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1.
Introduction
The discovery of
monoamine oxidase inhibitors (MAOIs) and tricyclic
antidepressants (TCAs) in the 1950s revolutionised the
treatment of depression. Although these compounds can
bring profound benefit and relief from suffering they are
associated with considerable side effects and even
toxicity (Gumnick
and Nemeroff, 2000; Pacher
et al., 2001; Martinez
and Marangell, 2004; Pacher
and Kecskemeti, 2004).
The introduction in the mid-1980s of more selective and
better tolerated drugs, the selective serotonin reuptake
inhibitors (SSRIs), has enabled many patients to benefit
from effective antidepressant therapy without
uncomfortable, distressing and often dangerous adverse
effects.
SSRIs are now used
as a first-line treatment for depression, in part because
of their relatively benign adverse effect profile and
safety in overdose, especially compared with the older
TCAs and MAOIs. However, their efficacy in depression is
no greater and their onset of action is no more rapid
than that of the MAOIs or TCAs. In addition, they are not
completely devoid of side effects (Mourilhe
and Stokes, 1998).
Sexual dysfunction, weight gain and sleep disturbance are
the most troubling adverse events seen during long-term
SSRI therapy (Ferguson,
2001).
SSRIs are devoid of receptor interactions and their
associated side effects which characterise MAOIs and TCAs
(Richelson,
1996), and
their only apparent pharmacological activity is the
inhibition of the reuptake of serotonin. Most of side
effects result from an over-stimulation of various
serotonin receptors in both the brain and the periphery
(Lieberman,
2003). The
most common side effects associated with SSRIs such as
nausea and headache, nervousness, insomnia and sexual
dysfunction (Kelsey,
2001) are
related to the stimulation of 5-HT2 and 5-HT3 receptors.
Many of the side
effects of SSRIs are transient and subside over time, and
can be minimized by having patients take the drug with
meals and starting treatment with low doses followed by a
slow titration to recommended doses (Kelsey,
2001).
Overall, compared
to the old generations of antidepressants, the SSRIs
present a therapeutic option that is attractive to the
majority of primary care physicians, psychiatrists and
patients. However, with the passage of time certain
problems are emerging in relation to long term treatment
with the SSRIs.
2.
Cardiovascular side effects
Cases of
arrhythmias, prolonged QTc interval on electrocardiogram
(Isbister
et al., 2004;
Odar-Cederlöf
et al., 2006)
and orthostatic hypotension (Pacher
and Ungvari, 2001)
have been reported with SSRIs in patients with no
previous history of cardiovascular disorders suggesting
possible exceptions to the cardiovascular safety of these
compounds. Experimentally, in different mammalian animal
and human cardiovascular preparations, SSRIs have been
shown to elicit strong cardiovascular depressant effects
by inhibiting cardiac and vascular Na+, Ca2+ and K+
channels, providing possible mechanistic explanations of
the clinical reports (see
the review by Pacher
and Kecskemeti, 2004).
Although rare, the existence of clinically important
cardiac and vascular effects shows the need for vigilance
especially when prescribing SSRIs to patients with
cardiovascular disorders.
3.
Suicidality
Cases of
SSRI-induced suicidality (suicide attempts and suicidal
ideation) have been reported both in adults
(Teicher
et al., 1990;
Rothschild
and Locke 1991; Hawthorne
and Lacey 1992)
and in adolescents and children. It is worth noting,
however, that in spite of a certain risk of suicidality
with SSRIs (and probably with all antidepressants) a
recent study demonstrated that continued antidepressant
treatment is associated with overall reduced risk of
suicide (Sondergard
et al., 2007).
- Paediatric
and adolescent patients
Recent attention
has focused on the possible risks of antidepressant
treatment in children and adolescents. The US Food and
Drug Administration (FDA) reviewed 24 placebo-controlled
trials of antidepressants in paediatric and adolescent
patients with depression and found that they cause a
2-fold (4% v 2%) increased risk for suicidal
behaviour/ideation. Thus in 2004 the FDA warned the
public about the risks of these drugs in children and
adolescents (under 18 years) but did not prohibit their
use. In 2005, FDA asked manufacturers of SSRIs to include
a black box warning statement in product labelling
recommending monitoring in young patients for the
occurrence of suicidality. Following the FDA warnings,
families and clinicians have become increasingly
reluctant to use antidepressants in children and
adolescents and prescriptions numbers have reduced
dramatically with a disconcerting parallel increase in
adolescent suicide (Lineberry
et al., 2007).
A meta-analysis in
patients younger than 19 years with major depressive
disorder showed that the benefits of second-generation
antidepressants (SSRIs, nefazodone, venlafaxine, and
mirtazapine) was significantly greater than the risks of
suicidal ideation and suicide attempts which supports the
careful, well-monitored use of these agents
(Bridge
et al., 2007).
In May 2007 the FDA
proposed that makers of all antidepressant medications
extend the existing black box suicidality warning to
young adults aged 18 to 24. The new proposed warning
emphasizes, however, that depression itself may lead to
suicide and that antidepressant medications benefits most
patients. The FDA advises that patients of all ages who
are started on antidepressants should be monitored for
worsening depressive symptoms, especially suicidal
thoughts or behaviours or unusual changes in behaviour.
For more details on
these findings and decisions, see Controversy section.
- Elderly
patients
Despite the
frequent use of antidepressants in elderly patients
(Mamdani
et al., 2000;
Sambamoorthi
et al., 2003)
only two studies have addressed the risk of suicidality
in this population. One study found a substantial
increase in the relative risk of suicide following the
initiation of SSRI treatment in older patients
(Juurlink
et al., 2006),
while the other (Barak
et al., 2006)
has shown that elderly depressed patients treated with
SSRIs may be at reduced risk of attempting
suicide.
4.
Sexual dysfunction
Sexual dysfunction
is common among both men and women with major depressive
disorder. A study revealed that of 134 patients with
major depression surveyed, 40% of men and 50% of women
reported decreased sexual interest (Kennedy
et al., 1999),
while 40% to 50% of the sample also reported reduced
levels of arousal. Sexual dysfunction is also a common
side effect of SSRIs (Balon,
2006). The
assessment of SSRI-induced sexual dysfunction is thus
complicated by the fact that such effects may result from
the depressed state. It is clear, however, that SSRIs may
negatively influence any or all phases of the sexual
cycle with decreased or absent libido, impairment of
arousal and erectile dysfunction but delayed ejaculation
and absent or delayed orgasm are their most common
effects (Rosen
et al., 1999).
A European survey (Williams
et al., 2006)
estimated the prevalence of SSRI-induced sexual
dysfunction to be 26.6% of a French sample and 39.2% of a
British sample. Patients reported that experiencing these
sexual impairments negatively affected their quality of
life, self-esteem, mood and relationships with sexual
partners.
If ignored, sexual
dysfunction can maintain the depression, compromise
treatment outcome and lead to non-compliance. This may be
a particular problem for patients on maintenance therapy
since treatment interruption may trigger recurrence of
depression (Werneke
et al., 2006; Cohen
et al., 2007).
Consequently, patients should be monitored early in the
treatment with SSRIs for adverse sexual effects.
5.
Risks during pregnancy
Up to 20% of
pregnant women suffer from depression (Patkar
et al., 2004;
Ryan
et al., 2005)
and pharmacotherapy for depression is often necessary
during pregnancy (Ryan
et al., 2005).
In a study of 201 women with a history of major
depressive disorder before pregnancy, 68% of those who
discontinued treatment relapsed during pregnancy compared
with only 26% of those who continued treatment
(Cohen
et al., 2006),
indicating the importance of treating depressed pregnant
women. The question remains as to whether infants of
women taking antidepressants have worse birth outcomes
and, if so, whether the risks are due to the medication
or to the psychiatric condition. SSRIs cross freely the
placental barrier and are thus transferred to foetus as
well as to the newborn during lactation (Lattimore
et al., 2005;
Austin,
2006).
Therefore both the foetus and the newborn can suffer from
the adverse effects of the SSRIs, including long-term
neurodevelopmental disturbances. There is an increased
risk for neonatal adaptation problems in offspring
exposed to SSRIs in late (third trimester) pregnancy,
which may cause irritability, constant crying, eating and
sleeping difficulties, and even seizures in newborns
(Laine
et al., 2003).
It has been suggested that the symptoms were related to
central nervous system serotonergic over
stimulation.
The main effects of
SSRIs during pregnancy are the following:
Teratogenicity
In general SSRIs
are not major teratogenic compounds. However, some recent
studies have shown that the use of SSRIs, particularly
paroxetine, early in pregnancy is related to a moderately
increased risk of congenital malformations in offspring
(Wogelius
et al., 2006; Donnelly
and Paton, 2007).
Increased risk of having an infant with major congenital
malformations (adjusted OR = 2.23), or major cardiac
malformations (adjusted OR = 3.07) was found in women
exposed to > 25 mg/day of paroxetine during the first
trimester of pregnancy (Berard
et al., 2007).
Another recent study (Louik
et al., 2007)
did not find any significantly increased risks of defects
associated with SSRI use overall. Specific SSRIs, notably
paroxetine and sertraline; may confer increased risks for
some specific defects. These defects are rare, however,
and the absolute risks are small.
Persistent
pulmonary hypertension
When taken during
late (after the 20th week of gestation) pregnancy SSRIs
can be associated with the development of persistent
pulmonary hypertension in the newborn, according to the
results of a recent case-control study (Chambers
et al., 2006).
Neonatal
withdrawal syndrome
A database analysis
has found that SSRIs given during pregnancy may lead to
withdrawal symptoms in the neonate characterised by
convulsions, irritability, abnormal crying, and tremor
(Sanz
et al., 2005).
A review by Thormahlen (2006)
has concluded that SSRIs are associated with neonatal
withdrawal symptoms such as respiratory distress,
irritability, lethargy, and tremors. Paroxetine is more
commonly associated with neonatal withdrawal than other
SSRIs. In a cohort study, 30% of infants exposed to SSRIs
had poor neonatal adaptation, compared with 9% of
drug-free controls (p = 0.018) (Oberlander
et al., 2004).
In 2006, the
American College of Obstetricians and Gynaecologists
(ACOG
) has recommended against the use of SSRIs during
pregnancy, unless treatment is absolutely required and no
other options exist. The ACOG proposes that clinicians
and patients should decide on an individual basis whether
the benefits of SSRI therapy outweigh the associated
risks.
6.
Hyponatremia
Hyponatremia (serum
sodium concentrations below 130 mEq/l) can lead to
disturbing symptoms (Table 1) which can cause serious
morbidity and even death (Guay,
2000).
Table 1.
|
Symptoms
related to hyponatremia
|
|
Na+
(mEq/l)
|
Symptoms
|
|
120 -
130
|
Nausea and
malaise
Headache
Lethargy
Muscle cramps
Disorientation
Restlessness
|
|
<
120
|
Seizures
Coma
Respiratory arrest
|
Hyponatremia is
associated with SSRI use, with an incidence which varies
from 0.5% to 32% (Jacob
and Spinler, 2006).
The condition develops within the first few weeks of
treatment and resolves within 2 weeks of therapy
discontinuation. SSRI-induced hyponatremia is probably
secondary to development of a syndrome of inappropriate
secretion of antidiuretic hormone (Romero
et al., 2007; Rottmann,
2007). Risk
factors for developing SSRI-induced hyponatremia are
advanced age, female gender and the concomitant use of
diuretics. This potentially life-threatening adverse
event should be taken seriously particularly in the
fragile population of elderly who often are polymedicated
and take diuretics.
7.
Bleeding
Release of
serotonin from platelets facilitates platelet
aggregation. Platelets do not synthesize serotonin and
are dependent on the reuptake process for their serotonin
content. SSRIs, by inhibiting the reuptake of serotonin
into the platelet, cause a decrease in platelet
serotonin, leading to a decrease in serotonin release,
resulting in reduced platelet aggregation and prolonged
bleeding (Dalton
et al., 2003).
The few epidemiology studies that have investigated the
association between SSRIs and upper gastrointestinal
tract bleeding provide only weak evidence to support a
link (Yuan
et al., 2006).
In general the risk of bleeding with SSRI treatment is
low (Serebruany,
2006; Reeves
et al., 2007).
However, the risk of bleeding is increased with
concomitant use of aspirin or non-steroidal
anti-inflammatory drugs (NSAIDs) (Yuan
et al., 2006; Turner
et al., 2007 ).
Two studies found that the risk for an upper
gastrointestinal bleed from the concurrent use of NSAIDs
or low-dose aspirin with a SSRI exceeded the additive
risk of the agents alone (Mort
et al., 2006).
A multicentre retrospective analysis (Wessinger
et al., 2006)
concluded that it is highly recommendable to avoid the
combination of SSRIs with any medication that increase
bleeding risk.
8.
Risk of fracture and osteoporosis
SSRI use in older
adults (over 50 years) is associated with increased risk
of incident clinical fragility fracture, increased odds
of falling and lower bone mineral density at the hip
(Richards
et al., 2007).
Another study in men over 65 has also reported
significantly lower bone mineral density in SSRI users
but not in those taking other antidepressants
(Haney
et al., 2007).
Since depression and bone fragility are both common in
the elderly, it is highly recommendable to avoid the SSRI
therapy in this age group. Osteoblasts and osteoclasts
possess both 5-HT receptors and 5-HT transporters which
probably explains the action of SSRIs in osteoporosis and
skeletal fractures (Lerner,
2005).
9.
Extrapyramidal symptoms
Extrapyramidal
symptoms (EPS) are rare adverse drug reactions to SSRIs.
The risk of EPS seems to increase with advanced age (>
65 years) and with the presence of the A1 allele of D2
dopamine receptor gene Taq1A polymorphism
(Hedenmalm
et al., 2006a).
The mechanism involved in SSRI-induced extrapyramidal
symptoms has been suggested to be the inhibitory
influence of serotonin on dopaminergic neurotransmission
(Arya,
1994). This
same mechanism is thought to be involved in other rare
dopaminergic adverse events seen with SSRIs namely
hyperprolactinemia, galactorrhea, mammary hypertrophy,
and gynaecomastia (Damsa
et al., 2004).
10.
Apathy, amotivation and frontal lobe
syndrome
Rare cases of
apathy, lack of motivation and frontal lobe syndrome have
been reported in adults, adolescents and children treated
with SSRIs (Hoehn-Saric
et al., 1990, 1991;
George
and Trimble, 1992; Garland
and Baerg, 2001).
A recent case control study in elderly depressed patients
also showed that apathy occurred more frequently in those
receiving SSRIs than non-SSRI antidepressants
(Wongpakaran
et al., 2007).
A comparison of SSRIs and selective noradrenaline
reuptake inhibitors in depression (Dubini
et al., 1997)
concluded that, while both classes were similarly active
on most depressive symptoms, serotonergic drugs produce
less improvement in motivation than the noradrenergic
agents. This is consistent with a more widespread
negative effect on motivation by SSRIs.
11.
Weight gain
When used for 6
months or less, SSRIs are not likely to cause weight gain
and opinions vary as to whether they cause weight gain
when used for one year or longer (Deshmukh
and Franco, 2003).
Paroxetine may be more likely than other SSRIs to cause
weight gain during both short-term or long-term treatment
(Pae
and Patkar, 2007).
However this adverse event induced by the SSRIs is less
of a problem than that caused by other recent
antidepressants such as mirtazapine (Laimer
et al., 2006)
and many older antidepressants (tricyclics and monoamine
oxidase inhibitors) (Cassano
and Fava, 2004).
12.
Sleep disturbance
SSRIs interfere
with sleep architecture. Fluoxetine, paroxetine and
sertraline delay REM sleep onset, while fluoxetine and
paroxetine increase awakenings and reduce REM sleep,
slow-wave sleep, total sleep time and sleep efficiency.
In contrast sertraline tends to reduce nocturnal wakening
(Ferguson,
2001). In a
naturalistic setting, drowsiness was reported by 17% of
patients receiving SSRIs (Hu
et al., 2004)
The acute adverse effects of SSRIs on sleep persist with
long-term treatment (Ferguson,
2001;
Silvestri
et al., 2001).
SSRI use by older women, including those with no
depressive symptoms, is associated with sleep
disturbance, including poor sleep efficiency, long sleep
latency, and sleep fragmentation, manifested by multiple
long wake episodes (Ensrud
et al., 2006).
13.
Other effects
Cases of alopecia
associated with SSRIs have been reported, notably with
sertraline administered for one year at 50 mg per day
(Hedenmalm
et al. 2006b).
Hair loss improved after a dose reduction to 25 mg per
day(Hedenmalm
et al. 2006b).
However this adverse event is rare and appears to be more
common in women. Although SSRIs do not increase road
accident risk in depressed patients (Barbone
et al., 1998),
a controlled study assessing actual driving performance
has found that depressed patients receiving long-term
treatment with SSRI antidepressants showed impaired
driving performance, without deficits in memory,
psychomotor and attention functions (Wingen
et al., 2006).
The impairment observed following the acute
administration of the SSRIs persisted with time for up to
a year.
14.
Discontinuation effects
When SSRIs are
discontinued, adverse effects such as nausea,
irritability, anxiety, and muscular aches can also occur
(Himei
and Okamura, 2006).
These effects can be minimized by gradually tapering the
dose when discontinuing an SSRI (Martinez
and Marangell, 2004).
The discontinuation syndrome is most commonly associated
with the use of paroxetine and is more likely to occur in
patients who experienced adverse reactions in the early
phase of treatment (Himei
and Okamura, 2006).
Persistent sexual side effects after SSRI discontinuation
have been observed (Csoka
and Shipko, 2006).
15.
Conclusion
Depression is a
highly prevalent, chronic and recurrent disorder.
Long-term treatment of depression consolidates the
improvement obtained during the acute phase of the
treatment and prevents relapses and recurrences of the
disorder. Many early-onset side effects of the SSRIs such
as nausea, diarrhoea, headache and agitation, disappear
within 2-3 weeks. Long-term side effects may, however, be
more important in terms of patient compliance and quality
of life. Adverse events that persist as long as the
patient takes the medication such as those described here
represent a knottier problem. Unfortunately many of them
are not as well described as those in the drug package
insert, which are based on short-term studies. In
addition many of the long-term adverse effects such as
sexual dysfunction, weight changes and sleep disorders
can be confused with depressive symptoms making it
difficult to distinguish them from residual depressive
symptoms (Wingen
et al., 2006).
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