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Choosing
the right antidepressant
Points
to be considered
by
David
Baldwin MB
BS FRCPsych
David
Baldwin is Reader in Psychiatry, Clinical Neuroscience
Division, Faculty of Medicine, Department of Health and
Life Sciences, University of Southampton,
UK.
Although
a major health problem, depression is still
under-recognised in primary care (1).
When diagnosed, however, depression can be
successfully treated in most cases. The variety of
antidepressant medication available is so rich that
the choice of the best treatment is not always easy.
This article highlights the important points to
consider when choosing the best antidepressant for an
individual depressed patient.
Please
note: Clicking on the link on the reference numbers,
for example [1,
2]
will open a window with the full reference. Please
remember to close the Reference window.
To treat or not
to treat?
According to the World Health Organisation Report
2001 (2),
the lifetime prevalence of a depressive episode is 16% to
18% (1 in 5 women, 1 in 10 men) with an annual prevalence
of 3% to 10%. After a first depressive episode whose
average duration is about 20 weeks, there is a 50%
lifetime risk of another episode. After a second episode
this risk increases to 80% to 90%. Generally the duration
is longer and the severity greater for each recurrent
episode. Between 2% and 15% of depressed patients develop
chronic depression. In spite of its frequency, depression
is under-recognised and consequently under-treated
leading to unnecessary suffering and cost to the
community. Approximately one patient in 10 seen in
primary care is suffering from a depressive disorder.
Because depressed mood is rarely the principal complaint
of the patient, depression often goes unrecognised by
both patient and doctor.
Are
antidepressants useful?
Anderson et al. (3)
have shown that moderate to severe depression
(Hamilton
depression rating scale
or HDRS > 17) is clearly improved by
antidepressant drugs and Montgomery and Dunbar
(4),
Terra and Montgomery (5)
and Rouillon et al. (6)
have shown that, in addition, antidepressants
significantly reduce the risk of new depressive episodes.
There is therefore a general concensus that moderate to
severe depression should be treated as quickly and as
effectively as possible.
Which
antidepressant?
The following criteria (Table 1) should contribute to
the choice of which particular antidepressant to
prescribe for a specific patient.
Table
1
Each of these are
discussed in detail below.
The following
criteria in Table 2 are not valid elements to guide the
choice
Table
2
|
Non-valid
selection criteria
|
|
Drug
acquisition costs*
|
|
Drug
company
|
|
Fashion
|
*
drug aquisition costs represent a very small part of
overall cost of treating depression (6a)
Efficacy
The symptoms of depression are associated with a
decrease in the neurotransmission of monoamines, mainly
serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline
(NA) (7,
8).
Virtually
all antidepressants
have been conceived with the aim of correcting this
deficiency.
Several
meta-analyses (3,
9,10)
have compared short-term efficacy (< 3
months) between different classes of antidepressant
(Table 3).
Table
3
|
Short-term
efficacy of different antidepressant classes
|
|
All
studies
|
TCA =
SNRI = SSRI
|
|
Hospitalised
patients
|
TCA =
SNRI > SSRI
Dual action TCA > SSRI
Single action* TCA = SSRI
|
|
*acting
only on NA such as desipramine and
maprotiline
|
Taken overall
the activity of the major classes of antidepessants are
similar. When results in the more seriously
depressed, hospitalised patients are considered,
antidepressants acting with a dual mechanism of action
(inhibition of the reuptake of serotonin and
noradrenaline) have a greater efficacy. This greater
efficacy is clearly visible in the comparison of the
results from three meta-analyses (11,12,13)
(Figure 1) showing that the remission rate at 6 weeks is
equivalent for different classes of dual acting
antidepressants, TCA (imipramine) and SNRI (milnacipran
and venlafaxine) but significantly less with SSRI.
Figure 1.
Short-term remission with dual action antidepressants
and SSRI
Long-term
efficacy
60 to 80% of patients respond (defined as a 50% reduction
in the severity or number of symptoms to antidepressant
therapy) (3)
to short-term antidepressant treatment. However, full
remission (negligible symptoms or < 8 on HDRS) is
obtained in less than 50% of patients. In addition to the
suffering, a high level of residual symptoms is a strong
risk factor for recurrence of new depressive episodes. A
follow-up of patients treated with antidepressants found
that after 6 years only 19% had recovered and were
continuously well. 18% were continuously ill or had
committed suicide while 63% had recovered but had
suffered one or more subsequent recurrent episodes
(14).
The long-term
efficacy in preventing the recurrence of new depressive
episodes has been demonstrated for several TCA with
imipramine being the most studied for periods of up to 5
years (15).
The results of long-term treatment with SSRI
and SNRI
show that these classes of antidepressants are also
significantly more efficacious than placebo in preventing
recurrent depressive episodes.
Adverse
events
Tricyclic antidepressants are prescribed at the
recommended dose and for the recommended duration in less
than 40% of depressed patients (16).
The majority of patients take these antidepressants at
insufficient doses and for inadequate durations. In
contrast, SSRI and SNRI are nearly always given at doses
shown to be effective and more frequently prescribed for
an adequate duration (3).
The discrepancy between TCA and SSRI/SNRI is explained by
the frequent occurrence of undesirable and unpleasant
side effects with TCA. These adverse effects are
responsible for the poor compliance seen with these
antidepressants (3,17).
Nearly 15% of patients receiving TCA withdraw from
treatment because of adverse events, compared with less
than 8% of patients taking SSRI (18).
The
tolerability of SNRI
such as milnacipran and venlafaxine is globally
comparable with that of SSRI and much better than that of
TCA.
Safety
in overdose
The safety margin is small with TCA since ingestion
of only 5 times the daily dose can be lethal. In contrast
SSRI and SNRI show only some rare serious adverse events
at 30 times the daily dose. A study of mortality due to
overdose (19)
calculated the fatal toxicity index (deaths per million
prescriptions from 1987 to 1992). For TCA the index
was 34.1 and for SSRI 2.0. In a similar study
(19)
for the period 1993-1999 the index for venlafaxine was
found to be 13.2. Data for milnacipran is not available.
The lethal potential of an antidepressant drug is an
important element to consider in cases where an overdose
may be taken to attempt suicide.
Suicide
risk
Although the use of modern antidepressants reduces
the risk of toxicity in overdose whether accidental or as
a suicidal act, suicide remains a risk inherent to the
management of depression. All successful antidepressant
treatments reduce the risk of suicide in the long term.
There are suggestions, however, that some antidepressants
may reduce the risk to a geater extent than others. In a
post-hoc analysis (Figure 2) of the clinical development
database of the SNRI, milnacipran, Kasper
(20)
showed that suicides and attempted suicides (standardised
to events per 100 patient years) differed between
treatment groups.
Figure
2. Suicides and suicide attempts with milnacipran and
comparator compounds during the clinical development
programme of milnacipran
(Data
standardised to events per 100 patients
years.)
The incidence
was considerably higher in the SSRI-treated group than in
the two other groups. More recently, a meta-analysis has
suggested that suicides and suicide attempts in patients
treated with SSRI are in excess of that found with
placebo (21).
However, another study based on a review of FDA summary
reports concludes that the risk of suicide with SSRI was
no greater than with placebo or other types of
antidepressants (22).
Finally, as
mentioned above, the toxicity of tricyclic
antidepressants is likely to increase the number of
"successful" suicides when these antidepressants are
prescribed even though the number of suicide attempts may
be reduced.
Sexual
dysfunction
Sexual dysfunction is now seen as a major problem
with SSRI treatment. In an 8 week study with fluoxetine,
paroxetine and sertraline, for example, 60% of men and
57% of women spontaneously reported sexual dysfunction
associated with SSRI therapy. Most commonly problems were
associated with orgasm (22a).
The situation with SNRI antidepressants is unclear.
Sexual dysfunction has been reported to be frequent with
venlafaxine (22b).
Although there have been no specific studies with
milnacipran, in clinican trials spontaneous reports of
sexual dysfunction have been very infrequent
(22c).
Deakin and Dursan (22d)
have estimated the prevalence to be lower with
milnacipran than with venlafaxine and much lower than
with the SSRIs.
Potential
drug interactions
Most foreign substances are metabolised in the liver
by the enzymes of the cytochrome P450 system and their
metabolism is thus sensitive to hepatic insufficiency,
enzyme polymorphism and drug-induced enzyme inhibition or
induction. More particularly psychotropic drugs such as
TCA, antipsychotics such as clozapine, haloperidol,
benzodiazepines etc. are metabolised by various
cytochrome P450 enzymes and many SSRI inhibit these
enzymes at clinical doses (23).
Such inhibition can reduce drug metabolism and lead to
adverse effects or intoxication due to high circulating
doses. The risk of interactions of SSRI with other drugs
represents a constant danger that the physician must be
aware of because the consequences can be dramatic.
Although TCA have been shown to inhibit cytochrome P450
enzyme in the laboratory, this does not occur at clinical
doses. Similarly the effects of venlafaxine are only seen
at high doses. Interestingly the SNRI, milnacipran, is
not metabolised in the liver and is eliminated mainly as
the parent compound and the inactive glucuronide
conjugate (24).
It is therefore completely devoid of interactions with
the cytochrome P450 system so that there is no risk of
interaction with co-prescribed medication
(25).
Withdrawal
effects
As mentioned above, most antidepressants have an
impact on the serotonergic system. Following repeated
treatment the serotonergic system adapts to the new level
of stimulation. If this stimulation is abruptly
interrupted, as in case of sudden treatment
discontinuation, a cluster of symptoms, known as the
serotonergic discontinuation syndrome (Table 4), occurs.
This is particularly true for the SSRI whose action is
strictly concentrated on the serotonergic
system.
Table
4
|
Serotonergic
discontinuation syndrome
|
|
Dizziness
|
Unstable gait
(has
been mistaken for stroke)
|
|
Nausea
|
Insomnia
|
|
Fatigue
|
Restlessness
|
|
Headache
|
Shock-like
sensations (rare
but very characteristic)
|
In untreated
patients, the syndrome lasts more than one week. If the
original SSRI is reintroduced, the syndrome lasts less
than 72 h (3,26).
Severity and
frequency of the syndrome depend on the drug, the rank
for the SSRI is following:
|
Paroxetine
>
|
Fluvoxamine
>
|
Sertraline
>
|
Citalopram
>>
|
Fluoxetine
|
(26).
The syndrome can be
confused with side effects of another antidepressant in
case of switching (27).
The phenomenon is
not limited to SSRI. There are also numerous reports
(28,
29)
that suggest that up to 30% of patients on imipramine
also suffer from withdrawal symptoms. Indeed in a
comparison between paroxetine and clomipramine
(30)
found a higher rate of withdrawal symptoms with the
tricyclic drug.
Among the SNRI
antiderpessants, there have been some reports of
withdrawal effects with venlafaxine(31).
As part of a long-term treatment protocol, milnacipran,
was abruptly discontinued after 24 weeks treatment when
half of the patients were switched to placebo. No
symptoms of the serotonergic discontinuation syndrome
were observed (6).
Conclusions
Depression is a common and disabling condition which
can be succesfully treated in the majority of cases. The
treatment of depression is difficult, however, since
clearly the dysfunction of several neurobiological
systems are involved. There is no overall "best
antidepressant" and it is unlikely that the ideal drug
for all patients will ever be found. However, there is an
antidepressant that is most suitable for an individual
patient and this is what the physician must try to
identify. Not all of the above criteria have the same
importance in all patients.
In a severely depressed patient, the physician might
consider that efficacy is the most important factor. In
elderly, polymedicated patients, a benign side-effect
profile and a low risk of drug interaction will be of
paramount importance. In sexually active patients,
antidepressants giving a low level of sexual dysfunction
would be sought. In a patient with a history of suicide
attempts, a drug which might increase suicide risk would
be avoided ...and so on.
Poorly tolerated drugs lead to poor compliance, others
can lead to withdrawal problems. Such effects
frequently result in a loss of mutual confidence between
doctor and patient (32)
which is an essential prerequisite for therapeutic
success in depression. To patients reading this article
the recommendation is to find a skilled clinician with
whom you can establish a relationship of mutual
confidence. Doctor and patient together have then to
chose the best antidepressant for that patient. This
choice depends on the importance of the different
criteria for each patient. Establishing a
grid
of criteria priority
may help the clinician weigh each criteria in relation to
the patient's state and finally select the mostly adapted
medication.
Greater
professional training, especially of primary care
physicians, is necessary to improve the clinical outcomes
in depression. Knowledge of the a patient's history and
the characteristics of his depression, understanding of
the properties of each available antidepressant and
estimation of importance of each criteria of choice for
the individual patient give the depressed patient the
best chance to recover and remain well
permanently.
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Last
updated January 2006
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