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10.1517/14656560902849258 © 2009 Informa UK Ltd ISSN 1465-6566
1
All rights reserved: reproduction in whole or in part not permitted
Baselineseverityofdepressionpredictsantidepressantdrugresponserelativetoescitalopram
Clinton D Kilts, Alan G Wade, Henning F Andersen & Thomas E Schlaeper
†
†
University Hospital, Department of Psychiatry, Brain Stimulation Group, Sigmund-Freud-Strasse 25,53105 Bonn, Germany
Objective
: The intent of this pooled analysis was to determine the relationshipbetween baseline depression symptom severity and treatment response forescitalopram compared to that for other pooled antidepressant medications(citalopram, duloxetine, fluoxetine, paroxetine, sertraline and venlafaxine).
Methods
: Data were pooled from controlled clinical trials comparing escit-alopram with other antidepressants for the treatment of major depression.The 15 trials meeting the inclusion criteria comprised 2,216 patients treatedwith escitalopram and 2,085 treated with one of the other antidepressants. Theprimary outcome measure of change from baseline to week 8 in theMontgomery–Åsberg Depression Rating Scale (MADRS) total score was analyzedby an analysis of covariance, using the method of
last-observation-carried-forward
for missing values and adjusting for baseline and center values.
Results
: There was a significant interaction between baseline MADRS totalscore and treatment group (p
=
0.0208). Response to escitalopram wasstable regardless of baseline severity. For the pooled active comparators,response decreased with increasing baseline symptom severity. Thisdifferential efficacy of escitalopram with increasing symptom severity wasconfirmed by the analyses of the pooled 24-item Hamilton DepressionRating Scale (HAMD-24) results. A HAMD-24 single item analysis indicatedthat the sum of the baseline psychomotor retardation and hopelessnessitem scores significantly predicted which patients would benefit fromtreatment with escitalopram versus a comparator.
Conclusion
: Newergeneration antidepressant medications clearly differ in their efficacy as afunction of baseline symptom severity. The selective serotonin reuptakeinhibitor escitalopram had superior efficacy in the treatment of more severedepression, perhaps attributable to differential efficacy related to symptomsof negativistic thinking.
Keywords:
escitalopram, item analysis, meta-analysis, severe depression
Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Major depressive disorder (MDD) is common and highly debilitating. Individuals with severe depression, most oten characterized by a high intensity and numbero depressive symptoms, suer rom heightened unctional impairment, somaticcomplaints and risk or suicide and relapse relative to individuals with mild ormoderate severity depression
[1,2]
. Beyond symptom severity, the metrics o diagnosiso severe depression are controversial and have included the presence o treatmentresistance, need or hospitalization, comorbid diagnoses, psychotic eatures, cognitivedysunction, suicide risk and chronicity
[3]
. The dimensional versus categorical
1. Introduction2. Patients and methods3. Results4. Discussion5. Conclusions
Baselinesymptomseverityandantidepressantefcacy
2
ExpertOpin.Pharmacother.
(2009)
10
(6)
relationship between mild, moderate and severe depressionremains widely debated. Whereas the preponderance o asmall database suggests that severe depression is not categor-ically distinct rom milder orms, at least some studies sug-gest that severe depression diers in its etiology, neurobiology and predictors o treatment response. For instance, women who had been physically and sexually abused in childhood were more severely depressed than those who were notabused in childhood
[4]
. Moreover, the observed interactionbetween a promoter region polymorphism in the serotonintransporter gene and stressul lie events in conerringheightened risk or depression
[5]
was signiicantly stronger with increasing severity o depression
[6,7]
. Improvementin hypothalamic–pituitary–adrenal (HPA) unction associ-ated with repeated dexamethasone/corticotropin releasinghormone (DEX/CRH) testing signiicantly predicted anti-depressant treatment response in individuals with severedepression
[8]
.The heightened suering and disability associated withsevere depression makes it a particularly important targetor eective treatments
[9]
. Non-pharmacological therapies(electroconvulsive therapies, repetitive transcranial magneticstimulation, vagus nerve stimulation and deep brain stimu-lation) are oten advanced as second- and third-line thera-pies or severe depression and may represent importantoptions or some patients. However, medication with anti-depressants remains the best evidence-based approach to themanagement o depression
[3]
. Antidepressant therapies are,however, not equally eective in the treatment o severedepression. Pooling o clinical study results in meta-analyseso treatment outcomes initially supported the superioreicacy o tricyclic antidepressants relative to the selectiveserotonin reuptake inhibitors (SSRIs) in hospitalizedpatients
[10]
. Subsequent meta-analyses suggested a superi-ority o the dual serotonin-norepinephrine reuptake inhibitor(SNRI) venlaaxine relative to SSRIs in the treatment o depression
[11]
, or o venlaaxine versus luoxetine but notother SSRIs
[3]
. These pooled analyses, however, did notinclude an analysis o antidepressant eicacy as a unction o baseline symptom severity. Among the SSRIs, escitalopram has been shown to beeective in the treatment o severe depression and moreeective than either citalopram or paroxetine
[12,13,14]
. A recent meta-analysis
[15]
conirmed that escitalopram wasassociated with superior antidepressant eicacy compared toother SSRIs and comparable to venlaaxine and urtherdemonstrated that the eicacy advantage o escitalopramincreased with increasing baseline depression severity.The present study was designed to re-evaluate thecomparative eicacy o escitalopram as a unction o increasingbaseline symptom severity in a larger sample and to extendthe comparison by an analysis o single items or both theMontgomery–Åsberg Depression Rating Scale (MADRS)and the Hamilton Depression Rating Scale (HAMD) todeine discriminating symptoms.
2.
Patientsandmethods
2.1
Studydesign
Individual patient data were obtained rom all studiessponsored by H. Lundbeck A/S and Forest Laboratories,Inc. that included escitalopram and an active comparatorand was completed by January 2007. For inclusion, studieshad to use randomized, double-blind treatment designs, with symptom severity and antidepressant eicacy assessedby MADRS
[16]
. A total o 15 trials met the inclusioncriteria (see later) o which 5 were placebo-controlled. TheHAMD
[17]
was additionally used as an assessment instru-ment in 10 o the studies. In 4 o the trials, the escitalo-pram dose was ixed at 10 mg (trials 10 – 12 and 15)(
Table 1
). Eleven o these studies have been published intheir entirety in peer-reviewed journals, and the remaining4 have been presented preliminarily at scientiic meetings(trials 6, 8 – 10). Summaries o all trials can be ound ateither www.orestclinicaltrials.com or www.lundbecktrials.com. A search o the Medline, EMBASE and Biosis databases,and clinical trial registry websites identiied an additional 7controlled clinical trials in MDD with escitalopram and anactive comparator completed as o January 2007 that were notsponsored by H. Lundbeck or Forest Laboratories
[13,18-22]
.These data were not available to us on request and were notincluded in this pooled analysis. O the 15 trials, 9 wereincluded in previous pooled analysis
[23]
and all 15 trials arein the most recent meta-analysis
[24]
. Neither o thesearticles analyzed the eect o increasing baseline severity ontreatment response, or the contribution o individual itemso the assessment scales.
2.2
Patientbaselinecharacteristics
The pooled trials included 2,216 patients treated withescitalopram, 2,085 patients treated with active comparatorand 710 patients treated with placebo (
Table 1
). Patients were predominantly Caucasian (86.5%) with a mean age o 45 years and approximately two-thirds o the patients were women (
Table 2
). The baseline mean MADRS score o 30.3indicated a patient sample with moderate to severe depression.There were no signiicant statistical dierences in patientdemographics or severity o depression between the pooledescitalopram and comparator groups.Patients rom the trials included in the pooled analysesulilled DSM-IV criteria or a current episode o MDD andhad a baseline MADRS total score cut-o or inclusion o
≥
22 in 11 trials,
≥
26 in 2 trials,
≥
30 in 1 trial and
≥
18in 1 trial, and a HAMD-17
≥
17 in 1 trial and HAMD-24
≥
20 in 1 trial. The enrolled trial patients had no otherserious medical or psychiatric illnesses. Patients were excludedi they: were pregnant, breast-eeding or without adequatecontraception at time o screening; met DSM-IV criteriaor any psychotic disorder, mental retardation or any pervasivedevelopmental disorder; had a MADRS score
≥
5 on item 10(suicidal thoughts); were receiving treatment with antipsychotics,
Kilts,Wade,Andersen&Schlaepfer
ExpertOpin.Pharmacother.
(2009)
10
(6)
3Table1.Summarydataforstudiesincludedinpooledanalysis.
Studynumber Duration(inweeks)Dose(mg/day) NumberofpatientsMeanage(years) Meandosage
§
Ref.
1*8PBOESC 10 – 20CIT 20 – 4015415515943434411.724.4
[41]
GP28ESC 10 – 20VLF 75 – 150146142494712.195.2
[42]
PC. MADRS
≥
18327ESC 10 – 20PAR 20 – 40165156454513.925.4
[43]
424ESC 20PAR 4022822344452040
[14]
MADRS
≥
3058PBOESC 10ESC 20CIT 4011911812312539404041–102040
[44]
68PBOESC 10 – 20CIT 20– 40125124119424142–13.425.2
[45]
78ESC 20VLF 2259798373720225
[46]
HAMD-24
≥
2088ESC 10 – 20FLU 20 – 409698373717.734.1
[47]
98PBOESC 10 – 20SER 50 – 200132131135414040–19.2155
[48]
108ESC 10SER 50 – 200104107413810147
[49]
11*24ESC 10CIT 2016417446461020
[50]
12*8ESC 10FLU 2011811337411020
[51]
Chinese HAM-D17
≥
17138ESC 20DUL 6013612642432060
[52]
MADRS
≥
2614*24ESC 20DUL 6014114643452060
[29]
MADRS
≥
2615*8PBOESC 10FLU 20180170164757575–1020
[53]
elderly
Total MADRS HAMD-24ESC
=
2,216ESC
=
1,468COMP
=
2,085COMP
=
1,329
*HAMD-24 not assessed.
§
mg/day at end of study.CIT: Citalopram; COMP=Comparator; DUL: Duloxetine; ESC: Escitalopram; FLU: Fluoxetine; HAMD: Hamilton Depression Rating Scale; MADRS: Montgomery-ÅsbergDepression Rating Scale; PAR: Paroxetine; PBO: Placebo; PC=Primary care setting; SER: Sertraline; VLF: Venlafaxine XL.
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19317630 - Baseline Severity of Depression Predicts Antidepressant Drug Response Relative to Escitalopram
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