The Committee recommended the addition of a square box symbol to the current listing of fluoxetine on the core list of the EML for treatment of depressive disorders.
The Committee noted that medicines within the pharmacological class of selective serotonin reuptake inhibitors all have demonstrated efficacy, but can differ in terms of pharmacokinetics, adverse events and drug-interaction
profiles. The availability of different SSRIs as essential medicines may be beneficial at country level to expand therapeutic alternatives for patients and support better procurement.
As a consequence of the recommendation for the square box with fluoxetine, the Committee did not recommend the separate addition of escitalopram to the core list of the EML. Escitalopram, and other SSRIs should be considered therapeutically equivalent alternatives to fluoxetine for selection at national level.
Two applications regarding the listing of selective serotonin reuptake inhibitors (SSRIs) were received:
Application 1: requested the inclusion of escitalopram on the core list of the EML for the treatment of adults with major depressive disorder.
Application 2: requested the addition of a square box symbol to the current listing of fluoxetine on the core list of the EML for treatment of depressive disorders.
Fluoxetine was added to the core list of the EML in 2007. The Committee considered that the available evidence supported the public health need, comparable effectiveness and generally more favourable tolerability of
fluoxetine compared to amitriptyline. A square box was not recommended as the Committee felt there may be significant within-class differences among SSRIs in relation to safety (1).
Public health relevance
The public health relevance of depressive disorders is well established and has been previously accepted by the Committee. However, the global burden of disease due to depressive disorders is increasing over time. In 2017, depressive disorders were estimated to affect over 260 million people globally, including 160 million with major depressive disorder. According to the Global Burden of Disease Study 2017, depressive disorders were responsible for over 43 million disability-adjusted life years (DALYs) annually, accounting for 1.7% of total estimated DALYs due to any disease. Depressive disorders were also responsible for over 43 million years lived with disability (YLD), accounting for 5.0% of the total YLD globally (2).
Both applications presented the findings of a 2018 systematic review and network meta-analysis (NMA) of 522 randomized controlled trials (RCTs) involving 117 477 participants, which evaluated the comparative efficacy and tolerability of 21 antidepressant medicines compared to each other and to placebo for the treatment of depression in adults (3).
Compared to placebo, all SSRIs were associated with statistically significantly greater response rates. The greatest response rate seen was for paroxetine (odds ratio (OR) 1.75, 95%CI 1.61 to 1.90). With regard to
acceptability, as measured by dropout rates, all SSRIs except for fluvoxamine showed an advantage over placebo, however this was only statistically significant for fluoxetine (OR 0.88, 95%CI 0.80 to 0.96).
In comparisons between SSRIs, there was moderate level GRADE evidence of statically significant superior efficacy of escitalopram compared to citalopram, fluoxetine, and fluvoxamine, and of paroxetine compared to fluoxetine. Other comparisons were not statistically significant.
The findings of a 2009 Cochrane systematic review of 22 RCTs comparing escitalopram to other antidepressants were largely consistent with the 2018 NMA (4). In six studies (1823 participants) that compared response rates between escitalopram and citalopram, there was a statistically significant difference in favour of escitalopram (OR 0.67, 95%CI 0.50 to 0.89, p=0.006), also found in remission rates (OR 0.57, 95%CI 0.36 to 0.90, p=0.02). Three studies (783 participants) that directly compared escitalopram and fluoxetine did not find a statistically significant difference in response or remission rates but did find escitalopram to be more efficacious than fluoxetine in reduction of depressive symptoms from baseline (SMD −0.17, 95%CI −0.32 to −0.03, p=0.02). Two studies (784 participants) that compared escitalopram to paroxetine, and two studies (489 participants) that compared escitalopram to sertraline, did not find any statistically significant differences for any of the above parameters.
In the above-mentioned Cochrane review, 14 RCTs compared escitalopram to another SSRI (4). Escitalopram did not have significantly different rates of mild to severe adverse events than citalopram (n = 1802 in six RCTs), fluoxetine (n = 804 in four RCTs), or paroxetine (n = 784 in two RCTs). Also, there was no significant difference in serious adverse events for escitalopram compared to sertraline (n = 483 in 2 RCTs); however, escitalopram had a decreased incidence of diarrhoea. Overall, escitalopram and other SSRIs had similar rates of agitation, anxiety, constipation, diarrhoea, dry mouth, hypotension, insomnia, nausea, urinary complaints, drowsiness, vomiting, deaths, suicide, suicidality and other adverse events.
With respect to acceptability as measured by dropout rates, in the abovementioned NMA, escitalopram was associated with moderate level GRADE evidence of superiority compared to fluvoxamine. There were no other statistically significant differences between SSRIs with regard to acceptability (3).
A 2006 meta-analysis using patient-level data from published and unpublished clinical trials based on mandatory reporting by pharmaceutical companies assessed the risk of suicidality (ideation or worse) amongst
antidepressants (5, 6). Half of the treatment indications were related to depression, with the remaining 50% for other psychiatric or non-psychiatric indications. Among SSRI, considering only data for adults with psychiatric
diagnoses, suicidality risk was found to be lowest for sertraline and fluoxetine (low quality evidence). Suicidality risk was greatest for citalopram and escitalopram although the differences did not reach statistical significance (very low-quality evidence).
A 2014 meta-analysis examined the association between SSRI antidepressants and QTc (corrected QT) prolongation (7). Citalopram and escitalopram were associated with the greatest amount of QTc prolongation, while sertraline was associated with the least. Fluvoxamine was associated with shortened QTc. Results for fluoxetine and paroxetine were not statistically significant.
With regard to sexual dysfunction, escitalopram and paroxetine have been associated with a higher risk of sexual dysfunction than fluoxetine. Pairwise comparisons of other SSRIs have not shown statistically significant
The pharmacokinetic properties of individual SSRIs differ considerably. Considering potential for drug–drug interactions, many SSRIs are inhibitors of cytochrome P450 enzymes and may interact with other drugs that are
metabolized by these enzymes. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine is a potent inhibitor of CYP1A2. Fluoxetine and fluvoxamine are also moderate inhibitors of CYP2C19. Citalopram, escitalopram
and sertraline are considered to have the lowest potential for CYP enzyme-mediated interactions (9).
Fluoxetine has a half-life of one to four days and an active metabolite (norfluoxetine) with a half-life of seven to fifteen days. The half-lives of the other SSRIs are considerably shorter. Therefore, fluoxetine will take longer to reach steady-state concentrations and will remain in the body for longer following discontinuation of therapy. As a result, adverse reactions and drug-interactions with fluoxetine may persist for some time following cessation of treatment (10). Paroxetine has the shortest half-life among the SSRIs (one day) and has been found to have a higher potential for withdrawal symptoms following discontinuation (11).
Cost / cost effectiveness
SSRIs vary in price globally, but are generally inexpensive, with multiple generic brands available. Cost-effectiveness analyses in different settings have shown SSRIs to be cost-effective interventions (18–27).
The WHO Mental Health Gap Action Programme (mhGAP) Guidelines make the following recommendations in relation to antidepressants for treatment of adults with depression (12):
– Antidepressants should not be considered for the initial treatment of adults with mild depressive episode. (Strength of recommendation: Conditional; Quality of evidence: Low);
– Tricyclic antidepressants or fluoxetine should be considered in adults with moderate to severe depressive episode/disorder. (Strength of recommendation: Conditional; Quality of evidence: Low);
– If drug treatment is required in older people, tricyclic antidepressants should be avoided if possible. (Strength of recommendation: Conditional; Quality of evidence: Low);
– If drug treatment is required in women with depressive episode who are planning a pregnancy or are pregnant or breastfeeding, tricyclic antidepressants or fluoxetine should be considered. (Strength of recommendation: Conditional; Quality of evidence: Low).
SSRIs are also recommended as first-line treatment choices in numerous international guidelines (13–17). The choice of individual SSRI should be made after taking into consideration the differing safety and tolerability profiles, pharmacokinetic and pharmacodynamic factors, price and individual patient factors and patient preferences.
SSRIs are widely available globally, with off-patent generic formulations available.
Letter of support for escitalopram application from the Ministry for Health and Welfare, National Centre for Mental Health, Republic of Korea: “More than one SSRI should be considered as essential drugs. It is an important point that patients may respond to specific SSRIs differently and it is difficult to predict which agent will be the most effective for each patient.”
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