehension, and the patient may be
afraid to travel, go in to a shop, or be left alone in
the house. Somatic symptoms of anxiety and
tension may occur as well as dizzy feelings, with fear
of falling or disgracing himself, and complaints of
breathlessness, or more exactly, an inability to fill
his lungs with air, often associated with a tight
choking feeling in the throat and pain over the
praecordium. Concentration is often impaired and
symptoms suggestive of a mild depersonalisation
make the patient feel he is losing his mind. Self
blame and guilt about past behaviour is unusual, as
are delusional beliefs; rather, the patient tends to
blame circumstances or other people for his
troubles.
Pollit & Young (1971) noted that many of these
MAOI-responders had a physiological shift in the
reverse direction to the typical endogenous depres
sions and the fact has been remarked on that such
patients may have difficulty in getting to sleep;
appetite, weight and libido may be increased and
symptoms may be worse in the evening (Davidson
et a!, 1981a; Da@'idson & Turnbull 1983). These
symptoms may suggest a neurotic disorder secon
dary to an inadequate personality. In fact, patients
who respond well to MAOIs have a good previous
personality, marked perhaps by an excessive com
petitiveness and conscientiousness hiding some
underlying insecurity. After an accumulation of
nonspecific stresses, the depression is often precipi
tated by some emotional happening which is
particulary upsetting to the patient, but the degree
of symptoms is always out of proportion to what one
would expect. Arguing that ‘¿atypical' depressions
responsive to MAOIs might be undetected in trials
of heterogenous depressive disorders, Liebowitz et
a! (1984) have reported a well conducted trial on 60
patients who were selected as being likely to
respond to MAOIs. The clinical criteria were: (1)
RDC criteria for major, minor, or intermittent
depression. (2) Maintenance of mood reactivity
even when depressed. (3) The patient should show
two or more of the following: (a) Increased appetite
or weight gain when depressed. (b) Over-sleeping
or more time in bed when depressed. (c) Rejection
sensitivity as an adult trait.
Briefly, such patients showed a 67% response
rate to pheneizine, in a dose of 60-90mg daily, over
four to six weeks, contrasted with a 43% response
to imipramine in a dose of 200—300mg, which was
not significantly different from placebo. Patients
with panic reactions and with symptoms of
hysteroid dysphoria (Liebowitz & Klein 1979) were
especially responsive to phenelzine.
Thus, MAOIs benefit some patients with a
depressive illness, but are not effective for normal
grief, when the patient's symptoms are in propor
tion to the stress, as in a straightforward bereave
ment reaction. Similarly, they do not clear up
neurotic symptoms secondary to a lifelong inad
equate personality. When the patient responds, the
improvement is obvious and often dramatic. The
drug works or it does not work (Hamilton, 1982).
Anxiety: There is virtual agreement that MAOIs
are effective in anxiety states. (Solyom et a!, 1973;
Kelly, 1973; Lipsedge eta!, 1973; Tyrer, 1973; Tyrer
et a!, 1973a,b; Sheehan el a!, 1980; Nies &
Robinson, 1981) and this anxiolytic effect is not
dependent on the presence of concomitant depres
sive symptoms (Pohl et a!, 1982). The MAOIs are
particularly effective for patients with the
agoraphobic/claustrophobic syndrome, for many
with social phobias, and for others subject to panic
attacks. In a placebo-controlled study where 57
patients completed a three-months trial, Sheehan et
a! (1980) showed that phenelzine, 45 mg a day, was
more effective than imipramine, 150 mg a day, for
panic attacks. Kelly et al(1970) suggested that it was
by this reduction of panic that the MAOIs were
effective in phobias. Thus, once the panic is
controlled, the patient can enter the previously
feared situation with less apprehension until, be
repeated exposure, avoidance behaviour is dimin
ished and the phobia overcome.
 THE PRESENT STATUS OF MONOAMINE OXIDASE INHIBITORS
It is clear that MAOIs have both antidepressant
and anxiolytic properties; as far as can be
ascertained, the dosage required and the time for an
anxiolytic effect to be observed are similar to those
for the antidepressant effect. Thus, in a
heterogenous group of patients with symptoms of
depression and anxiety, these features responded
equally both in time and degree to MAOIs (Rowan
eta!, 1982; Bhat eta!, 1984). In a similar sample of
patients, symptoms of anxiety and depression both
showed little response over six weeks to 30 mg of
phenelzine, but improved with 60mg a day (Rowan
eta!, 1982). Tyrer eta! (1980) studied three groups
of patients—with depressive neurosis, anxiety neu
rosis, and phobic anxiety respectively—and found
that they all showed a similarly poor response to 45
mg of phenelzine, but a similarly good response,
both in time and degree, to 90 mg of phenelzine a
day. Phenelzine did not appear to be primarily
anxiolytic, antidepressive, or antiphobic in action,
and this similar activity in all three diagnositc
groups supported Tyrer's view (1976) that MAOIs
might be delayed psychostimulants with a similar
profile to amphetamine.
Side-effects of MAOIs
These have been reviewed by Marks (1965) and by
Pare (1977). Here, discussion will be limited to the
often exaggerated risk of serious consequencies,
such as death, from a food or drug interaction.
However, it should again be stressed that the
relative safety of the MAOIs depends to a great
extent on the doctor selecting them only for patients
who can be relied on to carry out his instructions,
which must be explained carefully, going over with
the patient the ‘¿MAOI
card' or whatever written
instructions are given to take home. McGilchnst
(1975) gave an excellent discussion of the tenuous
evidence on which reports of adverse reactions
were frequently based and of how such reports were
then perpetuated in the literature: over a ten-year
period, only 17 cases of reactions (none fatal)
between phenelzine and foodstuffs had been re
ported to the manufacturers or to the Adverse
Reactions Committee of the Committee on Safety
of Medicines. These figures are remarkably low,
considering that phenelzine is one of the best selling
MAOIs in Britain and that this was the period when
‘¿cheese
reactions' were most likely to be reported.
Marks (1965) suggested that tranylcypromine
was the MAO! most likely to result in hypertensive
reaction. During the period January 1975 to
December 1983 seven deaths in association with
tranylcypromine and dietary items were identified
as having occurred in the United Kingdom, but it
579
would seem likely that three of these were dupli
cates. (Acknowledgements to Adverse Reactions
information service of the DHSS and Dr Flind,
Smith Kline & French). However, it should be
stressed that the association with tranylcypromine
as a causal effect with diet is difficult to prove. Of
the four deaths for which information is available,
at least one and probably two involved cheese,
while in the two other cases, although deaths
occurred in association with tranylcypromine, a
toxic interaction with dietary items remains uncer
tain. During this nine-year period, based on the
sales figures for the UK and assuming an average
dose of three tablets a day, a total of 98,000 patient
years of tranylcypromine were prescribed. Thus,
with these admittedly unreliable statistics and
assuming seven deaths (and no duplicates) a figure
of one death per 14,000 patient-years is obtained,
suggesting that the risk from MAOIs is much
smaller than is often believed. Shaw (1977) in
discussing the management of depressed patients,
concludes that: “¿although
the risk for MAOIs is
greater than that from tricyclics, it is so much
smaller than that from the illness itself that it is not
in the interest of patients to withhold MAOIs if
there are indications for their use―.
The place of MAOIs in the treatment of depression
Many cases of depression are of mild degree or,
perhaps because of circumstances, can be expected
to improve in a short time; such patients should
obviously be treated with explanation, reassurance
and support. More serious degrees of depression
may be considered for treatment with a tricyclic
antidepressant and in suitable patients. good im
provement may be expected in 60 to 70% of cases.
Some who fail to respond to tricyclic
antidepressants, particularly if they are of the
classical endogenous type, may respond to ECT,
but it is in the treatment of therapy-resistant
patients that the MAOIs have an important place.
This is illustrated by Nolen (1984), who reported 43
patients suffering from a major depressive illness
according to DSM III who had failed to respond to
one or more re-uptake inhibiting antidepressants.
These patients were given a ‘¿second generation'
antidepressant—either a specific 5-hydroxytryp
tomine (5-HT) or noradrenaline re-uptake inhibi
tor—for four weeks; of those who failed to respond,
all but three were then treated for a further four
weeks with the other drug. At tbe end of the eight
weeks, only 20% had improved, but after further
treatments with sleep deprivation and 5-
hydroxytryptophan (5HTP), 26 patients who had
not dropped out received tranylcypromine, and 15
580 C. M. B. PARE
(58%) of these responded well. He concluded that
only a small percentage of patients who had not
responded to one or more re-uptake inhibitors
subsequently responded to selective re-uptake
inhibitors; and that tranylcypromine, but not sleep
deprivation or 5HTP, is the alternative treatment
for depressed patients who do not respond to re
uptake inhibitors.
There should always be some urgency in the
treatment of depression, quite apart from the risk of
suicide, the illness is not only very distressing to the
patient but also to the family. Furthermore,
continuing depression leads to loss of social activi
ties and friends and often to unemployment,
financial hardship, and perhaps marital difficulties,
all of which militate against recovery. For these
reasons, waiting until all other treatments have
failed is not to be advised before recommending an
MAO!. I usually give a tricyclic first, perhaps even
try a second tricyclic, but if that fails, I would
certainly advise an MAO!. Furthermore, if the
patient has much anxiety and other atypical fea
tures, and particularly if he reacts badly to a small
dose of a tricyclic antidepressant, there should be
no hesitation in prescribing an MAO!.
Such tricyclic- and ECT-resistant conditions are
often found in the elderly, and certainly patients in
this group frequently react badly even to the new
generation of tricyclic-type antidepressants.
Georgotas et a! (1981, 1983) have shown how
effective MAO!s can be in such patients; they
reported 30 patients, all of whom had received at
least two tricyclic antidepressants in full dosage
(e.g. imipramine 150—300 mg a day for one to eight
months); more than a third had received ED'. Of
the 20 patients who took phenelzine for two to
seven weeks, 65% had a good response, most of
these having an inhibition of platelet MAO of more
than 80%. Particularly reassuring was the lack of
side-effects, especially confusion and intellectual
impairment, as compared to the tricyclic type of
antidepressant they had previously experienced.
Mechanism of action
The first and original idea was that by inhibiting
MAO, the MAOIs increase the availability of
amines at nerve terminals, thus increasing@receptor
stimulation. Van Praag (1983) has marshalled
cogent reasons in favour of this being a direct
antidepressant effect. The time relationship
between MAO inhibition, increased availability of
amines, and clinical response is obviously crucial;
platelet MAO is inhibited quickly, sometimes
within one to two days (Murphy 1981), but the
antidepressant effect is delayed for two to three
weeks. However, what the time sequence is in
human brain, with the dose of drugs used in clinical
practice, is not established. The best evidence
comes from post-mortem studies of elderly patients
dying while taking an MAO! (MacLean eta!, 1965).
Patients dying within a week of starting MAOIs
showed little change in brain concentrations of 5-
HT, but these concentrations approximately dou
bled in patients who had received an MAO! for two
to three weeks, which would be the time when an
antidepressant effect would be expected. In the last
few years, more emphasis has been directed to the
delayed post-synaptic receptor-mediated events,
similar to those described for tricyclic
antidepressants (Sulser et a!, 1983). It has been
suggested that reduced deamination of noradren
aline results in an increase of that substance at the
synapse. As an adaptation to this, and probably of
equal importance to changes in the 5-HT system,
there is a reduction in the alpha 1, alpha 2, and beta
adrenoceptors and reduced firing of the locus
ceruleus; in other words, an opposite effect to the
original hypothesis (Charney et a!, 1981; Cohen et
a!, 1982; Murphy et a!, 1983). These changes, like
the antidepressant effect, only develop after two to
three weeks' treatment, and the down-regulation of
the cyclic adenosine monophosphate system devel
ops even later.
Finally, it must be remembered that the MAOIs
in present use have actions other than inhibition of
MAO and Mendis et a! (1981a) have given reasons
for suggesting that the antidepressant properties
may be more related to the cheese reaction and
noradrenaline release, and that this may be quite
independent of the MAO inhibitory effect.
Combination of MAOIs and tricyclic
antidepressants
Until recently, this was considered highly danger
ous, but in fact, it is not so, and reviews by Schukit et
a!(1971), Sethna (1974), Ananth & Luchins (1977),
and White & Simpson (1981) all agree that,
provided the drugs are given properly, the inci
dence of adverse effects other than weight gain,
orthostatic hypotension, and possibly impotence is
no higher than when the two kinds of
antidepressants are given separately. Fatal or
serious reactions have virtually all been due either
to overdoses, combining four or five drugs to
gether, usually with alcohol, or giving imipramine,
sometimes parenterally, to a patient already on an
MAO!. Severe reactions are of an agitated delirium
progressing to coma, generalised hypertonicity,
seizures, and hyperpyrexia; these symptoms are
largely non-specific, and can be caused by an
 THE PRESENT STATUS OF MONOAMINE OXIDASE INHIBITORS
overdose of either drug given alone. Emergency
treatment is to keep the patient cool and to give
chlorpromazine and anti-convulsants.
Marley & Wozniack (1983) have suggested, on
the basis of animal work, that 5-HT re-uptake
inhibitors should not be combined with MAOIs.
Certainly, clinicians would agree that a combina
tion of clomipramine and an MAO! is dangerous
(Beaumont, 1973). However, many patients have
been treated with amitriptyline and an MAOI
without untoward effects, perhaps because in
addition to 5-HT uptake inhibition, amitriptyline
also has a blocking action of post-synaptic 5-HT
receptors. (Ogren ci a!, 1979; Stolz & Marsden,
1982). Whether combining the antidepressants is
more effective in depression than giving the drugs
separately is still not proven. Many clinicians,
myself included, think that it is, but on the other
hand, the only two controlled trials have not shown
there to be any advantage. In a double-blind trial
involving 71 patients, Razani eta! (1983) compared
amitriptyline up to 300 mg a day, tranylcypromine
up to 40mg a day, and a combination of the two but
in half these doses. All groups had improvement
rates of about 75%, and it is very difficult to show an
added improvement at that level. The other trial
compared trimipramine, phenelzine, and
isocarboxazid in average doses of 100 mg, 45 mg,
and 30 mg a day respectively with combinations of
the MAO! and trimipramine in similar dosage, in
135 out-patients (Young ci a!, 1979). The patients
on trimipramine alone showed a significantly
greater improvement than any of the other groups,
but doses of MAO!s as low as this frequently give
negative results.
There may, however, be an advantage in combin
ing a drug such as amitriptyline with an MAO!;
amitriptyline, because of its action in inhibiting the
uptake of tyramine into noradrenergic storage sites,
might afford some protection from an inadvertent
ingestion of cheese. We investigated this hypothe
sis, giving increasing doses of tyramine intrave
nously until a dose was reached which produced a
rise in systolic blood pressure of 30 mm Hg (Pare ci
a!, 1982). Depressed patients on no medication
require 2 to 3 mg of tyramine; as expected, patients
on an MAO! are very much more sensitive, and the
blood pressure rises 30 points with a tenth of the
dose. Amitriptyline, however, does seem to inhibit
this reaction, and in patients on a combination of an
MAO! and amitriptyline, the response to intrave
nous tyramine is normal. However, these intrave
nous studies involved only 2 to 3 mg of tyramine,
and investigations giving it orally, where the doses
are much larger are less convincing: between 200
581
and 400 mg of oral tyramine is normally required to
produce a rise of systolic blood pressure of 30 mm
Hg. In normal subjects who received 20 mg of
tranylcypromine for eight days, a 30 mm rise of
systolic blood pressure was obtained with a mean of
15 mg of tyramine (range 7.5—30mg) (Bieck ci a!,
1982). In a recent (unpublished) study we found
that in ten patients receiving a combination of an
MAO! and a tricyclic antidepressant, the response
was very variable. Five of the patients required 50-@
100 mg of tyramine to produce a rise in systolic
blood pressure of 30mm Hg, and could therefore be
considered to have gained considerable protection
from a cheese reaction. Two patients, however,
developed a blood pressure rise with as little as 15
mg of tyramine, and were obviously susceptible to
an inadvertent ingestion of a tyramine-rich meal.
New generation of MAOIs
The new generation of MAO!s stemmed from the
finding of Johnston in 1968 that MAO could be
divided into two types, MAO-A and MAO-B, by
their activity on different substrates. MAO in the
lining of the gut is predominantly of the A type,
while platelet MAO is of the B type. Clorgyline is a
specific inhibitor of MAO-A and Murphy (Lipper ci
a! 1979; Murphy ci a!, 1981, 1983) compared this
drug in a clinical trial against pargyline, which is an
inhibitor of MAO-B. This trial showed a clear
superiority in favour of clorgyline, and this was
associated with a marked effect on noradrenaline
metabolism, as shown by the fall of 3-methoxy-4-
hydroxyphenyl glycol (MHPG) in the plasma and
cerebrospinal fluid. There was much less change in
5-HIAA. Murphy argued that his results pointed to
MAO-A rather than MAO-B inhibition as being
the antidepressant factor, and that this might be
because of the effect on noradrenaline metabolism.
Scientifically, this is very interesting and has
probably led to the development of the new
reversible MAO-A inhibitors. Clinically, however,
clorgyline itself does not seem to possess any
advantages over the standard MAOIs in present use
and, in particular, orthostatic hypotension and
cheese reactions are just as likely.
Deprenyl is a specific inhibitor of MAO-B. It
does not result in hypertension when tyramine is
given and, provided the dose is not so large that its
specificity for MAO-B is lost, patients may eat
cheese; furthermore, there is no postural hypoten
sion and the other side-effects seen with standard
MAOIs are absent. Care must be taken, however, if
deprenyl is given to a patient already on a standard
MAO!, as severe postural hypotension may then
occur (Pare ci a!, 1982). The question is, does it
582
have an antidepressant effect? Open studies have
been encouraging (Mendis eta!, 1981b; Mann eta!,
1982), but only three placebo-controlled studies
have been carried out. Mendis et a! (1981a,b)
compared deprenyl to placebo in 22 out-patients in
a dose of 10 mg for one week, followed by 20mg for
three weeks. Virtually complete inhibition of
platelet MAO was obtained, but no antidepressant
effect was shown. Mendlewicz & Youdim (1983),
however, in a 40-day trial of 27 depressed in
patients, using a similar dose of 5 mg three times a
day, demonstrated a striking antidepressant effect
compared to placebo. The study by Aarons et a!
(1984) differs in that both a low-dose (10-15 mg a
day) and high-dose (20-50 mg a day) schedule were
used in a study of 36 depressed patients. The
response rate of 30% to low-dose deprenyl was only
a little higher than that to placebo (20%). With the
higher dose, when MAO-A might well be inhibited,
a 50% response rate was achieved. A similar
opinion, that patients only respond when doses of
30-50 mg a day are given, has also been formed by
C. M. B. PARE
Klein (personal communication). In an open study
of 150 unipolar depressed patients, Birkmayer eta!
(1984) claimed that almost 70% became symptom
free within three weeks, when deprenyl in a dose of
5-10 mg daily was combined with phenylalanine,
250 mg a day. Obviously, this drug deserves much
more study as, apart from its academic interest, it
could be a very useful antidepressant for the
clinician because of its freedom from causing
orthostatic hypotension or the cheese effect.
Finally, there are a range of MAO-A inhibitors at
present being developed by various companies, and
already approaching the stage of clinical trials.
These are all reversible inhibitors, and the aim is to
produce a drug which has the antidepressant effect
of the MAO-A inhibitor clorgyline, but with a
reduced tendency to cause the cheese effect.
Obviously, until a series of clinical trials are com
pleted, we will not know whether they have a good
antidepressant effect. However at least one of them
appears to have a reduced tendency to produce a
tyramine-induced hypotension (Bieck eta!, 1982).

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C. M. B. Pare, MD.FRCP.
FRCPsych.
Consuhani Psychiatrist, Si. Barihomcw's Hospita!, West Smithfic!d,
London ECJA 7BE

(Accepted 20 December 1984)