Selective Serotonin Re-Uptake Inhibitors

The use of SSRIs

As implied by their name, the selective serotonin re-uptake inhibitors, commonly abbreviated to SSRIs, selectively inhibit the re-uptake of the neurotransmitter serotonin (also known as 5-hydroxytryptamine or 5-HT for short). The major SSRIs in clinical use are:

fluvoxamine (which was the first SSRI to be introduced into clinical practice in the UK, in 1987)
fluoxetine (launched in the UK in 1989)
sertraline (launched in the UK in 1990)
paroxetine (launched in the UK in 1991)
citalopram (launched in the UK in 1995)
escitalopram (launched in the UK in 2002).

In contrast to tricyclic antidepressants, tricyclic-like antidepressants and MAOIs (see Chapters 7 and 8), SSRIs and SSRI-related antidepressants (see Chapter 10) were promoted as having the virtue of being safer in overdose and, unlike tricyclic antidepressants, being less likely to cause antimuscarinic and cardiac side-effects.

Risk of suicide or hostility

Starting in the 1990s, the use of SSRIs has become increasingly controversial. In particular, it has been suggested that there appears to be a risk of suicidal and perhaps even homicidal thoughts in patients who receive SSRI medication; this risk appears to be increased when there is a change in dosage of the SSRI (either an increase—including starting the drug in the first place—or a decrease). For example, the review by Healy and Whitaker (2003) of randomized controlled trials, meta-analyses of clinical trials, and epidemiological studies undertaken to investigate this issue concluded that

‘These same [randomized controlled trials]… revealed an excess of suicidal acts on active treatments compared with placebo, with an odds ratio of 2.4 (95% confidence interval 1.6-3.7). This excess of suicidal acts also appears in epidemiological studies. The data reviewed here make it difficult to sustain a null hypothesis that SSRIs do not cause problems in some individuals.’

On the other hand, there have been several systematic studies which have failed to detect such a risk in adults (Isacsson et al., 2005; Gibbons et al., 2005; Martinez et al., 2005; Fazel et al., 2006), although there is some evidence of a possible risk in those aged 18 years or younger, particularly if unpublished trial results are taken into account (see, for example, Whittington et al., 2004; Martinez et al., 2005). The issue remains controversial (see, for example, Goldsmith and Moncrieff, 2011).

The British National Formulary (62nd edition; September 2011) gives the following advice:

‘Depressive illness in children and adolescents

The balance of risks and benefits for the treatment of depressive illness in individuals under 18 years is considered unfavourable for the SSRIs citalopram, escitalopram, paroxetine, and sertraline, and for mirtazapine and venlafaxine. Clinical trials have failed to show efficacy and have shown an increase in harmful outcomes. However, it is recognised that specialists may sometimes decide to use these drugs in response to individual clinical need; children and adolescents should be monitored carefully for suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment.

Only fluoxetine has been shown in clinical trials to be effective for treating depressive illness in children and adolescents. However, it is possible that, in common with the other SSRIs, it is associated with a small risk of self-harm and suicidal thoughts. Overall, the balance of risks and benefits for fluoxetine in the treatment of depressive illness in individuals under 18 years is considered favourable, but children and adolescents must be carefully monitored as above.’

All patients being treated with SSRIs and SSRI-like antidepressants should be regularly checked for evidence of:

hostility
self-harm
suicidal behaviour.

This is particularly important at the time of sudden changes in dosage, including:

at the start of treatment
at the time of dose change (in either direction).

Interactions with MAOIs

Treatment with an MAOI should be stopped at least 2 weeks before starting treatment with an SSRI or related antidepressant. However, if switching from an SSRI to an MAOI (or to the RIMA moclobemide), a treatment-free period is needed, as follows:

at least 5 weeks if switching from fluoxetine
at least 2 weeks if switching from sertraline
at least 1 week if switching from another SSRI (other than fluoxetine or sertraline).

Withdrawal reactions and dependency

The following advice has been issued by the Committee on Safety of Medicines (CSM) (from the Report of the CSM Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor Antidepressants, December 2004):

‘It has been known for some time that, as with other antidepressants, the SSRIs and related antidepressants are associated with withdrawal reactions, although different SSRIs appear to cause withdrawal reactions to different extents. The Group considered data from clinical trials, the published literature and spontaneous reports from health professionals and patients. The Group’s conclusions can be summarized as follows:

All SSRIs may be associated with withdrawal reactions on stopping or reducing treatment. Paroxetine and venlafaxine seem to be associated with a greater frequency of withdrawal reactions than other SSRIs. [Paroxetine and venlafaxine have relatively short half-lives.] A proportion of SSRI withdrawal reactions are severe and disabling to the individual.
The most commonly experienced withdrawal reactions are dizziness, numbness and tingling, gastrointestinal disturbances (particularly nausea and vomiting), headache, sweating, anxiety and sleep disturbances.
Awareness of the risk of withdrawal reactions associated with SSRIs needs to be increased amongst both prescribers and patients.
There is evidence that withdrawal reactions are less severe when the dose is tapered gradually over a period of several weeks, according to the patient’s need. Availability of low dose formulations to allow gradual titration is important.
There is no clear evidence that the SSRIs and related antidepressants have a significant dependence liability or show development of a dependence syndrome according to internationally accepted criteria (either DSM-IV or ICD-10).’

Side-effects of SSRIs

The following side-effects apply to all the SSRIs. Additional side-effects that relate to individual SSRIs are listed for each drug.

general:
- hypersensitivity reaction—may include rash and vasculitis; it is probably prudent to stop the SSRI if an otherwise unexplained skin rash appears
- urticaria
- angio-oedema
- anaphylactoid reaction
- asthenia
- chills
- dry mouth
- photosensitivity
- pruritus
- serum sickness-like reaction
- sweating
- vasodilatation
- arthralgia
- myalgia
- hyponatraemia (may be caused by inappropriate ADH secretion)
- galactorrhoea
gastrointestinal:
- nausea
- vomiting
- dyspepsia
- abdominal pain
- diarrhoea
- constipation
- dysphagia
- taste alteration
haematological:
- ecchymosis
- purpura
nervous system:
- hypomania or mania
- anxiety
- headache
- insomnia
- tremor
- dizziness
- asthenia
- hallucinations
- drowsiness
- convulsions
- movement disorders and dyskinesias
- blurred vision
- mydriasis
- impaired concentration
urogenital:
- anorgasmia
- delayed or absent ejaculation
- priapism
- prolonged penile erection
- impotence
- reduced libido
- urinary frequency
- urinary retention.