DRUG EXPERIE CE

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Drug Safety 10 (I): 18-46. 1994

0114-5916194/0001-0018/$14.5010
© Adis International Limited. AU rights reserved.

Comparative Tolerability Profiles of the Newer versus

Older Antidepressants
Matthew V. Rudorfer, Husseini K. Manji and William Z. Potter
Section on Clinical Pharmacology, Experimental Therapeutics Branch, Intramural Research Program,
and Clinical Treatment Research Branch, Division of Clinical and Treatment Research, National
Institutes of Health, National Institute of Mental Health, Bethesda, Maryland, USA

Contents
8 Summary
19 1. Classical Tricyclic Antidepressants
20 1.1 Cardiovascular Effects
21 1.2 Anticholinergic Effects
23 1.3 Sedation
23 1.4 Weight Gain
23 1.5 Drug-Drug Interactions
24 1.6 Overdose Toxicity
24 1.7 Other Central Nervous System Toxicity
24 2. New-Generation Antidepressants
26 2.1 Selective Serotonin Reuptake Inhibitors
34 2.2 Amfebutamone (Bupropion)
37 3. Monoamine Oxidase (MAO) Inhibitors
37 3.1 Classical MAO Inhibitors
38 3.2 Comparative Tolerability of Newer MAO Inhibitors
38 3.3 Selective MAO-B Inhibition: Selegiline
39 3.4 Reversible Inhibition of MAO-A: Moclobemide and Others
40 4. Conclusions

Summary Although the standard tricyclic antidepressants (TCAs) are generally effective in the treatment
of depression, they can cause several troublesome adverse effects. Chief among these are their
anticholinergic actions, which range from annoying dryness of the mouth and constipation to
potentially dangerous urinary retention and confusion or delirium in the ill and elderly. Cardio-
vascular effects of TCAs include orthostatic hypotension, tachycardia and cardiac conduction
slowing. Many TCAs are sedating and promote weight gain. Also problematic is the potential
lethality of TCAs in overdose. The continual introduction of a host of new antidepressants over
the past 15 years has provided an opportunity to improve the benefit-risk ratio for many patients
by reducing medication-related toxicity. Selective serotonin reuptake inhibitors (SSRIs) and
amfebutamone (bupropion), among others, are examples of effective antidepressants free of tri-
cyclic-like anticholinergic, cardiovascular, sedating and appetite/weight-increasing effects. How-
ever, the new-generation drugs also present adverse effects of their own, including gastrointestinal
distress, agitation and drug-drug interactions in the case of the SSRIs, and the risk of seizures or
psychosis in amfebutamone recipients. Monoamine oxidase (MAO) inhibitors have also been
Newer versus Older Antidepressants
refined; reversible inhibitors of MAO-type A afford protection against the usually feared hyper-
tensive reaction to indirect sympathomimetic substances. The availability of new-generation an-
tidepressants thus increases the likelihood of clinical response with a reduction in unwanted
toxicity.
Depression is one of the most common and also
most treatable mental disorders in both psychiatric
and general healthcare settings (Eisenberg 1992).
Available antidepressant medication options have
multiplied over the past decade and a half, consti-
tuting a now aging - but ever expanding - new
generation of pharmacotherapies which co-exist
with, and in some cases eclipse, the original group
of tricyclic antidepressants (TCAs) and mono-
amine oxidase (MAO) inhibitors which date back
to the 1950s (Rudorfer & Potter 1989).
For the treatment of major depression as broadly
defined, all antidepressants, old and new, are con-
sidered equally efficacious (Potter et al. 1991). In-
deed, given the recent trend for large-scale clinical
trials to target relatively mildly depressed outpa-
tients (e.g. Lineberry et al. 1990), it is not clear that
all new-generation antidepressants, e.g. trazodone,
are actually comparable to the original 'gold stand-
ard' TCAs in efficacy in severely ill depressed in-
patients (Rudorfer et al. 1984). On the other hand,
a recent report from the US Epidemiologic Catch-
ment Area study (Johnson et al. 1992) documents
the degree of morbidity and extent of health ser-
vices utilisation which result not just from diagnos-
able clinical depressive illness but also from the
much more prevalent depressive symptoms which
fall short of frank disorders. The large outpatient
population identified by this study has proven to be
a major market for some of the newer antidepres-
sants, often as treatment of first choice (Potter et
al. 1991).
In major depression, the greater impact of the
newer antidepressants has been in reducing the de-
nominator of the benefit-risk ratio for some pa-
tients. The older medications, while quite effective,
are not very well tolerated in many patients.
Clearly, some individuals are more vulnerable
to adverse effects than others. Thus, outpatients re-
port more adverse effects with antidepressants than
19
inpatients (Nierenberg & Cole 1991), and panic
disorder patients more so than those with depres-
sion. The elderly constitute a particularly high-risk
group, due to both physiological changes and the
frequent co-occurrence of physical and mental ill-
ness, necessitating multiple, potentially interact-
ing, medications (Rudorfer 1993).
Adverse effects were implicated in the reported
25 to 50% rate of treatment noncompliance among
psychiatric outpatients (Blackwell 1976). This is a
particular problem for medications such as the an-
tidepressants with a several-week lag time to ther-
apeutic efficacy. A large British survey of family
practices (Johnson 1981) revealed that 68% of pa-
tients at 29 days, and 57% of treatment non-
responders at 6 weeks, defaulted from antidepres-
sant medication (generally TCAs); unpleasant
anticholinergic effects constituted the most com-
monly cited reason for noncompliance.
In comparing the tolerability of older with
newer antidepressants, we will first review the
standard TCAs. Then we will survey a sample of
new-generation medications, highlighting issues
of current concern and investigation. Separately,
we will consider the recent progress in overcoming
the legacy of feared toxicity during MAO inhibitor
therapy.
1. Classical Tricyclic Antidepressants
Nearly 40 years after the introduction of imip-
ramine, the TCAs remain the first-line standard of
care for the pharmacotherapy of severe major de-
pression throughout the world. Advances in poten-
tiation strategies over the past decade, such as the
addition of lithium or thyroid hormone, have
halved the usual 20 to 30% nonresponse rate to
TCAs (Potter et al. 1991), thereby lessening the
absolute need for an alternative antidepressant.
Nevertheless, a host of potential and often ex-
pected adverse effects, ranging in severity from an-
20
noying to life threatening, limit the overall clinical
applicability of the TCAs (Nierenberg & Cole
1991).
An appreciation of the scope of the problem can
be gained from an understanding of the myriad of
biochemical effects associated with use of tricyclic
compounds (table I). These medications are con-
sidered pharmacologically 'dirty drugs', as in ad-
dition to their desired action, i.e. inhibition of
monoamine neurotransmitter uptake, they bind to
other receptors in brain and periphery (table I),
with consequent unwanted actions.
As indicated in table II, there are distinctions
among the TCAs in the frequency and severity of
adverse effects. Thus, as predicted from the variety
of greater receptor affinities among the tertiary
amine TCAs (table I), in general they show more
pronounced anticholinergic, antihistaminic (Hl
and H2), sedative and hypotensive actions than
their secondary amine counterparts. Other distinc-
tions among these compounds are noted in the fol-
lowing survey of TCA adverse effects.
1.1 Cardiovascular Effects
Most common (and benign) in this category is
a rise in heart rate, often about 15 to 20 beats per
minute. While generally ascribed to vagal inhibi-
tion, in the case of the secondary amine TCAs, such
as desipramine, noradrenaline (norepinephrine)
reuptake blockade also plays a role (Ross et al.
1983).
0.1- Adrenergic blockade appears responsible for
TCA-induced orthostatic hypotension, which may
be associated only with transient benign dizziness
on standing in young, physically healthy patients
but with falls and injury in older individuals (Ray
1992). Nortriptyline appears to be associated with
a lower incidence of orthostatic hypotension than
other TCAs, presumably resulting from a combin-
ation of relatively lower potency at al-receptors
and therapeutic effects at low blood concen-
trations.
Potentially the most dangerous TCA cardiac ef-
fect is a quinidine-like membrane stabilisation
which results in slowed impulse conduction. While
this results in innocuous prolongation of electro-
Drug Safety 10 (1) 1994
cardiogram (ECG) parameters during routine TCA
administration in physically healthy individuals
(Laird et al. 1993; Rudorfer & Young 1980a), and
can suppress pre-existing premature atrial or ven-
tricular contractions, it may precipitate frank bun-
dle-branch or complete heart block in cardiac pa-
tients (Glassman et al. 1987), with consequent
morbidity or mortality.
This property may relate to cases of sudden
death in patients taking therapeutic doses ofTCAs,
most recently reported in several children receiv-
ing desipramine (Tingelstad 1991). Widening of
the QRS complex on the ECG, correlated with
postoverdose red blood cell concentrations of tri-
cyclic demethyl-metabolites (Amitai et al. 1993),
has become a standard index of serious TCA poi-
soning, especially in overdose situations (Jarvis
1991). Preskorn and Fast (1991) have speculated
that the association of serious cardiac conduction
slowing with TCA plasma concentrations higher
than the therapeutic range may explain some cases
of sudden death during TCA therapy in presumed
slow metabolisers of these drugs.
Recent data have raised concerns that the risk of
sudden death during TCA treatment in patients
with ventricular arrhythmias or ischaemic heart
disease may be greater than previously appreciated
(Glassman et al. 1993). Impaired left ventricular
function during TCA treatment may have been
overestimated in the past (Glassman et al. 1987)
but is reported occasionally in patients with severe
underlying heart disease (Dalack et al. 1991).
Seeking to resolve a poorly founded belief in the
relatively greater cardiac safety of doxepin, Roose
and associates (1991b) demonstrated the usual
TCA adverse effects, and consequent poor toler-
ability, of doxepin in cardiac patients suffering
from depression. Likewise, the structurally similar
dothiepin, despite negligible cardiovascular ef-
fects in some trials, is quite capable of inducing
ECG abnormalities and reduced myocardial con-
tractility in some patients comparable to that of
reference tertiary amine TCAs (Lancaster & Gon-
zalez 1989b). Dothiepin overdose is as lethal as
that of amitriptyline (Leonard 1992). Only the
Newer versus Older Antidepressants 21

most recently developed TeA, lofepramine
(Kerihuel & Dreyfuss 1991; Lancaster & Gonzalez
1989a), offers a profile of cardiovascular effects
and overdose toxicity which in early reports ap-
pears as benign as those of the newer non-TeAs
reviewed below (table II). Such claims, however,
must be reconciled with the extensive metabolism
of lofepramine to desipramine.
1.2 Anticholinergic Effects
As with some cardiac effects, antimuscarinic
actions of TeAs are ubiquitous, presenting minor
annoyances to most young, otherwise healthy pa-
tients but posing major hazards to some others.
Even the commonly-experienced dry mouth has
been associated with serious dental pathology. Re-
duced tear flow and impaired visual accommoda-
tion, with resultant blurred vision, may impair
daily function and be a hazard to contact lens
wearers (reviewed by Nierenberg & Cole 1991).
Constipation may be a minor discomfort, being
responsive to increased fluid intake and bulk: laxa-
tives, or could progress to life threatening paralytic
ileus in medically vulnerable patients. A similar

Table I. In vitro short term biochemical activity of selected older and newer antidepressant drugs. Adapted from Potter et al. (1991) and
Pirmohamed et al. (1992), plus data from Richelson & Nelson (1984) and Lancaster & Gonzalez (1989a,b)
Drug Reuptake inhibition Receptor affinity
NA 5-HT D III IX2 Hl MUse D2
Older drugsa
Amitriptyline ± +t 0 +++ ± +t+t +t+t 0
Clomipramine ± +++ 0 +t 0 + +t +t

Desipramine +++ 0 0 + 0 ± + 0
Dothiepin ± ± 0 ± 0 +++ +++ 0
Doxepin +t + 0 +++ 0 +t+t +t 0
Imipramine + + 0 +t 0 + +t 0
Nortriptyline +t ± 0 +t 0 + +t 0
Trimipramine + 0 0 +++ ± +t+t +t +t

Newer drugs
Amfebutamone (bupropion) ± 0 +t 0 0 0 0 0
Amoxapine +t 0 0 +t 0 + 0 +t

Citalopram 0 +++ 0 0 0 0 0 0
Fluoxetineb 0 +++ 0 0 0 0 0 0
Fluvoxamine 0 +++ 0 0 0 0 0 0
Lofepramine +++ 0 0 + 0 + +t

Maprotiline +t 0 0 +t 0 +++ + +
Mianserin 0 0 0 +++ +t +t+t 0 0
Paroxetineb 0 +t+t 0 0 0 0 ± 0
Sertralineb 0 +++ 0 0 0 0 0 0
Trazodone 0 + 0 +++ ± ± 0 0
a Tricyclic antidepressants.
b Selective serotonin selective reuptake inhibitors.
Abbreviations and symbols: NA = noradrenaline (norepinephrine); 5-HT = 5-hydroxytryptamine (serotonin); D = dopamine; III =
ill-adrenergiC receptor; 1X2= lX2-adrenergic receptor; Hl = Hl histamine receptor; MUse = muscarinic (cholinergic) receptor; 02= D2dopamine
receptor; 0 = no effect; ± = equivocal effect; + = small effect; +t = moderate effect; +++ = large effect; +t+t = maximal effect.
22 Drug Safety 10 (1) 1994

spectrum exists for urinary retention, a major
risk of TCA use in older men with prostatic hyper-
trophy.
Narrow-angle glaucoma may constitute a con-
traindication to the use of medications with any
anticholinergic effects.
Cognitive toxicity of TCAs, ranging from con-
fusion and memory impairment to frank delirium,
is a serious risk of tricyclic use in the elderly. AI-
though some cases of TCA-related sexual dysfunc-
tion have been ascribed to anticholinergic effects,
such a correlation was not observed in a recent sur-
vey (Balon et al. 1993). Indeed, sexual dysfunction
has emerged as a more prominent adverse effect
associated with the use of selective serotonin (5-
hydroxytryptamine; 5-HT) reuptake inhibitors

Table II. Adverse effects of antidepressant drugs (adapted from Potter et al. 1991)
Drug Sedation Insomnia Anticholinergic Orthostatic Delay in cardiac Sexual Nausea
effects hypotenSion conduction or arrhythmia dysfunction
Older drugsa
Amitriptyline +++ 0 +++ +++ Yes 0 0
Clomipramine ++ 0 +++ ++ Yes ++ ++
Desipramine + + + + Yes 0 0
Dothiepin ++ 0 ++ ++ Yes 0 0
Doxepin +++ 0 ++ +++ Yes 0 0
Imipramine ++ 0 ++ ++ Yes 0 0
Nortriptyline ++ 0 + + Yes 0 0
Protryptyline + ++ ++ + Yes 0 0
Trimipramine +++ 0 +++ ++ Yes 0 0
Monoamine oxidase inhibitors
lsocarboxazid 0 ++ 0 ++ Very rare + 0
Moclobemide 0 + 0 + Very rare 0(+) 0
Phenelzine + + 0 +++ Very rare ++ 0
Tranylcypromine 0 ++ 0 +++ Very rare + +
Newer agents
Amfebutamone (buprop- 0 ++ 0 0 Rare 0 +
ion)
Amoxapine ++ 0 + ++ Rare 0 0
Citalopram 0 ++ 0 0 Rare ++ ++
Fluoxetineb 0 ++ 0 0 Rare ++ ++
Fluvoxamine 0 ++ 0 0 Rare ++ ++
Lofepramine ± ± ± + Rare 0 0
Maprotiline ++ 0 + ++ Yes 0 0
Mianserin +++ 0 0 0 Rare 0 0
Paroxetineb 0 ++ 0 0 Rare ++ ++
Sertralineb 0 ++ 0 0 Rare ++ ++
Trazodone +++(+) 0 0 ++ Low + +
a Tricyclic antidepressants.
b Selective serotonin reuptake inhibitors.
Symbols: 0 =no adverse effect; ± =equivocal effect; + =minor adverse effect; ++ =moderate adverse effect; +++ =major adverse effect.
Newer versus Older Antidepressants
(SSRIs), as well as the strongly serotonergic TCA,
clomipramine (Aizenberg et al. 1991) discussed
below.
Although correlations between TCA plasma
concentrations and anticholinergic effects have
been identified (Rudorfer & Young 1980b), these
adverse effects are maximal at subtherapeutic
plasma concentrations of tertiary amine forms
(Preskorn & Fast 1991), making dosage adjust-
ment an inefficient means of reducing them. While
cholinergic agents, such as bethanechol, are some-
times used in the treatment of peripheral anti-
muscarinic actions ofTCAs, most clinically signif-
icant problems require change of medication.
Thus, the tertiary amine TCAs may need to be
avoided, or used judiciously (Rahman et al. 1991),
in older patients. Symptomatic relief can be ob-
tained with use of artificial saliva or tears.
While desipramine has the lowest anticholiner-
gic activity among the classical TCAs, its potency
is still appreciable (Ross et al. 1983; Rudorfer &
Young 1980b). Lofepramine, which is extensively
metabolised to desipramine, also affords a mild an-
ticholinergic profile among the TCAs (tables I and
II) [Kerihuel & Dreyfus 1991; Lancaster & Gon-
zalez 1989a].
1.3 Sedation
Sedation reflects the antihistaminic and Ill-
blocking as well as anticholinergic activity of
TCAs, particularly the tertiary arnines (table I). It
is one of the few adverse effects that can be used
therapeutically in drug selection. Thus, the tertiary
amine TCAs are commonly given as a once-daily
night-time dose for sleep disturbance in insomniac
depressed patients (Potter et al. 1991). An inciden-
tal benefit of the antihistaminic activity of TCAs
has been antiallergic and antiulcer activity, which
have been credited particularly to doxepin. A high
degree of correlation between sedation and anti-
cholinergic actions is common to all antidepres-
sants except mianserin and trazodone.
23
1.4 Weight Gain
A negative consequence of the histamine and
possibly Ill-receptor blocking actions of TCAs, as
well as a still not well-understood TCA-induced
carbohydrate craving and slowing of metabolism,
is weight gain. This gain more than compensates
for any prior weight loss associated with depres-
sion-related anorexia.
In one survey of clinical practice (Berken et al.
1984), outpatients treated with amitriptyline (pos-
sibly the worst offender among TCAs) gained an
average of over 7kg (with craving for sweets) dur-
ing 6 months of treatment, in a dose-related fash-
ion, with subsequent loss of weight following drug
discontinuation. In that study, excessive weight
gain was the most common reason for termination
of treatment, which occurred in half the patients.
This effect varies among the TCAs (Fernstrom et
al. 1986) and is minimal or absent in the most stim-
ulatory representatives, e.g. protriptyline and desi-
pramine.
1.5 Drug-Drug Interactions
TCAs interact pharmacodynamically and/or
pharmacokinetically with a variety of other com-
pounds. The well-established adverse cognitive
and psychomotor consequences of combining ter-
tiary amine tricyclics with alcohol (Shoaf &
Linnoila 1991) are complemented by pharmacoki-
netic studies. As recently reviewed by Shoaf and
Linnoila (1991), TCA clearance is generally de-
creased by alcohol in the short term and increased
by long term alcohol use, unless cirrhotic liver
damage has occurred.
Most adverse TCA pharmacodynamic interac-
tions with other medications involve additive sed-
ative or anticholinergic effects, e.g. with hypnotics
or neuroleptics. The dependence of TCAs on he-
patic metabolism is the basis of pharmacokinetic
interactions with drugs which induce or impair the
liver cytochrome P450 microsomal enzyme system
(Rudorfer & Potter 1987). In some cases, plasma
drug concentration monitoring may be useful in
24
accounting for and correcting pharmacokinetic in-
teractions (Preskom & Fast 1991).
Apparently reversible abnormalities of liver
function tests have also been reported in associa-
tion with TCAs, most notably lofepramine (Lack
et al. 1990; Pirmohamed et al. 1992).
1.6 Overdose Toxicity
A major problem of TCAs is their potential le-
thality in overdose, an all-too-frequent occurrence
among the severely depressed, 15% of whom com-
mit suicide at some point in their illness. Even a
I-week supply of a TCA may be fatal if taken all
at once (Rudorfer & Robins 1982). As noted, the
primary toxicity of the TCAs is cardiovascular,
with hypotension and conduction blocks poten-
tially progressing to ventricular arrhythmias and
shock. Convulsions are also common in TCA over-
dose (Rudorfer & Robins 1982). Moreover, TCA
blood concentrations may remain elevated for sev-
eral days after overdose, presenting a cardiac risk
even after apparent clinical improvement (Jarvis
1991).
All TCAs are potentially lethal in overdose. A
decade ago, amitriptyline and dothiepin accounted
for 82% of single-drug TCA overdose fatalities in
the UK (Dorman 1985). More recent survey data
from the US and the UK (Kapur et al. 1992) suggest
a relatively higher rate of fatalities following over-
dose with desipramine compared with other TCAs.
Lofepramine, on the other hand, may have the low-
est lethality among the TCAs (Dorman 1985;
Henry & Martin 1987; Lancaster & Gonzalez
1989a).
While the new-generation antidepressants, with
the exception of maprotiline (Cassidy & Henry
1987; Montgomery 1992), are considerably safer
after overdose than the older drugs, combinations
with fluoxetine may actually increase the danger of
a TCA overdose by impairing metabolism of the
TCA and thus delaying its elimination (Jarvis
1991).
Drug Safety 10 (1) 1994
1.7 Other Central Nervous System Toxicity
The relatively low seizure rate (as low as 1 in
1000) during routine treatment with TCAs (Ayd
1993), although it has been as high as 0.3 to 0.6%
in some series (Rosenstein et al. 1993), is favour-
able compared with several of the newer com-
pounds discussed below. Preskom and Fast (1991)
note that a seizure might be the first sign of an
unexpected high plasma TCA concentration. VIrtu-
ally all effective antidepressants, old and new, have
been associated with switches into mania or hypo-
mania (Goodwin & Jamison 1990), a development
generally interpreted to indicate an underlying bi-
polar diathesis.
2. New-Generation Antidepressants
A number of the would-be replacements for the
TCAs which have appeared on the market over the
past 15 years have generated enough longitudinal
experience and data to allow for a more proper per-
spective on their therapeutic role (Rudorfer et al.
1984). Some, such as zimeldine and nomifensine,
the prototypical serotonin and dopamine reuptake
inhibitors, respectively, have been withdrawn due
to excessive, potentially fatal toxicity (Rudorfer &
Potter 1989). Others, including amoxapine and
maprotiline, have proved to have an adverse effect
profile no better than, and in some cases worse
than, reference TCAs (tables I and II; Blackwell
1981b). Both of these drugs are anticholinergic,
cardiotoxic and potentially lethal in overdose
(Rudorfer & Potter 1989). The neuroleptic proper-
ties of the 7 -hydroxy metabolite of amoxapine,
while therapeutic in psychotic depression (Anton
& Burch 1990), convey all the associated adverse
effects, from galactorrhoea to extrapyramidal
symptoms and even the risk of tardive dyskinesia.
The excessive incidence of seizures during
maprotiline treatment has resulted in a ceiling on
the recommended daily dose, similar to the situa-
tion with the more recently developed amfebut-
amone (bupropion) [see section 2.2]. As in the case
of arnfebutamone, the dose-dependent nature of
the major adverse effects of maprotiline has
Newer versus Older Antidepressants
prompted interest in the viability of a low-dose
paradigm, which did in fact prove useful in an
extremely large year-long maintenance study in
unipolar depression (Rouillon et al. 1991). The
higher of two maprotiline dosages was only 75
mg/day (one-third the maximum recommended),
providing protection against depressive relapse but
no more adverse effects than placebo.
Obviously, since such studies utilise set doses
instead of set blood concentrations, rapid metabo-
lisers of the drug are less likely to reach therapeutic
concentrations on a fixed low dose, and the overall
group response rate would be expected to be lower.
Trazodone, although unremarkable in terms of
antidepressant efficacy (Rudorfer & Potter 1989),
has achieved a special niche because of its unusual
combination of adverse effects (shared with
mianserin): strong sedation without anticholiner-
gic toxicity (tables I and II). Increasingly,
trazodone is used in combination with stimulatory
antidepressants, particularly MAO inhibitors and
SSRIs (see below) to combat medication-related
sleep disturbance (Jacobsen 1990; Nierenberg &
Keck 1989). Even low doses of trazodone, how-
ever, rarely can produce priapism (Thompson et al.
1990). In contrast, it has not been established that
mianserin can safely be combined with MAO in-
hibitors (Graham 1988).
Indeed, concerns about medical complications
have clouded the development of mianserin in the
US (Vinar et al. 1991) and have led to restrictions
in its use elsewhere (Coulter & Edwards 1990).
With its introduction in the 1970s, mianserin, a
tetracyclic compound with an apparently novel
<X2-, serotonin- and histamine receptor-blocking
mechanism of action (table I), was among the early
non-MAO inhibitor alternatives to TCAs. Initial
toxicity profiles of mianserin were favourable, as
the drug offered antidepressant efficacy without
tricyclic-like cardiotoxicity, and the newer agent
proved substantially safer in overdose (table II).
Deaths per million prescriptions of mianserin in
the UK, for example, are one-tenth those reported
for the reference TCAs, dothiepin and amitripty-
line (Leonard 1992).
25
In recent years, however, reports of hepato-
toxicity and especially of blood dyscrasias (a-
plastic anaemia, agranulocytosis) associated with
mianserin treatment have overshadowed therapeu-
tic considerations (Chaplin 1986). Epidemiologi-
cal surveys have yielded disparate rates of
mianserin-associated haematological toxicity. The
lack of cases of agranulocytosis in a UK survey of
general practitioners (Inman 1988) has been ques-
tioned with respect to possible underreporting
(Coulter & Edwards 1990). In contrast, as many as
1 in 1354 mianserin recipients in New Zealand
were reported to a national medication monitoring
programme as experiencing agranulocytosis
(Coulter & Edwards 1990). Dose and patient age
were associated risk factors, but of particular con-
cern was the fact that blood dyscrasias were most
commonly seen with usual therapeutic doses. De-
spite extensive clinical and preclinical investiga-
tion (Chaplin 1986; Lambert et al. 1989), the mech-
anism of mianserin-associated myelotoxicity
remains elusive. Nonetheless, mianserin remains
widely used in some locations, including the UK,
where it has assumed the status of a reference an-
tidepressant in clinical trials of SSRIs (Moon &
Jesinger 1991; Muijen et al. 1988). In such studies,
the common adverse effects of mianserin have
been weight gain and drowsiness, rather than more
dramatic and life-threatening blood dyscrasias.
The long term future of mianserin awaits more
definitive data to enable clinicians across settings
to assess accurately its potential benefit-risk ratio
for any given patient.
Another novel compound dating from the mid-
1970s, viloxazine, a short half-life antidepressant
with stimulant properties (Pisani et al. 1986), has
achieved much less acceptance in Europe and the
UK than mianserin. Neither compound is commer-
cially available in the US. Despite a profile of re-
duced anticholinergic and cardiovascular adverse
effects (Corona et al. 1987) compared with TCAs
the use of viloxazine is complicated by the frequent
occurrence of gastrointestinal adverse effects, in-
cluding nausea and vomiting. Moreover, although
the stimulant action of viloxazine has suggested a
26
possible role in the treatment of narcolepsy (Mitler
et al. 1990), the performance of this atypical anti-
depressant in studies of primary depression has
been uneven (reviewed by Corona et al. 1987).
However, a dearth of potential drug-drug interac-
tions with viloxazine and the smaller effect of this
medication on seizure threshold compared with
TCAs [though not SSRIs (Ayd 1993, Edwards &
Glen-Bott 1984)] offer two potential targeted in-
dications for viloxazine: the treatment of second-
ary depression associated with alcohol dependence
(Altamura et al. 1990) and, combined with anticon-
vulsants, in the treatment of depressed patients
with concurrent seizure disorders (Pisani et al.
1986). Further controlled trials are necessary to de-
fine the optimal role of viloxazine in the treatment
hierarchy across the depressive spectrum.
2.1 Selective Serotonin Reuptake Inhibitors
2.1.1 General Considerations
As is evident from the representative SSRIs
listed in tables I and II, these compounds lack af-
finity for the various receptors implicated in TCA-
induced adverse effects. Thus, as a group, these
more selective agents are much better tolerated
(Danish University Antidepressant Group 1990).
Fortunately, the hypersensitivity syndrome seen
with zimeldine is not specific to serotonin reuptake
and does not recur on challenge with newer drugs
of this class (Bengtsson et al. 1991).
The SSRls lack TCA-like anticholinergic, car-
diovascular, sedative and weight-increasing prop-
erties, as well as lethality in overdose. However, in
at least a quarter of patients, different adverse ef-
fects during routine use are seen, including head-
ache, gastrointestinal disturbances, anxiety or agi-
tation, and impaired sexual function (Boyer &
Feighner 1991; Rudorfer & Potter 1989).
In large double-blind trials comparing fluoxet-
ine with TCAs (Fabre et al. 1991; Nielsen et al.
1993), the major adverse effects were gastrointes-
tinal (nausea, diarrhoea) and anticholinergic (dry
mouth), respectively. Similar findings have been
reported for the newer SSRls. Thus, sertraline re-
cipients experienced more gastrointestinal com-
Drug Safety 10 (1) 1994
plaints and male sexual dysfunction (Guthrie
1991) than groups receiving placebo or the refer-
ence TCA, amitriptyline (Reimherr et al. 1990); the
latter patients experienced more anticholinergic ef-
fects, sedation and dizziness. Older depressive pa-
tients likewise reported more nausea and headache
on paroxetine, versus more anticholinergic effects,
sedation and confusion on doxepin (Dunner et al.
1992). TCA-associated adverse effects cause more
premature treatment termination than do those
caused by SSRls (Boyer & Feighner 1991; Dunbar
et al. 1991).
2.1.2 Comparison Among Selective
Serotonin Reuptake Inhibitors
Compared with TCAs, the SSRls represent a
more biochemically and clinically homogeneous
group of compounds (tables I and II). With their
continued availability and clinical use around the
world, distinctions among these agents are emerg-
ing.
Preclinically, the SSRls differ in potency and
selectivity of serotonin reuptake inhibition
(paroxetine > citalopram > sertraline > fluvoxam-
ine > fluoxetine) and in the capacity to down-reg-
ulate post-synaptic cortical ~-receptors in a rat
model (demonstrated by fluoxetine, sertraline and
fluvoxamine, but not by citalopram or paroxetine)
[reviewed by Milne & Goa 1991; Leonard 1992].
Any clinical implications of these neuropharmaco-
logical variables remain unknown. Burton (1991)
has noted that although there are differences in re-
ceptor binding activity among these drugs, e.g.
greater 5-HT2 binding for fluoxetine and (X2 bind-
ing for sertraline, these variations are modest and
probably inconsequential (table I). Differences
among SSRls in neuropsychological testing are
small (Kerr et al. 1991), with an alerting effect of
sertraline and paroxetine, as well as the now-dis-
continued zimeldine, identifiable by increased crit-
ical flicker fusion thresholds.
In contrast, pharrnacokinetic differences among
the SSRls are proving more significant and clinic-
ally relevant (De Vane 1992). Two such parameters
are the presence of active metabolites (observed for
fluoxetine alone among SSRls in current use) and
Newer versus Older Antidepressants
Table III. Comparative properties of selective serotonin reuptake inhibitors
SSRI Active metabolite
Fluoxetine Norfluoxetine
Sertraline None
Paroxetine None
Fluvoxamine None
Citalopram None
Zimeldine Norzimeldine
Symbols: 0 = no effect; + = mild effect; ++ = moderate effect; +++ =severe effect; ++++ =maximal effect; (?)
elimination half-life (tYz). The latter parameter is
doubly relevant for fluoxetine, which itself has a
long Viz and a considerably longer one for its active
metabolite (table III).
These features contribute to the potential toxic-
ity of fluoxetine by promoting drug accumulation
with daily administration and increasing the likeli-
hood of drug-drug interactions; for instance, the
washout time necessary after the discontinuation
of fluoxetine before the 'safe' introduction of an
MAO inhibitor (at least 5 weeks) is more than
twice that required for other SSRls (2 weeks).
These issues are discussed in detail below, along
with the implications of inhibition of drug-metabo-
lising hepatic oxidising enzymes by fluoxetine, re-
sulting in a number of drug-drug interactions.
While experience thus far reflects a lesser inci-
dence of such interactions with other SSRls (table
III), data continue to accrue regarding all relevant
hepatic enzyme systems (e.g. that mediating ben-
zodiazepine metabolism). Furthermore, a growing
anecdotal literature suggests the need to investi-
gate a possibly increased propensity for drug-drug
interactions involving fluvoxamine (see below).
However, genetic polymorphism, resulting in slow
and rapid hydroxylators, has not been seen in
patients taking fluvoxamine, while it has for
fluoxetine and paroxetine (reviewed by Leonard
1992).
Other pharmacokinetic differences among the
SSRls, such as a lesser binding to plasma proteins
for citalopram (50%) or fluvoxamine (77%) com-
pared to over 90% for other SSRIs (and TeAs)
27
Elimination half· life Inhibition of hepatic oxidising enzymes
1-3 days (parent drug) ++++
1-3 weeks (metabolite)
26 hours +(?)
24 hours ++(?)
15 hours +++
33 hours 0
8 hours (parent drug) 0
31 hours (metabolite)
=inconclusive.
[Leonard 1992; Milne & Goa 1991; Rudorfer &
Potter 1989], are of uncertain clinical significance.
Drug secretion in breast milk, of great clinical rel-
evance for nursing mothers, appears to be signifi-
cant for paroxetine, but not for fluoxetine or
fluvoxamine (Leonard 1992).
As with the TeAs, all of the SSRIs used clini-
cally are considered of equal therapeutic efficacy.
Furthermore, drugs from these two classes (imip-
ramine versus zimeldine, citalopram, or fluvoxam-
ine) proved equally efficacious during a 6-week
trial in a meta-analysis performed by Bech and as-
sociates (1990). Recent comparative studies have
raised methodological issues important in the in-
terpretation of these findings. Kasper et al. (1992)
have noted that most SSRI trials have been con-
ducted only in outpatients; these authors cite
fluvoxamine as an exception to that limitation. In
addition, when paroxetine was compared with the
TeA, clomipramine, in a 1990 Danish collabor-
ative study of severely depressed inpatients, the
superior tolerability of the SSRI was offset by the
greater efficacy of the TeA.
More recently, at multiple centres in Belgium, a
direct outpatient double-blind comparison of
fluoxetine and paroxetine demonstrated no dif-
ference in efficacy at the conclusion of a 6-week
trial, with a faster onset of antidepressant and anti-
anxiety action, and a lower rate of the common
gastrointestinal adverse effects (nausea and vomit-
ing) in the paroxetine group (DeWilde et al. 1993).
Both of these findings are consistent with the phar-
macokinetic factors noted previously. The long
28
elimination tI/2 of fluoxetine and its active metabo-
lite delay attainment of steady-state plasma con-
centrations and thus, potentially, therapeutic re-
sponse compared with the other SSRIs. Moreover,
nearly all the patients in the fluoxetine group re-
ported by DeWilde and associates (1993) received
at least 40 mg/day in 2 daily doses, a regimen likely
to have been supratherapeutic or even toxic in
some patients (Rudorfer & Potter 1989), exacer-
bating adverse effects.
In that regard, Kasper et al. (1992) have com-
mented that the incidence of SSRI-associated nau-
sea is increased by the use of high doses early in
the course of treatment. Thus, it will be important
to incorporate the pharmacokinetic differences
among SSRIs (van Harten 1993) in future compar-
ative trials to assess accurately their relative effi-
cacy and tolerability.
A provocative interpretation of the cumulative
efficacy and tolerability data on the SSRIs emerged
from a recent meta-analysis of controlled SSRI and
TCAclinical trials by Song et al. (1993). This sur-
vey, complicated by a wide range of methodologies
in mostly outpatient studies, confirmed the re-
peated finding of equivalent efficacy for both
classes of antidepressants. However, the only
slight advantage of the newer medications in terms
of adverse effects, coupled with their higher acqui-
sition cost, led the authors to question the routine
use of SSRIs as the first-line treatment of depres-
sion.
No pharmacokinetic interaction has been de-
scribed between SSRIs and alcohol (Shoaf &
Linnoila 1991). Moreover, these newer antidepres-
sants, in contrast to TCAs, do not potentiate the
psychomotor performance impairment caused by
alcohol (Weingartner et al. 1983). The lack of in-
teraction with alcohol has now been demonstrated
for several SSRIs, including sertraline (Gill et al.
1988), fluvoxamine (Linnoila et al. 1993) and
paroxetine (de Jonghe & Swinkels 1992; McClel-
land & Raptopoulos 1985). Indeed, preliminary
data suggest a role for SSRIs in reducing excessive
alcohol use (Lawrin et al. 1986; Milne & Goa
1991; Naranjo et al. 1992).
Drug Safety 10 (1) 1994
While reduction in appetite and mild weight
loss commonly accompany treatment with these
compounds, apparent tolerance to this effect has
blunted interest in their use for sole treatment of
obesity (Rudorfer & Potter 1989): a synergistic ef-
fect with behaviour modification was demon-
strated for fluoxetine in one placebo-controlled
trial (Marcus et al. 1990).
Pending systematic studies, it is anticipated that
the newer SSRIs, including sertraline and paroxet-
ine, will show lesser degrees of pharmacokinetic
drug-drug interactions than fluoxetine, given the
shorter half-lives (about 1 day) of the first 2 drugs,
and lack of strongly active metabolites (see below).
However, all SSRIs appear to inhibit P450 en-
zymes and thus concomitant TCAs or other
hepatically metabolised drugs should be adminis-
tered cautiously and, if possible, with plasma con-
centration monitoring. Evidence to date indicates
a similar pattern of adverse effects among this cat-
egory of drugs (Dunbar et al. 1991), including an
alerting effect (Keck et al. 1991b), which Kupfer
et al. (1991) speaking of fluvoxamine have de-
scribed as 'not just a lack of sedation, but a level
of increased wakefulness' .
Another interaction of note is that between
fluoxetine and electroconvulsive therapy (ECT).
Although concern had been raised that this antide-
pressant would prolong seizure duration during
ECT, the largest series reported, albeit retrospec-
tive, did not find this to occur (Gutierrez-Esteinou
& Pope 1989). Case reports have been mixed (Car-
acci & Decina 1991; Kellner et al. 1991). Single
doses of fluoxetine did not affect ECT seizure du-
ration in a recent prospective series (Zis 1992).
Other SSRIs, especially fluvoxamine, have also
demonstrated little effect on seizure threshold. In
contrast, seizure diathesis may be a major limita-
tion to use of an otherwise promising novel antide-
pressant, amfebutamone, which will be reviewed
below.
2.1.3 Fluoxetine
The worldwide popularity of this compound,
hailed as a breakthrough treatment for depression
on news magazine covers, helped the transition of
Newer versus Older Antidepressants
first-line antidepressant therapy from the TCAs to
the SSRIs by the late 1980s (Rudorfer & Potter
1989). Within a decade fluoxetine had achieved the
status of a reference drug against which newer
SSRIs are compared (DeWilde et al. 1993).
Fluoxetine is associated with a variety of ad-
verse effects, including gastrointestinal distur-
bances and agitation noted above. Many of the
more common adverse effects of fluoxetine, in-
cluding activation (Beasley et al. 1992b), appear
early in treatment at low doses, and thus cannot be
ameliorated by dosage reduction, although some
abate with continued treatment. Sedation, how-
ever, may persist (Beasley et al. 1992b). In most
trials to date, patients with anxiety disorders toler-
ate fluoxetine as well as those with depression (Van
Ameringen et al. 1993). Allergic skin reactions to
fluoxetine have been treated successfully with a
desensitisation paradigm (Leznoff et al. 1992).
A major controversy emerged following reports
of intense suicidal ideation and actions during
fluoxetine treatment in a group of 6 outpatients
(Teicher et al. 1990). No conclusive cause-and-ef-
fect relationship has been shown (Fava &
Rosenbaum 1991). However, a reanalysis of the
latter data (Mann & Kapur 1991), which were de-
rived from naturalistic survey information, did
show a higher rate of new-onset suicidality in pa-
tients treated with fluoxetine (alone or in combina-
tion with TCAs) compared with other antidepres-
sants. Meta-analysis of controlled trials by the
manufacturer (Beasley et al. 1991, 1992a), how-
ever, has shown no emergent or worsening suicidal
ideation in fluoxetine-treated depressed or obses-
sive-compulsive disorder patients compared with
those receiving placebo or TCAs. Similar negative
findings have been reported for other SSRIs (re-
viewed by Montgomery 1992).
Concern remains that fluoxetine-related akathi-
sia [perhaps related to an indirect antidopamin-
ergic action (Lipinski et al. 1989) or to serotonin
toxicity (Power & Cowen 1992)] might intensify
nonresponding depressive feelings (Hamilton &
Opler 1992; Rothschild & Locke 1991; Wirshing
et al. 1992). Questions also have been raised that
29
the multiple diagnoses and polypharmacy evi-
denced in most of the cases of Teicher et al. (1990)
may have contributed to the untoward outcomes.
Recent epidemiological data related to antide-
pressant poisoning (Kapur et al. 1992) have shown,
in addition to the low lethality of SSRI overdose
(Boyer & Blumhardt 1992; Boyer & Feighner
1991), that the risk of this means of suicide attempt
was no higher with fluoxetine than with other an-
tidepressants. An important lesson of the SSRIIsui-
cide experience, both the Teicher et al. (1990) and
follow-up data as well as the overdose literature
(Kincaid et al. 1990; Lebegue 1990), is that no
medication is prescribed in a vacuum. Careful ad-
ministration, with close monitoring and follow-up
of patients, is an essential part of the pharmacother-
apy of depression and related illnesses (Potter et al.
1991; Power & Cowen 1992).
Only after the SSRIs were in use for some time
did the nature and extent of interactions with other
drugs become apparent. Again, this has predomi-
nantly involved fluoxetine, which has now been
demonstrated to inhibit competitively the hepatic
metabolism of a variety of other drugs (Ciraulo &
Shader 1990a,b).
Pharmacodynamic Interactions
The serotonergic action of fluoxetine appears
responsible for most of its pharmacodynamic inter-
actions, both positive and negative. Its antidepres-
sant efficacy, as with TCAs and MAO inhibitors,
can be potentiated in many patients by the addition
oflithium (Potter et al. 1991). In several instances,
however, apparent toxic reactions to combined
fluoxetine and lithium have occurred, with either
therapeutic or elevated lithium concentrations
noted (Noveske et al. 1989; Salama & Shafey
1989; Sacristan et al. 1991). The reported effects
have included absence seizures and other neuro-
toxicity, as well as mania (Hadley & Cason 1989).
The naturalistic nature of these cases precludes
conclusions regarding the relative role of fluoxet-
ine or its interaction with lithium as causative.
Preliminary data suggest a similar role for bu-
spirone (a 5-HTl a receptor partial agonist) aug-
mentation of fluoxetine in depression (Jacobsen
30
1991) or obsessive-compulsive disorder (Jenike et
al. 1991; Markovitz et al. 1990); however, toxic
responses to this combination also have been de-
scribed.
Based on theories of synergistic pharmacody-
namic effects, leading to rapid central ~l-receptor
down-regulation, preliminary efforts at employing
combined antidepressant treatments including
fluoxetine have been reported. Weilburg and col-
leagues (1989) successfully converted 26 of 30
(86.7%) cyclic antidepressant nonresponders to re-
sponders with the addition of fluoxetine. Starting
fluoxetine coincident with desipramine in 14
hospitalised depressive patients, Nelson et al.
(1991) found a more rapid antidepressant response
than previously observed in patients treated with
the tricyclic alone. The possible role of pharmaco-
kinetic interactions, discussed below, could not be
ruled out in either of these studies.
Other therapeutic drug interactions with
fluoxetine involve efforts at ameliorating adverse
effects. As noted above, these include the addition
of the sedating antidepressant, trazodone, to treat
the insomnia commonly associated with fluoxet-
ine. Oversedation, dizziness and ataxia, however,
have occurred with a fIuoxetine/trazodone
combination (Metz & Shader 1990), presumably
resulting from a pharmacokinetic interaction
causing elevated trazodone concentrations (see
below) or pharmacodynamically synergistic
hyperserotonergic actions of the 2 drugs.
Another relatively common (in up to a third of
patients) adverse effect of fluoxetine in both men
and women is sexual dysfunction (Jacobsen 1992;
Zajecka et al. 1991), which should be inquired for
in all patients on antidepressants (Balon et al.
1993; Segraves 1992). Again, paralleling ex-
perience with TCAs and MAO inhibitors,
cyproheptadine, an antihistaminergic compound
typically prescribed on an as required basis (4 to
8mg), has proven beneficial in some patients with
fluoxetine-induced delayed orgasm or anorgasmia
(McCormick et al. 1990). Interestingly, recent de-
scriptions of cyproheptadine actually interfering
with a previously achieved antidepressant (Feder
Drug Safety 10 (1) 1994
1991) or antibulimic response (Goldbloom & Ken-
nedy 1991) to fluoxetine are consistent with the
known post-synaptic receptor (5-HT2) blocking
action of cyproheptadine. Recent open case series
have also suggested the possible utility of the CX2-
adrenergic blocking agent, yohimbine (Jacobsen
1992) and the dopaminergic compound, amantad-
ine (Balogh et al. 1992) in the treatment offluoxet-
ine-associated sexual dysfunction. Controlled tri-
als are awaited.
Hypermetabolic reactions, the so-called 'sero-
tonin syndrome' (Sternbach 1991), have resulted
from interactions with fluoxetine, most notably in-
volving MAO inhibitors (Feighner et al. 1990;
Sternbach 1988). Even at low, presumably MAO-
B-selective doses (see below), a relatively new
MAO inhibitor, selegiline (deprenyl), has been im-
plicated in a case of hypertension and vasocon-
strictive symptoms in combination with fluoxetine
(Suchowersky & deVries 1990). The long elimina-
tion tYz of fluoxetine and norfluoxetine require a
5-week minimum washout period after fluoxetine
discontinuation prior to the introduction of a MAO
inhibitor.
Metz (1990) reported a case of anxiety, restless-
ness, pacing, insomnia and muscle spasms in a pa-
tient taking combined fluoxetine and buspirone, re-
lated either to combined serotonergic activity of
the 2 drugs or to elevated buspirone concentrations
secondary to fluoxetine.
Pharmacokinetic Interactions
These have been reviewed recently by
Goodnick (1991). The initial, and still best studied,
pharmacokinetic interaction with fluoxetine en-
tailed the benzodiazepines. Lemberger et al. (1988)
administered single 10mg oral doses of diazepam
to volunteers alone and following pretreatment
with 1 or 8 daily 60mg doses offluoxetine. Impair-
ment of diazepam metabolism by fluoxetine was
demonstrated, with reduced clearance and tY2 pro-
longation of the benzodiazepine during concurrent
fluoxetine administration. Similar findings have
been reported with alprazolam but not clonazepam,
which is metabolised by a nitro-reduction pathway
(Greenblatt et al. 1992).
Newer versus Older Antidepressants
Subsequently, a series of anecdotal clinical re-
ports have described similar (often 200 to 300%)
elevations in plasma concentrations (and in effects
or toxicity) of TCAs following the addition of
fluoxetine (Aranow et al. 1989; DeMaso & Hunter
1990; Downs et al. 1989; Preskom et al. 1990;
Vaughn 1988). Again, even after discontinuation,
fluoxetine and/or its metabolite may be present for
weeks, interfering with metabolism of a sub-
sequently introduced TCA, as described by Extein
(1991). This phenomenon is of considerable clini-
cal significance, calling for reduced TCA dosage
perhaps by as much as 75% (Westermeyer 1991)
and, if available, plasma TCA monitoring during
combined treatment with fluoxetine. As noted
above, this action of fluoxetine may increase the
risk of TCA overdose, due to elevation and slowed
clearance of toxic TCA concentrations (Rosenstein
et al. 1991).
Bergstrom and associates (1992) recently dem-
onstrated reduced hydroxylation of imipramine by
concurrent fluoxetine and doubling of the plasma
concentration of the former, implicating the P450
IID6 isoenzyme in the liver as the site of this drug-
drug interaction. Thus, concomitant fluoxetine
plus desipramine is associated with elevated desi-
pramine plasma concentrations and lower concen-
tration ratios of 2-hydroxy-desipramine : desipra-
mine (Nelson et al. 1991; Wilens et al. 1992).
A similar, if less well documented, series of
cases also suggest possible increased neurotoxicity
related to an interaction between fluoxetine and an-
tipsychotics, especially haloperidol (reviewed by
Ciraulo & Shader 1990a,b). Fluoxetine has been
reported to enhance the extrapyramidal effects of
antipsychotics (Lock et al. 1990) and may have
been implicated in an unusually early onset of tar-
dive dyskinesia in a patient treated with low-dose
haloperidol (Stein 1991). Although fluoxetine ap-
pears to inhibit antipsychotic metabolism, as in the
case of TCAs, this may be a more modest effect, as
evidenced by the mean 20% rise in steady-state
haloperidol plasma concentrations following the
addition of fluoxetine (Goff et al. 1991), without
any change in extrapyramidal symptoms.
31
Complicating interpretation of these reports,
and more recent ones of Parkinsonism during
combined fluoxetine/carbamazepine treatment
(Gernaat et al. 1991), and fluoxetine-associated in-
creased motor disturbances in 4 patients with Par-
kinson's disease (Jansen Steur 1993), is the pre-
viously noted propensity for fluoxetine alone to
produce extrapyramidal symptoms (Rudorfer &
Potter 1989).
2.1.4 Sertraline
As fluoxetine was in the forefront of the 1980s
replacement of the TCAs by the SSRls as the most
popular first-line pharmacotherapy of depression,
the newer compounds, sertraline and paroxetine,
are expanding SSRl treatment options in the 1990s.
Their enhanced tolerability for some patients rests
primarily on their pharmacokinetic differences
from fluoxetine (table ill): a shorter t~, lack of
active metabolites and a lower propensity for drug-
drug interactions. The database on the newer
SSRls remains limited, however, and conclusions
about them should be regarded as tentative.
A year-long multinational study of short term
(open) and maintenance (double-blind) treatment
with sertraline of several hundred patients with
major depression (Doogan & Caillard 1992) is rep-
resentative of the experience thus far with this
compound. In addition to demonstrating the long
term efficacy of sertraline, the data illustrated its
mild adverse effect profile. While more than one-
third of patients on active drug (and nearly as many
taking placebo) reported adverse effects (the ex-
pected complaints of headache, gastrointestinal
disturbances, insomnia or somnolence), each treat-
ment-emergent effect was endorsed by fewer than
10% of patients. Changes in bodyweight were neg-
ligible. Unexpectedly, the safety of SSRls in over-
dose was documented in this trial with the benign
outcome of a suicide attempt by a sertraline-treated
patient (Doogan & Caillard 1992).
The substantial interactions between fluoxetine
and TCAs or other drugs metabolised by hepatic
oxidation reviewed above have highlighted this
property as an important consideration in the eval-
uation of new SSRls (table ill). Preskorn and as-
32
sociates (1992) have directly compared fluoxetine
and sertraline with respect to the propensity for
interactions with TCAs. Following 8 days of desi-
pramine 50mg daily, 18 healthy male volunteers
received for an additional 3 weeks either fluoxetine
20 mg/day or sertraline 50 mg/day, while desipra-
mine was continued. At the end of the period of
combined treatment, mean desipramine plasma
concentrations had risen by 400% in the fluoxetine
group, compared with a 30% mean increase in the
sertraline recipients. Following discontinuation of
the SSRI, desipramine concentrations remained el-
evated (about 3 times pre-SSRI baseline) for 3
weeks only in those volunteers who had received
fluoxetine.
These data have important clinical implications
regarding SSRIITCA interactions. Further studies
are awaited to extend such SSRI interaction para-
digms to other hepatic pathways, such as those me-
diating benzodiazepine metabolism.
A truncated version ofthe Preskorn et al. (1992)
methodology was employed in another healthy
volunteer study (Apseloff et al. 1992). This study
explored potential interactions of sertraline with
lithium, in light of the previously reviewed reports
of toxicity resulting from lithium in combination
with fluoxetine or with another SSRI, fluvoxamine
(see below). 20 men received lithium 1200 mg/day
for 9 days; on the final day this was supplemented
by 2 doses of either sertraline 100mg or placebo.
Volunteers who received sertraline demonstrated
only minimal and insignificant changes in lithium
serum concentrations and renal clearance but did
tend to experience adverse effects (tremor and nau-
sea) lacking in the placebo group. Apseloff and as-
sociates (1992) interpret these findings as possibly
supportive of a pharmacodynamic synergism of the
serotonergic actions of sertraline and lithium but
not consistent with a pharmacokinetic interaction.
Two other pharmacodynamic effects of sertral-
ine appear to be shared by all members of the SSRI
class. According to the manufacturer, sertraline is
toxic in combination with MAO inhibitors, al-
though as noted, a shorter washout time is neces-
Drug Safety 10 (1) 1994
sary prior to introduction of the latter compared to
the situation with fluoxetine.
Sertraline use is associated with sexual dys-
function, primarily diminished libido and delayed
ejaculation, in about 1 of 6 men (reviewed by
Seagraves 1992); a much smaller number of
women also experience orgasmic difficulties dur-
ing sertraline treatment. The omission of sexual
disturbances from the list of reported adverse ef-
fects during the multi centre sertraline maintenance
treatment study described above (Doogan &
Caillard 1992) is therefore surprising.
2.1.5 Paroxetine
As with sertraline, this compound might best be
thought of as being in its postmarketing surveil-
lance period, with new tolerability information
continually reported. With a tY2 of about 1 day (ta-
ble III) and lacking active metabolites (DeVane
1992), paroxetine shares many characteristics with
the SSRIs other than fluoxetine. At daily doses be-
tween 20 and 50mg paroxetine is effective in out-
patient major depression, with the usual array of
SSRI adverse actions (C1aghorn et al. 1992;
DeWilde et al. 1993; Dunbar et al. 1991; Ohrberg
et al. 1992).
Although there have been few direct compari-
sons with other SSRIs (DeWilde et al. 1993),
paroxetine may be less likely than others to induce
or exacerbate anxiety or agitation (Claghorn et al.
1992; Sheehan et al. 1992). Paroxetine generally is
also not associated with weight loss (Claghorn et
al. 1992). While paroxetine inhibition of the
debrisoquine (and TCA) metabolising hepatic iso-
enzyme has been demonstrated in vitro (Crewe et
al. 1992), exceeding that of fluoxetine, norfluoxet-
ine or sertraline, the clinical significance of this
finding awaits further study and clinical experi-
ence.
As with most medications in the early
postmarketing stage, reports of adverse effects as-
sociated with paroxetine use are appearing in the
literature, but their full significance may not be
appreciated for some time. For instance, several
cases of paroxetine-associated hyponatraemia
(Chua & Vong 1993) may be related to the syn-
Newer versus Older Antidepressants
drome of inappropriate secretion of antidiuretic
hormone (as has been caused by fluoxetine), but
this remains speculative. Choo (1993) has de-
scribed the British experience with postmarketing
surveillance of adverse effects related to paroxet-
ine. Both extrapyramidal and post-discontinuation
withdrawal symptoms have been reported in a
small number of paroxetine recipients, with the na-
tional database suggesting that such effects may be
more common with this medication compared with
other SSRIs (Choo 1993). This must be regarded
as quite preliminary.
2.1.6 Fluvoxamine
Although still not marketed in the US,
fluvoxamine is no longer a new medication, having
been prescribed to more than 2.5 million patients
around the world over the past decade (Burton
1991). Effective even in severe depression (Bech
1990; Burton 1991; Mendlewicz 1992), fluvoxam-
ine like other SSRIs is increasingly being studied
in anxiety disorders as well (Black et al. 1993). Its
pharmacokinetic (table III) and adverse effect pro-
files are unremarkable. Fluvoxamine has little ef-
fect on cardiovascular parameters (Laird et al.
1993). However, the rate of treatment-emergent
nausea (15.7% according to the worldwide
fluvoxamine safety database compiled by Wagner
et al. 1992) tends to be higher and more severe with
fluvoxamine that with its competitors, contributing
to a relatively high rate of premature drug discon-
tinuation (Wagner et al. 1992). Bodyweight is often
unchanged and may even increase during
fluvoxamine treatment. Rates of fluvoxarnine-in-
duced anxiety or agitation are low (Wagner et al.
1992). Indeed, a dose-dependent syndrome of ap-
athy, amotivation and emotional blunting has been
described in several patients during fluvoxamine
or fluoxetine treatment (George & Trimble 1992;
Hoehn-Saric et al. 1990).
Despite its widespread use throughout most of
the 1980s, only relatively recently have a handful
of cases offluvoxarnine-related drug-drug interac-
tions been reported. In 3 cases from Germany
(Fritze et al. 1991) the addition of fluvoxamine to
a stable carbamazepine regimen was associated
33
with the onset of signs of carbamazepine toxicity
(nausea and vomiting, nystagmus, vertigo) accom-
panied by a 40 to 70% increase in plasma carbam-
azepine concentrations. A similar scenario ensued
when fluvoxamine was added to theophylline in an
ll-year-old Israeli boy (Sperber 1991); the result-
ing theophylline toxicity and elevated serum con-
centration did not recur when fluvoxamine was re-
placed with the TCA, clomipramine.
Co-administration of fluvoxamine and TCAs
has been associated with increased plasma TCA
concentrations in a case series of 3 patients (Berts-
chy et al. 1991). A pharmacokinetic interaction, re-
sulting in slowed antipsychotic clearance, might
have also accounted for a report of elevated blood
prolactin levels and accompanying amenorrhoea
and galactorrhoea in a patient whose antipsychotic
drug, loxapine, was supplemented by fluvoxamine
(Jeffries et al. 1992). Other drug-drug interactions
involving increased plasma concentrations of other
oxidatively metabolised compounds, including
propranolol and some benzodiazepines (Benfield
& Ward 1986), have been described. More system-
atic study, preclinically and in human volunteers
and patients, is required to assess fully the effect
of fluvoxamine on hepatic drug metabolising en-
zyme systems.
Another interaction of considerable concern is
that between flu vox amine and lithium. As dis-
cussed above with respect to fluoxetine, a number
of cases of toxicity in patients cotreated with
fluvoxamine and lithium have been reported. In
one instance (Evans & Marwick 1990) a bipolar
depressed patient who had previously tolerated
separate trials of fluvoxamine and lithium devel-
oped severe somnolence as soon as lithium was
added to a new ongoing trial of fluvoxamine.
Given a lack of toxic lithium concentrations, the
study authors hypothesised a pharmacodynamic
interaction (Evans & Marwick 1990). In 1989 the
UK Committee on Safety of Medicines reported
adverse reactions in 19 patients receiving com-
bined fluvoxamine and lithium, five of whom ex-
perienced convulsions. Again, further research is
required to clarify the mechanism and clinical sig-
34
nificance of this combination, which should be
used only with great caution.
In the absence of lithium, however, fluvoxam-
ine in therapeutic doses has a very low propensity
to induce seizures, as demonstrated in patients with
seizure disorders or a history of convulsions during
treatment with other antidepressants (Ayd 1993;
Harmant et al. 1990). These clinical observations
are consistent with the preclinical lack of pro-
convulsant activity with fluvoxamine in contrast to
most other tested antidepressants in a freely-mov-
ing rat model (Krijzer et al. 1984). As previously
noted, anticonvulsant dosages should be reduced
during concomitant fluvoxamine use due to the
pharmacokinetic interaction between the two med-
ications.
2.1.7 Citaiopram
Under review for a number of years (Bengtsson
et al. 1991), citalopram is beginning to move into
the SSRI mainstream. Although an effective anti-
depressant (Milne & Goa 1991), citalopram has
been studied with such a variety of methodologies
that a meta-analysis of clinical trials (Bech 1990)
proved difficult. As for paroxetine, citalopram
proved less effective but better tolerated in com-
parison to the reference TCA, clomipramine, in a
collaborative Scandinavian fixed-dose study of se-
vere depression (Danish University Antidepressant
Group 1986). A similar conclusion in terms of ef-
ficacy and tolerability was reached for citalopram
and imipramine used for the novel indication of
diabetic neuropathy (Sindrup et al. 1992).
The tolerability profile of citalopram is consis-
tent with the rest of the SSRI family. Its tI/2 of 33
hours (table III) and lack of active metabolites per-
mit once-daily administration without accumula-
tion. Headed by a 20% prevalence of nausea with
or without vomiting, the list of citalopram-associ-
ated adverse effects is unremarkable (Milne & Goa
1991). The drug is also well tolerated in long term
use. While to date no untoward interactions with
other psychotropic medications have been re-
ported, the experience with other members of this
class of drugs dictates caution with combination
Drug Safety 10 (l) 1994
treatment pending more systematic evaluation of
citalopram's effects on hepatic oxidising enzymes.
2.2 Arnfebutamone (Bupropion)
Despite the limited availability of this novel an-
tidepressant outside the US, an appreciation of its
therapeutic and toxic potentials is very instructive.
The difficult road to the drug's approval illustrates
the· challenge of developing new pharmacothera-
pies for depression which avoid the adverse effects
of the TCAs but which, more often than not, intro-
duce other liabilities of their own.
Therapeutically, amfebutamone is an effective
antidepressant, even in many otherwise refractory
patients, although it is reported to differ from most
other antidepressants in its lack of antipanic effi-
cacy (Rudorfer & Potter 1989). Arnfebutamone, a
noradrenaline- and perhaps dopamine-enhancing
compound, spares most central and peripheral re-
ceptors (table I), and consequently is associated
with few TCA-like adverse effects (table II).
Specifically, amfebutamone produces little to no
anticholinergic or cardiovascular effects, including
hypotension; however, reduced salivation (mecha-
nism unknown) is common (Posner et al. 1985).
In a direct comparison with amfebutamone, the
tertiary amine tricyclic doxepin produced signifi-
cantly more anticholinergic effects and sedation
(Feighner et al. 1986), which accounted for most
of the 21 % dropout rate in the doxepin group. In
contrast, although agitation, insomnia, and sweat-
ing were noted more often in amfebutamone recip-
ients, only 8% were dropped from the study due to
adverse effects. Moreover, during the 13-week
trial, amfebutamone-treated patients lost an aver-
age of 1.5kg of bodyweight; those on doxepin
gained almost twice that (see below).
In further contrast to TCAs, repeated doses of
amfebutamone, which does not affect {X2-adrener-
gic receptor sensitivity, do not diminish the antihy-
pertensive effect of clonidine in healthy volunteers
(Cubeddu et al. 1984). While neither imipramine
nor amfebutamone exacerbated pre-existing im-
pairment of left ventricular function in depressed
cardiac patients (Roose et al. 1987), half of the
Newer versus Older Antidepressants
imipramine group (but none of the amfebutamone
group) had to terminate pharmacotherapy because
of severe orthostatic hypotension. Although the
relative safety of amfebutamone in depressed pa-
tients with pre-existing cardiac disease has been
amply documented (Roose et al. 1987, 1991a);
Wenger et al. 1983), slight increases in blood pres-
sure during amfebutamone treatment may be clin-
ically significant in patients with baseline hyper-
tension (Roose et al. 1991a). Slower clearance of
amfebutamone and its metabolites (including its
active hydroxy metabolite) has been demonstrated
in patients with alcoholic liver disease (De Vane et
al. 1990).
Chemically related to the anorectic agent,
amfepramone (diethylpropion), the potentially
toxic (and possibly therapeutic) actions of amfe-
butamone may involve central dopamine systems.
Preclinically, amfebutamone produces dose-re-
lated central nervous system stimulant effects.
Behavioural pharmacology studies in rats and
primates have demonstrated stimulus generalisa-
tion between abusable psycho stimulants (includ-
ing amphetamine and cocaine) and amfebutamone
at high doses (as well as other dopaminergic anti-
depressants) [Lamb & Griffiths 1990]. Amfe-
butamone had been associated with seizures in ro-
dents and dogs at doses several-fold those used
clinically in the treatment of depression. Neverthe-
less, no psychostimulant action of single doses of
amfebutamone up to 200mg were observed in
healthy individuals undergoing auditory vigilance
or visual analogue testing (Hamilton et al. 1984;
Peck & Hamilton 1983). However, amfebutamone
100mg in combination with either alcohol or diaz-
epam prevented the impairment on auditory vigi-
lance seen with alcohol alone as well as diazepam-
associated impaired performance and drowsiness.
Moreover, volunteers with a history of amphet-
amine abuse showed neither objective nor subjec-
tive responses to single oral doses of amfe-
butamone (up to 400mg) that resembled those to
dexamphetamine (Griffith et al. 1983). Nonethe-
less, ongoing investigations of potential new clin-
ical indications for amfebutamone, including co-
35
caine abuse and attention deficit hyperactivity dis-
order, are predicated on putative psycho stimulant
actions of this medication.
The most common adverse effects encountered
in patients treated with amfebutamone are agita-
tion, insomnia, tremor, dry mouth, headache and
gastrointestinal disturbances, including nausea,
vomiting and constipation. In contrast to cyclic an-
tidepressants as well as the newer SSRIs,
amfebutamone treatment is not associated with im-
pairment of sexual functioning (Gardner & John-
ston 1985) and, in fact, anecdotally the drug is fre-
quently credited with enhanced libido and sexual
performance. Menstrual irregularities of unknown
aetiology have been reported during amfe-
butamone treatment (Halbreich et al. 1991). Per-
haps related to its structural resemblance to amfe-
pramone, treatment with amfebutamone is much
more likely to be associated with weight loss (>2kg
in a quarter of patients in typical clinical trials) than
the weight gain common with TCAs. Tolerance to
this effect renders amfebutamone unsuitable for
long term treatment of obesity; indeed, this medi-
cation is contraindicated in the presence of frank
eating disorders, due to the apparent increased risk
of seizures.
In fact, the scheduled 1986 marketing of
amfebutamone in the US was delayed by more than
3 years because of the occurrence of generalised
seizures in 4 of 69 non-depressed bulimic patients
at usual dosages (generally 450 mg/day in divided
doses) in a multicentre clinical trial (Home et al.
1988). Review of the drug's tolerability data (Da-
vidson 1989) and a subsequent 102-site prospec-
tive study (Johnston et al. 1991) documented a
dose- and apparently blood concentration-related
seizure risk from amfebutamone of approximately
0.4%, comparable to that for imipramine (Rosenst-
ein et al. 1993), at dosages of 450 mg/day or less.
This risk increased almost lO-fold as the amfe-
butamone dosage was raised to 600 mg/day.
Nearly half of the seizures reported at lower
amfebutamone doses and more than a third at high
doses were associated with predisposing factors,
including a past history of seizures, brain tumour,
36
head trauma, alcohol withdrawal and polypharm-
acy. This weighs against use of amfebutamone in
eating disorders or neurologically-compromised
patients, or its coadministration with medications
having the propensity to lower seizure threshold,
e.g. antipsychotics. On the other hand lithium,
while proconvulsant at toxic concentrations, has
been safely combined with amfebutamone in pa-
tients with bipolar disorder (Haykal & Akiskal
1990) or refractory depression (Apter & Woolfolk
1990).
The risk of seizures has led to revision in the
recommended dosage regimen of amfebutamone.
Although early inpatient clinical trials employed
daily doses of amfebutamone as high as 750mg, by
the time of final US marketing in mid-1989 the
maximum recommended dosage was 450 mg/day,
to be used only after several weeks' treatment at
300 mg/day had proven unsuccessful. Moreover,
to further minimise the risk of seizures, the manu-
facturer recommends a thrice-daily dose schedule,
with no single dose exceeding 150mg, and a grad-
ual upward titration of dose of no more than 100mg
daily in a 3-day period. If other risk factors are
absent, the short term use of amfebutamone in di-
vided doses not exceeding 450 mg/day poses an
acceptable chance of seizure comparable to that of
other antidepressants (Ayd 1993; Johnston et al.
1991; Rosenstein et al. 1993). A remaining quan-
dary is the apparent continuation of seizure risk
during treatment beyond a short term 8-week
amfebutamone trial, such as would occur in actual
clinical practice.
A range of other neuropsychiatric disturbances
have been associated with the therapeutic use of
amfebutamone at higher doses, ranging from per-
ceptual distortions (Becker & Dufresne 1982) and
exacerbation of psychosis in 3 of 9 schizoaffective
patients (Goode & Manning 1983) to the emer-
gence of dose-related acute psychosis in 4 of 13
depressed inpatients (Golden et al. 1985, 1988b).
In the latter study, Golden et al. (1988b) observed
a 36% rise in plasma concentrations of the princi-
pal dopamine metabolite, homovanillic acid
(HVA), and associated elevated plasma hydroxy-
Drug Safety 10 (1) 1994
amfebutamone concentrations (Golden et al.
1988a) in nonresponders to amfebutamone, with
no change in plasma HVA in responders to the med-
ication. Perturbation of dopaminergic systems was
hypothesised to explain these findings.
More recent reports of amfebutamone-associ-
ated delirium are confounded by the presence of
concurrent psychoactive treatments (Dager &
Heritch 1990), including in 1 case a dopamine re-
leaser and reuptake blocker as well as ECT
(Liberzon et al. 1990), with its own dopaminergic
activity (Rudorfer et al. 1991). In addition, even 1
day's treatment with amfebutamone is associated
with prolongation of (therapeutic) seizures during
ECT (Figiel & Jarvis 1990). Caution during
amfebutamone dosage titration and avoidance of
unnecessary concomitant treatments are recom-
mended.
Several examples of drug-drug interactions
with amfebutamone are clinically relevant, with
concurrent administration of amfebutamone
100mg blunting the sedation, mental slowing and
reduced auditory vigilance induced by an alcohol
challenge; degree of inebriation was unaffected
(Posner et al. 1984). Most importantly, however,
the use of and withdrawal from alcohol lowers the
seizure threshold and is regarded as a risk factor
for convulsions during amfebutamone treatment
(Davidson 1989; Johnston et al. 1991; Rosenstein
et al. 1993). Also, limited clinical data suggest an
increased risk of agitation, confusion, hallucina-
tions, and nausea and vomiting when amfe-
butamone is combined with levodopa, despite an
enhanced anti-Parkinsonian therapeutic action of
the combination (Goetz et al. 1984).
The well-documented ability of fluoxetine to
slow the clearance of concurrent drugs metabo-
lised by the liver, including TCAs, has raised con-
cern about the potential for toxicity from combin-
ing fluoxetine with amfebutamone and thereby
raising blood and brain concentrations of the latter.
In one published case (van Putten & Shaffer 1990),
delirium was observed after amfebutamone was
begun the day after a fluoxetine trial was discon-
tinued. The long half-life of fluoxetine and its ac-
Newer versus Older Antidepressants
tive metabolite may have played a role in this toxic
combination. Enhanced acute toxicity of
amfebutamone by phenelzine in rats has led to con-
cerns about adverse interactions between amfe-
butamone and MAO inhibitors, although as yet
there are no reports of problems from this combi-
nation in humans.
As with many new-generation antidepressants,
overdoses of amfebutamone, while toxic (produc-
ing seizures in a third of reported cases, according
to the manufacturer), are rarely fatal, in contrast to
the high lethality of TCAs.
Before turning to the tolerability issues of the
newer MAOIs, it is instructive to consider one of
the few clinical trials to compare new-generation
antidepressants with one another, rather than with
an older TCA with an admittedly problematic ad-
verse effect profile. In a 2-centre study, Feighner
and associates (1991) randomised depressed out-
patients to 6 weeks of double-blind treatment with
either fluoxetine (mean 38 mg/day) or amfeb-
utamone (mean 382 mg/day). Both treatments
were equally effective at all measured time points.
Similarly, both medications were well-tolerated.
Although more than a quarter of each group failed
to complete the trial, only a third of that number
was accounted for by treatment-emergent adverse
effects, most often related to overstimulation. No
seizures were reported. Patients on either medica-
tion lost over lkg in bodyweight during treatment.
These data support the efficacy and relative safety
of both fluoxetine and amfebutamone in short term
trials.
3. Monoamine Oxidase (MAO) Inhibitors
3.1 Classical MAO Inhibitors
The original class of antidepressants, the MAO
inhibitors, has been plagued by concerns about tox-
icity nearly from the time of their development in
the 1950s. Potentially fatal hepatotoxicity and hy-
pertensive crises drove some MAO inhibitors tem-
porarily or permanently off the market. In routine
use, MAO inhibitors avoid the cardiac conduction
slowing endemic to the TCAs, but carry a burden
of troublesome adverse effects of their own, in-
37
cluding orthostatic hypotension, sleep impairment
with daytime drowsiness, and sexual dysfunction
(Blackwell 1981a).
Dry mouth and other anticholinergic symptoms
may be present during MAO inhibitor treatment
but are generally mild. As is true for all the anti-
depressants under discussion, old and new, mood
switches are common among bipolar patients dur-
ing MAO inhibitor treatment, to hypomania more
frequently than to full-blown mania (Goodwin &
Jamison 1990). Concomitant coverage with lith-
ium or other mood-stabilising medication is re-
quired.
Perhaps the greatest reported success in com-
batting a MAO inhibitor-associated adverse effect
is the use of the new-generation antidepressant,
trazodone, for sedation in combination with MAO
inhibitors (Jacobsen 1990; Nierenberg & Keck
1989). Similarly, the antiserotonergic, anti-
histaminergic agent, cyproheptadine, reverses
some (Decastro 1985) but not all cases (Kahn
1987) of sexual dysfunction associated with MAO
inhibitor treatment, or fluoxetine and other SSRIs.
Although the feared dangerous interactions be-
tween MAO inhibitors and sympathomimetic and
serotonergic substances remain a limiting factor in
the use of these antidepressants, new under-
standing into the mechanisms, prevention and
treatment of toxicity has emerged from recent ex-
perience and investigation. Systematic review of
the limited data behind the often-anecdotal exclu-
sion criteria for the standard low-tyramine diet
(Brown et al. 1989) - even the much maligned Chi-
anti wine contains little tyramine by modern assay
techniques (Shulman et al. 1989) - has led to
streamlining of instructions to patients which
should facilitate compliance with and acceptance
of this treatment (Lippman & Nash 1990). Simi-
larly, ECT has been given safely to patients taking
MAO inhibitors (Remick et al. 1987), the earlier
blanket proscription against combining these
drugs with general anaesthesia notwithstanding.
With the more widespread use of MAO inhibi-
tors in recent years, however, new challenges have
emerged. Harrison and associates (1989) have de-
38
scribed the confusing array of over-the-counter
combination products, which increase the likeli-
hood of dangerous MAO inhibitor interactions, for
instance with a decongestant, even in diligent pa-
tients. Apparent autoinduction of 'spontaneous'
hypertensive crises has been reported in a number
of MAO inhibitor recipients who were adhering to
the appropriate diet and medication restrictions
(Fallon et al. 1988; Keck et al. 1989; Lavin et al.
1993).
The presumed metabolism of tranylcypromine
(the MAO inhibitor generally implicated) to am-
phetamine (Baker & Coutts 1989) has been pro-
posed as causative, and TCAs as being protective
(Zajecka & Fawcett 1991), but in fact no amphet-
amine-like metabolites of tranylcypromine were
identified in a recent prospective study (Jefferson
1992; Keck et al. 1991a). However, occasional re-
ports of tranylcypromine abuse (Brady et al. 1991)
and dependence (Briggs et al. 1990; Vartzopoulos
& Krull 1991) continue to suggest stimulant-like
properties of the drug, particularly at high doses.
This might also relate to the only recently appreci-
ated danger of hypertensive crises from a rapid
switch from a hydrazine member (phenelzine or
isocarboxazid) to tranylcypromine (Chandler
1987; Gelenberg 1987). Clinical reports, however,
document the safety of switching from a TCA to a
MAO inhibitor in tricyclic nonresponders, without
a washout period (Kahn et al. 1989), but not the
other way around.
Insight into the serotonergic nature of the ad-
verse interactions between MAO inhibitors and
some other substances, including pethidine
(meperidine) [Blackwell 1991; Browne & Linter
1987] and tryptophan (Thomas & Rubin 1984) has
prompted considerable study and awareness of the
'serotonin syndrome' (Nierenberg & Semprebon
1993; Sternbach 1991). A practical dilemma of this
phenomenon is the consequent necessity to avoid
combinations of MAO inhibitors with serotonin
reuptake inhibiting antidepressants such as
clomipramine (Nierenberg & Semprebon 1993) or
fluoxetine (Feighner et al. 1990; Sternbach 1988;
Suchowersky & deVries 1990). In the case of the
Drug Safety 10 (1) 1994
latter, the long half-life of fluoxetine (Rudorfer &
Potter 1989) has necessitated a 5-week or longer
washout time prior to the institution of MAO in-
hibitor treatment.
Meanwhile, advances in the treatment of hyper-
tension have led to the replacement in some
situations of the a-blocker (intravenous), phentol-
amine, by the calcium channel blocker (oral)
nifedipine as the treatment of choice for a MAO
inhibitor-associated hypertensive crisis (Clary &
Schweizer 1987; Gifford 1991).
3.2 Comparative Tolerability of
Newer MAO Inhibitors
With the description of two functionally distinct
subtypes of MAO a quarter-century ago came the
potential, only recently realised, for the develop-
ment of selective MAO inhibitor compounds
(Rudorfer & Potter 1989). In addition to possible
therapeutic advantages, the advent of inhibitors of
one particular SUbtype of MAO enables avoidance
or reduction of some of the toxicity associated with
use of the standard, nonselective MAO inhibitors.
Thus, the investigational irreversible MAO-A
inhibitor, clorgiline, (Rudorfer & Potter 1989) is a
very potent antidepressant of considerable value in
bipolar and unipolar depressed patients. However,
it offers no radical departure from conventional
MAO inhibitors in terms of adverse effects as it is
the A subtype of MAO that is found in the gut as
well as the brain and which metabolises noradren-
aline. Patients taking clorgiline therefore remain
vulnerable to hypertensive reactions from tyra-
mine and other indirect sympathomimetics.
In contrast, other recent advances in MAO in-
hibitor options that do permit substantial reduc-
tions in potential medication-related morbidity in-
clude the development of selective inhibitors of
MAO-B and reversible MAO-A inhibitors.
3.3 Selective MAO-B Inhibition: Selegiline
A derivative of methamphetamine, selegiline
may prove to be of more than heuristic value in the
treatment of depression. Initial enthusiasm greeted
the discovery that by selectively acting on MAO-
Newer versus Older Antidepressants
B, selegiline was not associated with hypertensive
reactions to tyramine or sympathomimetic interac-
tions (Pickar et al. 1981). Unfortunately, this ad-
vantage is lost when the daily dose is raised above
the tomg used as an adjunct in treatment of Par-
kinson's disease (McGrath et al. 1989; Rudorfer
1989; Sunderland et al. 1985), which is well below
that (generally ~30 mg/day) producing antidepres-
sant effects in either major (Mann et al. 1989) or
atypical (McGrath et al. 1989) depression.
Even so, at these higher doses the adverse effect
profile of this irreversible MAO-B inhibitor is of-
ten more benign than that of the conventional
MAO inhibitors in the treatment of depression
(Mann et al. 1989). However, hypomanic, psy-
chotic and aggressive symptoms have been de-
scribed following the addition of selegiline to other
anti-Parkinsonian medications (Boyson 1991).
Moreover, there is at least one report of a central
excitatory syndrome on even low MAO-B selec-
tive doses of selegiline in combination with pethid-
ine (Zornberg et al. 1991). The antioxidant proper-
ties of selegiline, probably related to its efficacy in
slowing the progression of Parkinson's disease,
prompted a recent controlled trial of low dose
selegiline in tardive dyskinesia (Goff et al. 1993).
The observed lack of therapeutic effect of the ac-
tive compound may have resulted from the dopa-
minergic activity of selegiline.
3.4 Reversible Inhibition of MAO-A:
Moclobemide and Others
The search for effective and better tolerated new
MAO inhibitors today has led to medications that,
like clorgiline, are selective for MAO-A but also
possess the novel property of reversibility of MAO
inhibition. In contrast to the conventional as well
as the earlier classes of selective MAO inhibitors,
the reversible inhibitors of MAO-A (RIMAs) in-
cluding moclobemide, brofaromine, cimoxatone
and toloxatone, do not require synthesis of the en-
zyme after drug discontinuation to handle tyra-
mine. Instead, removal of the drug by washout or
even displacement from the catalytic site on MAO-
39
A by excessive tyramine is associated with at least
partial return of MAO activity.
Reviewing the pharmacokinetics of moclobem-
ide, a benzamide compound on which the vast ma-
jority of data have been reported, Mallinger and
Smith (1991) noted that the time course of drug
action consisted of an elimination tl;2 of approxi-
mately 2 hours, with MAO-A inhibition lasting 8
to 10 hours after a dose, returning to baseline
within a day.
An even shorter acting drug, toloxatone, pro-
duces MAO-A inhibition that wanes prior to the
next dose (Berlin et al. 1990). This emphasises the
more clinically significant role of pharmacokinetic
factors for reversible than for irreversible MAO
inhibitors (Mallinger & Smith 1991).
The relative safety of the reversible MAO-A in-
hibitors has been demonstrated in studies using ty-
ramine challenges (now most commonly given in
food) with depressed patients and healthy volun-
teers. In a controlled comparison of a reversible
with a standard MAO inhibitor in volunteers ad-
ministered either medication for at least 15 days,
Berlin and colleagues (1989) derived the dose of
tyramine in a meal required to raise systolic blood
pressure by 30mm Hg. Starting from typical values
averaging 1200 to 1450mg during placebo admin-
istration, the mean 'tyramine 30' dose fell to about
300mg in those on long term moclobemide, and
dramatically to 35mg in those on tranylcypromine.
Similar data have been reported for a comparison
oflong term moclobemide with phenelzine (Simp-
son & Gratz 1992) and for toloxatone (Provost et
al. 1992), also in healthy volunteers.
These data replicated the findings of Korn et al.
(1986) that a standard wine and cheese meal con-
taining 65mg of tyramine did not affect volunteers
pretreated with moclobemide for 1 week; in con-
trast, the blood pressure response to this tyramine
challenge was severe after a week of tranylcypro-
mine, with one volunteer requiring intravenous
phentolamine.
Similarly, subchronic administration of bro-
faromine (Bieck & Antonin 1988) was associated
with a 7-fold increase in pressor sensitivity to oral
40
tyramine in volunteers, in contrast to a 56-fold en-
hancement (with longer duration) of this measure
with tranylcypromine administration. Moreover,
following medication discontinuation, return to
baseline tyramine sensitivity was achieved much
more quickly after brofaromine (8 days) than after
tranylcypromine (23 days). Unfortunately, the
manufacturer apparently has decided to forego de-
velopment ofbrofaromine; this is not related to any
known problem with toxicity.
Clinically, large-scale collaborative studies,
mainly in Europe, attest to the efficacy and toler-
ability of the RIMAs (Guelfi et al. 1992). These
new antidepressants in general are well-tolerated
(Alevizos et al. 1993; Versiani et al. 1990), with
fewer adverse effects than TCAs (or phenelzine)
[Versiani et al. 1992], most commonly dizziness,
mild nausea, insomnia and other excitatory symp-
toms.
Clinical trials to date have incorporated no ty-
ramine restrictions, making impressive the lack of
reported hypertensive reactions. Indeed, the toler-
ability profile of moclobemide is so benign it com-
pares favourably even with another new-genera-
tion antidepressant, fluvoxamine (Bougerol et al.
1992). Both medications proved effective in the
short term treatment of major depression in 126
inpatients and outpatients entered into a double-
blind parallel trial in France and Switzerland. Most
premature terminations of treatment (22% in the
moclobemide group and 30% on fluvoxamine) oc-
curred for reasons other than adverse effects.
Where differences in adverse effects did occur,
they tended to favour moclobemide. Thus, gastro-
intestinal effects (especially nausea, which oc-
curred in a third of fluvoxamine recipients), trem-
ors, dry mouth and headache all were reported
more often in the flu vox amine group. However,
sleep was disturbed more commonly during
moclobemide (21%) than fluvoxamine (13%)
treatment. Although these trends did not reach sta-
tistical significance, the investigators concluded
that the adverse effects of moclobemide were less
troubling to patients than those of fluvoxamine
(Bougerol et al. 1992). All 18 cases of intentional
Drug Safety 10 (1) 1994
moclobemide overdose reported to the manufac-
turer resulted in full recovery, without adverse se-
quelae (Hetzel 1992).
It should be noted, however, that RIMAs are
capable of inducing the serotonin syndrome. This
was demonstrated by a recent case of hyperther-
mia, myoclonus, muscle stiffness and convulsions
in an elderly patient switched from clomipramine
to moclobemide over a day (Spigset & Mjorndal
1993).
4. Conclusions
Treatment of a depressed patient with any mo-
dality involves an assessment of the prospective
benefit-risk ratio for each available therapeutic op-
tion (Henry & Martin 1987). Effectiveness in out-
patient studies is usually equivalent across treat-
ments, but as already noted, questions have been
raised about the efficacy of several newer antide-
pressants in severe endogenous depression. Past
personal or family history of prior response to a
given antidepressant treatment often predicts re-
sponse to the intervention in the future (Potter et
al. 1991).
Assuming adequate therapeutic potential, the
new-generation antidepressants offer the promise
of greater tolerability for many patients, based on
a lower adverse effect profile and greater safety in
overdose. A major limitation of these agents is sim-
ply that a complete understanding of the toxicity of
a new treatment requires sufficient time and expe-
rience, as illustrated for instance in the cases of
fluoxetine and amfebutamone.
Clinically promising new antidepressant com-
pounds, including zimeldine and nomifensine,
were withdrawn due to unexpected and unaccept-
able toxicity, which were only appreciated after
years of relatively widespread use (Henry 1992).
Time is also necessary to put spontaneously re-
ported adverse effects into perspective. A warning
by the UK Committee on Safety of Medicines re-
garding lofepramine-associated elevated liver en-
zyme levels was removed when continued usage of
the drug demonstrated the non specificity of the
finding (Henry 1992).
Newer versus Older Antidepressants
The process of managing patients with depres-
sion remains complex (Potter et al. 1991). The
principal advance represented by the newer com-
pounds may be simply to increase the options
available to the clinician. Despite potential toler-
ability challenges with antidepressants of all
classes, in the treatment of a potentially lethal dis-
order, the warning of Henry and Martin (1987)
must be borne in mind, that 'the greatest risk is to
leave the depression untreated'.
Acknowledgements
The authors are indebted to Mrs Gladys Kehnemui, whose
skilful editorial assistance is the culmination of a decade of
outstanding service to our research enterprise. We also thank Mrs
Lillian Dalton and Ms Penny Nolton for their help in preparation
of the manuscript.
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Correspondence and reprints: Dr William Z. Potter, Section on
Clinical Pharmacology, Experimental Therapeutics Branch,
National Institute of Mental Healtb, Building 10, Room 2D46,
9000 Rockville Pike, Betbesda, MD 20892, USA.