Statement of the AGNP-Work Group “Child and Adolescent Pharmacology” on the Decision of the Joint Federal Committee (GBA) of the 17/02/2011 to Combine Escitalopram with Citalopram into a Fixed Amount Group

On the 17^th February 2011, the Joint Federal Committee (Gemeinsamer Bundesausschuß, GBA) decided to combine the substance escitalopram (Cipralex^®), which is still under patent, with the substance citalopram into a fixed amount group. The justification for this decision was escitalopram shows no relevant therapeutic benefit compared with citalopram (www.kbv.de/39365.html).

Currently, the Higher Social Court (Landessozialgericht) Berlin-Brandenburg in summary proceedings has suspended the fixed amount for Cipralex^® (L 1 KR 140/11 KL). The court assumes a manifest illegality of the assessment of a fixed amount, as the GBA’s evaluation is not comprehensible. For child and adolescent psychiatrists there is now doubt concerning reimbursability of prescriptions of escitalopram to their patients.

The fixed amount for this group was determined to the 1^st of July 2011. Patients who are prescribed escitalopram, for example, have to pay an extra 152.65 € for a packet of Cipralex^® 10 mg N3 (medication cost 173.07 €/fixed amount 20–42 €).

In general it is of course necessary to challenge the theory of therapy equivalency. Escitalopram (s-citalopram) has a chemical relationship to citalopram (s- and r-citalopram racemate). Escitalopram is the effective enantiomer of the racemate escitalopram. R-citalopram is not active, but blocks the effect of escitalopram and leads to a weakening of effect. With escitalopram, lower doses of the substance can be used, and the rate of unexpected drug interactions is lower.

There are studies which question a superiority of escitalopram over citalopram; [(Carandang et al., 2011)] state that the FDA bases the approval of escitalopram for adolescents only on a prospective randomised multi-centric double-blind study, and [(Trkulja 2010)] concludes in his meta-analysis of studies with adults that escitalopram is not superior, at least regarding clinically relevant differences, although the response under escitalopram was larger than it was with citalopram. The data on efficacy and safety of escitalopram compared with citalopram are, however, inconclusive.

In their prospective, multi-center randomised double-blind study in the treatment of major depressive disorder (MDD), [(Moore et al. 2005)] found that the effect size in the escitalopram group was higher (MADRS − 22.4 vs. − 20.3; p<0.05), and that there were more responders in the escitalopram group than in the citalopram group (76.1% vs. 61.3%; p<0.01).

A prospective, multicenter randomised double-blind study with adult outpatients over 6 weeks indicated that escitalopram was superior to citalopram in relation to the targeted symptoms (MADRS − 28.7, escitalopram 10 mg, vs. 20.11, citalopram 10 mg, respective lower in the escitalopram group (7) than in the citalopram 10 mg group (16) and the citalopram 20 mg group (19) ([Yevtushenko et al. 2007]).

In a meta-analysis on the effectiveness and tolerability of new antidepressants, escitalopram is favoured along with sertraline ([Cipriani et al. 2009]).

In an open-label observational study of a heterogeneous group of 5 649 patients on escitalopram with depression and anxiety disorders, a remission of symptoms was observed with 52% of the test subjects; an improvement was seen after 14 days, and a remission after 24 days ([Holsboer-Trachsler et al. 2011]).

It must at least be recognised that the data for equivalence of citalopram and escitalopram are inconclusive.

For child and adolescent psychiatry, further aspects arise.

In some countries, for example the USA, escitalopram is available under the trade name Lexapro^® for the treatment of depressive syndrome adolescent patients ≥ 12 years. This is not the case for citalopram, and the data for escitalopram for young patients are significantly better than for citalopram ([Emslie et al. 2009]; [von Knorring et al. 2007]; [Wagner et al. 2006]; [Yang & Scott 2010]). Whilst in a controlled study [(Wagner et al. 2004)] described citalopram as effective in the treatment of children and adolescents, in a 12 week study, [(von Knorring et al. 2007)] found no superiority of citalopram compared to placebo.

With children and adolescents, the scientific literature shows a superiority of escitalopram compared to citalopram in the treatment of depressive disorders. In addition, only escitalopram is approved from the age of 12 years in some countries, but not citalopram. The BGA’s treatment of escitalopram as the equivalent of citalopram cannot be accepted for child and adolescent psychiatric patients.

One further aspect must not be ignored. A frequent co-morbidity of ADHD is depressive syndromes ([Jensen et al. 2001]; [Taurines et al. 2010]), which may mean that a combination of the treatment therapy of methylphenidate with antidepressants is required. Citalopram is not a particularly suitable substance here, as it increases the dopamine transporter density ([Kuguya et al., 2003]), and thus its effectiveness in the combination therapy with methylphenidate, as well as with amphetamine, is reduced.

From the point of view of child and adolescent psychiatric pharmacology, the decision of the GBA to view citalopram and escitalopram as equivalent cannot be accepted. There is a need for further alternatives for treatment of severe MDD besides SSRI fluoxetin, which is the only approved substance for children and adolescent with MDD. Citalopram and escitalopram have at present not been approved for the age group of minors in Germany, and “off label” treatments must anyway often be used. Particularly with the especially important safety aspects in the case of children and adolescents, is it not acceptable to favour a racemate which is known to have a higher rate of unexpected drug interactions, and which also is not approved for this age group in any country.

For German version of the statement, see: AGNP website: www.agnp.de/

• References

• 1 Carandang C, Jabbal R, MacBride A et al. A review of Escitalopram and Citalopram in Child and Adolescent Depression. J Can Acad Child Adolesc Psychiatry 2011; 20: 315-324
• 2 Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet online Jan 29 2009; 1-13
• 3 Emslie GJ, Ventura D, Korotzer A et al. Escitalporam in the treatment of Adolescent Depression: A randomized placebo-controlled multisite trial. J Am Acad Child Adolesc Psychiatry 2009; 48,7: 721-729
• 4 Holsboer-Trachsler E, Baumann P, Höck P et al. Escitalopram in der klinischen Praxis. Psychopharmakotherapie 2011; 18,2: 59-65
• 5 Jensen PS, Hinshaw SPO, Kraemer HC et al. ADHD comorbidity findings from the MTA study: comparing comorbid soubgroups. J Am Acad Child Adolesc Psychiatry 2001; 40,2: 147-158
• 6 von Knorring AL, Olsson GI, Thomsen PH et al. A randomized, double-blind, pacebocontrolled study of citalopram in adolescents with major depressive disorder. J Clin Psychopharmocol 2007; 26,3: 311-315
• 7 Kuguya A, Seneca NM, Snyder PJ et al. Changes in human in vivo serotonine and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology 2003; 28: 413-420
• 8 Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol 2005; 20: 131-137
• 9 Taurines R, Schmitt J, Renner T et al. Developmental comorbidity in attention deficit-/hyperactivity disorder. Atten Defic Hyperact Disord 2010; 2,4: 267-289
• 10 Trkulja. Is Escitalopram really relevantly superior to Citalopram in treatment of major depressive disorder? A meta-analysis of head-to-head randomized trials. Clinical Sciences 2010; DOI: 10.3325/cmj.2010.51.61.
• 11 Wagner KD, Robb AS, Findling RL et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004; 161,6: 1079-1083
• 12 Wagner KD, Jonas J, Findling RL et al. A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression. J Am Acad Child Adolesc Psychiatry 2006; 45,3: 280-288
• 13 Yang LPH, Scott LJ. Escitalopram in the treatment of major depressive disorder in adolescent patients. Pediatr Drugs 2010; 12,3: 155-163
• 14 Yevtushenko VY, Belous AI, Yevtushenko YG et al. Efficacy and tolerability of Escitalopram versus Citalopram in major depressive disorder: A 6 week multicenter, prospective, randomized, double blind, active controlled study in adult outpatients. Clin Ther 2007; 29, 11: 2319-2332