Ordinary article OA 580 EN

The place for the tricyclic antidepressants in

the treatment of depression

Philip Boyce, Fiona Judd

Objective: The new generation antidepressants have been an important advance in

the treatment of depression. Since their introduction, their use has become wide-
spread and the role of the older tricyclic antidepressants (TCAs) has been suggested
only as a second-line choice. This assumption is questioned and the role of the TCAs
as a first-line treatment for severe depression is discussed.
Method: The relevant literature concerning the efficacy, tolerability and safety of the
antidepressant drugs is reviewed, particularly those studies which compare the
newer antidepressant agents with the TCAs.
Results: The newer agents are equally as efficient as the tricyclics in the treatment
of mild to moderate depression. There are indications that the TCAs are more effi-
cacious for severe depression. The tolerability of the drugs appear about equivalent
in terms of discontinuation rates; however, the side effects are different and clini-
cians need to be mindful of drug interactions and the potential of the serotonin syn-
drome with the selective serotonin re-uptake inhibitors (SSRIs), problems not found
with the TCAs. The TCAs are potentially lethal in overdose; however, appropriate
clinical management appears to be a more important issue than the toxicity of the
medication.
Conclusions: The newer antidepressant agents are important advances in the
treatment of depression. However, the TCAs still have an important place as the first-
line treatment for patients with severe (melancholic/endogenous) depression.
Key words: depression, melancholia, side effect, suicide, tolerability, tricyclic anti-
depressant.

Australian and New Zealand Journal of Psychiatry 1999; 33:323–327

The pharmacological treatment of depression has
changed considerably over the last 10 years with
the introduction of the second-generation anti-
Philip Boyce, Professor and Head (Correspondence), and member of
the Aropax Advisory Board
Department of Psychological Medicine, University of Sydney,
Nepean Hospital, Penrith, New South Wales 2751, Australia.
Email: <pboyce@mail.usyd.edu.au>
Fiona Judd, Associate Professor and Reader, Department of Psychiatry,
University of Melbourne; and Consultant Psychiatrist
Inner West Area Mental Health Service, Inner West Area Mental
Health Service, The Royal Melbourne Hospital, Melbourne,
Australia. Email: <f.judd@medicine.unimelb.edu.au>
Received 30 October 1998; revised 10 February 1999; accepted 17
February 1999.
depressants. Four new classes of antidepressants are
now available in Australia; the selective serotonin re-
uptake inhibitors (SSRIs), a reversible inhibitor of
monoamine (RIMA), a serotonin and noradrenaline
re-uptake inhibitor (SNRIs) and 5-HT2 receptor antag-
onists. The use of these agents, especially the SSRIs,
has exploded since their introduction in 1991. In 1991,
the number of prescriptions written for the first SSRI,
fluoxetine, was 81 661 at a cost to Government of
$3.8 million. By 1997/1998, the number of prescrip-
tions written for the SSRIs was 28.9 million, at a cost
to Government of $93.1 million. Over the same
period, the use of the TCAs has dropped slightly from
2.8 to 2.3 million prescriptions, with the cost falling
from $10.5 million to $10.3 million. The newer agents
324 TRICYCLIC ANTIDEPRESSANTS
now account for 61% of the cost of all the anti-
depressants (data from the PBS). The use of these
newer antidepressants is becoming commonplace [1]
and is recommended by some as the first-line treat-
ment for depression [2]. With this change in prescrib-
ing patterns, the role for the TCAs is becoming
redundant, and it has been suggested that they should
only be used as a second-line drug. There has now
even been the suggestion that prescribing a TCAraises
the potential for a professional negligence claim to be
brought against the practitioner [3].
Three reasons are given to support the view that the
new antidepressants should be the first-line treatment
of depression: efficacy, tolerability and safety. It has
been argued that there is little, if any, difference in the
efficacy between the new antidepressants and the
TCAs and that the newer agents are better tolerated as
a result of their low side-effect profile. Finally, the new
agents are safer, particularly when taken in overdose;
a desirable attribute for a medication prescribed for
persons at risk for suicide. While these are persuasive
arguments in favour of the new antidepressants, they
do not necessarily mean that TCAs should not be used
as, we believe, they still have an important place as a
first line treatment for melancholia.
Efficacy
Depression is a biopsychosocial disease and the
optimal treatment involves both pharmacological and
non-pharmacological approaches. The treatment
approach depends upon the type of depression
(broadly speaking melancholic vs non-melancholic
depression [4,5]), the severity of the depression, causal
factors and patient preference. For those patients with
mild to moderate, non-melancholic (non-endogenous)
depression, non-pharmacological treatments such as
cognitive–behavioural therapy, interpersonal
psychotherapy or problem-solving therapy are as
effective as antidepressant medication [6–10] although
expensive in the short term. The two treatment modal-
ities should not be considered as mutually exclusive as
drug treatment in isolation is, in reality, only partial
treatment given that medications do not deal with
psychosocial antecedents and consequences of depres-
sion. In contrast, pharmacotherapy is the mainstay of
treatment for melancholia (or endogenous depression),
with non-pharmacological approaches being essential
adjuncts to treatment [4,5,10,11].
There have now been many studies evaluating the
efficacy of the second-generation antidepressants in
comparison with the older agents. The findings of these
studies have been subjected to meta-analyses [12–16].
In the main, these studies show that the both groups of
drugs have equivalent efficacy. This is hardly a surpris-
ing finding since, if both classes of drugs are more
effective than placebos, finding a significant difference
between classes of effective treatments requires large
sample sizes [17,18]. These studies have focused on
persons suffering from mild to moderate depression,
and there are few studies that have evaluated the effi-
cacy of the different classes of antidepressants in the
treatment of melancholia or delusional depression.
Where they have done so, the TCAs appear to be more
efficacious for the treatment of severe (melancholic,
endogenous or psychotic) depression [19–24]. There
are a number of studies which suggest that the classes
of antidepressants are equivalent or at least that there is
no statistical difference. A meta-analysis examining
studies of SSRIs versus TCAs [15] found that while
there was no difference in efficacy between SSRI and
comparator antidepressants for SSRIs taken together or
individually, when studies were classified into high and
low depression scores, based on a median split of initial
Hamilton Depression Rating Scale scores, there was a
slight advantage to TCAs in the high HDRS group. In
addition, SSRIs were slightly less effective than TCAs
in inpatients. The latter is of interest as inpatients are
often the more worrying or difficult-to-treat group, due
often to factors other than severity alone such as
suicide risk, personality problems and psychosis.
However, in those studies there is a trend to be seen for
the TCAs to be more efficacious (e.g. [25]).
Tolerability
The major advantage claimed for the newer agents
is their different side-effect profile, especially the
lack of anticholinergic and cardiovascular side
effects. While they have been promoted as being well
tolerated, they are not side effect free. They have a
distinct but different side-effect profile; prominent
effects are nausea, diarrhoea, anxiety, agitation and
insomnia. This different adverse-effect profile is an
advantage if it results in better tolerability, most often
measured as the number of patients who drop out of
treatment during a course of antidepressants.
However, discontinuation is only one measure of tol-
erance; others are the number, impact and severity of
side effects of the medication.
There are now several studies which have been sub-
jected to meta-analyses [13,16,26,27], all of which
seem to indicate that the new antidepressants are
better tolerated than the tricyclic antidepressants. This
 P. BOYCE, F. JUDD
holds for clinical trials as well as naturalistic studies
in primary care [27]. However, a recent review from
the Canadian Coordinating Office for Health
Technology [28] reported that while study completion
rates were equivalent, some side effects such as
nausea, diarrhoea, insomnia, headache, nervousness,
agitation and anxiety were more common for SSRIs.
By contrast, the TCAs had different side effects, par-
ticularly the anticholinergic ones. The differences in
discontinuation rates in the published studies are
small [29] and may in part be the result of some of the
studies using the older TCAs (with the most promi-
nent side effects) rather than the newer TCAs [16].
The main indicator of tolerability has been discontin-
uation rates; other measures of tolerability such as the
number, impact or severity of side effects have not
been used. The differences in discontinuation rates
are not great, although there do appear to be fewer
persons discontinuing when prescribed the second
generation antidepressants than those being treated
with TCAs. The number of side effects reported by
patients on the TCAs and the second-generation anti-
depressants appear to be equivalent [28].
A number of points could be made about discon-
tinuation studies.
(1) These studies were conducted in the first part of
the 1990s when the second-generation anti-
depressants were very new on the market. At that
time, they were touted as having few, if any, side
effects. The side effects of the tricyclics are well
recognised, particularly the anticholinergic side
effects. There may have been a preference for
medical practitioners to discontinue the TCAs if
these side effects were reported so that the patient
could be switched to the new antidepressants with
‘few side-effects’. This may have led to higher rates
of discontinuation with tricyclics than with the new
second-generation antidepressants.
(2) The majority of the studies that have evaluated
discontinuation have been conducted in treatment
trials. Such treatment trials are generally short-term,
up to 12 weeks. There is no doubt that the side effects
of the TCAs are particularly troublesome during the
early phase of treatment especially the anticholiner-
gic side effects. Such side effects are disabling for
patients who are, at the same time, struggling with
their depressive symptoms, although drowsiness and
sleepiness may be an advantage for some. In the
short term, it is highly probable that persons will dis-
continue medication as these side effects are at their
worse when the person is most depressed. By con-
trast, some of the side effects with the new anti-
325
depressants are not so troublesome when the person
is at their most depressed. For example, sexual dys-
function and somnolence may not be a particular
problem for the patient at the nadir of their depres-
sion but these side effects do persist and may become
more of a problem after recovery. Long-term follow-
up studies examining later rates of discontinuation
would be of benefit. With the tricyclics, side effects
diminish over time and when the person is well they
tend to be minimally disabled by side effects, partic-
ularly the anticholinergic ones, although constipation
may persist which is easily remedied by a high fibre
diet or bulk laxatives. In a recent paper, Zajecka et al.
[30] found treatment emergent sexual dysfunction in
60% of males and 57% of females studied who were
treated with SSRIs, with 30% of both unable to reach
orgasm. In our clinical experience, this side effect is
particularly distressing and requires switching med-
ication to a TCA, moclobemide, or nefazadone which
do not lead to sexual dysfunction.
The serotonin syndrome is a potentially severe
adverse drug reaction that may be associated with
SSRI use. Causes of the syndrome include excess
levels of or unusual sensitivity to SSRI agents, certain
drug combinations, and the administration of exces-
sive amounts of serotonin precursor agents [31].
One component of tolerability that has not been
adequately dealt with in this literature is the impact of
drug interactions. There has been a growing list of
drug interactions with the SSRIs. These drug interac-
tions can make prescribing these new agents prob-
lematic, particularly in the general medical setting
among older patients who may be taking a range of
drugs for coexisting medical illnesses [32]. By con-
trast, the TCAs do not have effects on the cytochrome
P450 system and thus have few potentially harmful
drug interactions. Contraindications of course do exist
for the TCAs, particularly for those who have glau-
coma, prostatic hypertrophy or cardiac disease.
Like the TCAs, the SSRIs have the potential to
produce withdrawal symptoms if the drug is ceased
abruptly. The most frequently reported symptoms are
dizziness, paraesthesia, nausea, visual disturbances
and headache. Symptoms have been reported to
occur despite slowly tapered withdrawal and to
persist for up to 21 days after drug withdrawal [33].
Safety
The major reasons for advocating the first-line use
of the new generation antidepressants is that they are
safe if taken in overdose and fatal outcomes do not
326 TRICYCLIC ANTIDEPRESSANTS
generally occur following overdose of these agents,
although it must be noted that fatal outcomes have
been reported [34]. Suicide is one of the likely seque-
lae of depression, with up to 6% of persons suffering
from depression going on to suicide [35], and about
half of successful suicides were suffering from
depression [36]. There is no doubt that the TCAs are
potentially fatal if taken in overdose, with 81% of
deaths caused by antidepressant overdoses attribut-
able to the TCAs [34]. This would appear to have
been a very powerful argument for not using the
TCAs to treat depression. However, only about 4%
of all suicides are due to overdoses of a single anti-
depressant [37], and other methods of suicide, such
as hanging or shooting are more common, especially
among young people (the most vulnerable group)
[38]. Among those who take an overdose as the
means to end, medications such as dextro-
propoxyphene and short-acting barbiturates were
used more commonly (after correcting for the
number of prescriptions) in a recent Australian study
[39]. Over-the-counter medications (such as parac-
etamol) can also be lethal in overdose, yet there is no
suggestion that these should be withdrawn from the
market or not used. By the same token, other effec-
tive psychotropic agents used in the treatment of
bipolar depression, such as lithium, are potentially
lethal in overdose yet there is no suggestion that we
should not use them because they can be potentially
harmful if taken in overdose.
The important issue is the appropriate management
of potentially suicidal depressed patients [37]. The
‘safety in overdose’ argument with the SSRIs would
suggest that good clinical care doesn’t come into it,
that the patient can just be given tablets that won’t
kill them if they overdose on them. The essence of
good management of the suicidal patient is compre-
hensive clinical care including: careful and compre-
hensive initial and ongoing clinical assessment; risk
assessment; treatment in an appropriate setting; and
the use of appropriate pharmacological, psycho-
logical and social interventions. Simply prescribing a
medication that won’t kill the patient if they take a
large dose is not the answer. Rather than representing
good care, this approach may encourage less com-
prehensive and vigilant treatment of a potentially sui-
cidal patient and pharmacological sloppiness,
presenting another situation where treatment falls
wide of the standard of reasonable skill and care
required of medical practitioners in Australia [3].
Second, younger persons (currently the most at-
risk group for suicide) who may have a non-melan-
cholic depression may have responded better to non-
pharmacological treatments than the injudicious and
inappropriate use of an antidepressant in the first
place.
Summary
It is premature to write off the tricyclics or relegate
them to second-line treatment for depression. We
argue that they have a place as a first-line treatment
for severe (melancholic) depression where they seem
to have a therapeutic advantage over the newer
agents. If prescribed properly, along with the appro-
priate counselling, they are well tolerated and have
few drug interactions to worry about. The risk of
suicide for depressed patients will always be there;
this needs to be dealt with by good clinical care and
taking the appropriate precautions with a potentially
lethal medication rather than selecting a drug which
is safe in overdose.
While we do not advocate the wholesale usage of
the TCAs (the newer agents have an important place
in the pharmacotherapy of depression), we consider
that they have an important role in the treatment of
severe depression. The TCAs do have a different
side-effect profile to the SSRIs. This different side-
effect profile may be a considerable advantage to
some patients, whereas to others it may be an imped-
iment to taking the TCA. In considering tolerability
issues, it is important to keep in mind potential drug
interactions related to the P450 system, and the
possibility of a serotonin syndrome arising. Finally,
while the new agents are safer when taken in over-
dose, managing suicidal patients involves high
quality clinical care, not just prescribing a safe agent.
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