Baldwin DS, Cooper JA, Huusom AK, et al. A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder

Clinical Neuroscience Division, University of Southampton, Royal South Hants Hospital, Southampton, UK.
International Clinical Psychopharmacology (Impact Factor: 2.46). 06/2006; 21(3):159-69. DOI: 10.1097/01.yic.0000194377.88330.1d
Source: PubMed


This multinational, randomized, double-blind, flexible-dose study evaluated the short- and long-term antidepressant tolerability and efficacy of escitalopram and paroxetine. Tolerability was assessed by monitoring adverse events throughout the study, and discontinuation events during brief treatment interruption and tapered withdrawal. Discontinuation-emergent effects were evaluated in two separate double-blind periods. First, to mimic the consequences of non-compliance, patients were randomized to one of two treatment interruption periods (placebo-substitution for 3-5 days). Second, patients were randomized to a 1-2-week tapered withdrawal period randomly scheduled between weeks 28 and 31. The pre-specified primary efficacy endpoint was the mean change from baseline in total Montgomery-Asberg Depression Rating Scale (MADRS) score at week 8, using the principle of last observation carried forward. A total of 323 patients entered 8 weeks of double-blind treatment and received at least one flexible dose of escitalopram (10-20 mg/day) or paroxetine (20-40 mg/day). Patients who demonstrated evidence of a significant clinical improvement (Clinical Global Impression-Improvement of 1 or 2) at week 8 entered a 19-week, double-blind maintenance period during which they were treated with the same dose they received at week 8, followed by a 1-2-week tapered withdrawal period. A total of 89 patients (28%) withdrew during the study; significantly (P<0.01) more patients withdrew from the paroxetine group (34%) than from the escitalopram group (21%), and significantly (P<0.05) more paroxetine patients withdrew due to lack of efficacy. The mean MADRS total score improved for both treatment groups from baseline to week 8, with no statistical difference between groups. In severely depressed patients (baseline MADRS total score >or=30), escitalopram was superior (P<0.05) to paroxetine at week 27 (end of maintenance treatment). There was a high prevalence of sexual dysfunction at baseline: the mean Arizona Sexual Experience Scale (ASEX) score was approximately 20 points in both treatment groups. Mean total ASEX scores increased slightly above baseline values during the acute period and declined slightly below baseline values towards the end of the maintenance period. During taper and cessation of treatment, patients in the paroxetine group demonstrated significantly more discontinuation symptoms relative to escitalopram based on the Discontinuation Emergent Signs and Symptoms scores.

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    • "A relapse prevention study of 325 patients conducted with escitalopram and paroxetine included 8 weeks of initial treatment, followed by a 19-week maintenance treatment period and finally a 1–2 week tapered discontinuation period (Baldwin et al., 2006). Overall, withdrawal of patients for lack of efficacy (normally referred to as relapses) was significantly less common on escitalopram than paroxetine (Baldwin et al., 2006). "
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    ABSTRACT: It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter.
    International clinical psychopharmacology 01/2014; 29(4). DOI:10.1097/YIC.0000000000000023 · 2.46 Impact Factor
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    • "Again, the inclusion criteria were more narrowly defined. The authors argued that the decline may have been due to the dropping-out of patients with more severe SD (Baldwin et al. 2006). However, drop-outs in the present study did not differ substantially from subjects who completed the protocol in terms of reported SD. "
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    ABSTRACT: Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant). A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery-Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the Sexual Functioning Questionnaire. The incidence of reported SD after 12 weeks of treatment was relatively low, and did not differ significantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no significant interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR. In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no apparent effect of the 5-HTTLPR on the observed decline in SD.
    The World Journal of Biological Psychiatry 03/2011; 12(7):528-38. DOI:10.3109/15622975.2011.559270 · 4.18 Impact Factor
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    • "Summary points for efficacy: (i) efficacy advantage for escitalopram versus citalopram has been demonstrated in five randomized studies (Burke et al., 2002; Colonna et al., 2005; Lepola et al., 2003; Moore et al., 2005; Yevtushenko et al., 2007) and two pooled analyses of clinical trials (Gorman et al., 2002; Lepola et al., 2004); (ii) escitalopram may have an efficacy advantage over paroxetine , in terms of significant improvements in MADRS, HAM-D and CGI-S scores and fewer discontinuations owing to lack of efficacy (Baldwin et al., 2006; Boulenger et al., 2006); (iii) the efficacy of escitalopram compared with fluoxetine (Mao et al., 2008; Kasper et al., 2005) and sertraline (Ventura et al., 2007) requires further evaluation; (iv) escitalopram and sertraline might be the best choice of antidepressant when starting treatment of patients with moderate to severe MDD (Cipriani et al., 2009); (v) the SNRI venlafaxine XR may be associated with greater remission or response rates in patients with MDD compared with SSRIs (Papakostas et al., 2007; Smith et al., 2002; Nemeroff et al., 2008; Thase, 2008 Thase et al., 2005; Burk et al., 2002); (vi) escitalopram has comparable efficacy to venlafaxine XR, with a possible slight advantage for escitalopram in patients with severe MDD (Bielski et al., 2004; Montgomery et al., 2004) Regarding safety and tolerability, escitalopram offers tolerability advantages over duloxetine, paroxetine and venlafaxine XR (see summary points below) and may be preferable to those antidepressants in some patients with MDD. Summary points for safety: (i) superior tolerability for escitalopram versus duloxetine, particularly for nausea, insomnia, dizziness and vomiting has been demonstrated in three randomized studies (Khan et al., 2007; Nierenberg et al., 2009; Wade et al., 2007) and a pooled analysis of two clinical trials (Lam et al., 2008) (ii) escitalopram offers tolerability advantages over paroxetine (Baldwin et al., 2006; Boulenger et al., 2006) and venlafaxine XR (Bielski et al., 2004; Montgomery et al., 2004, 2006); (iii) escitalopram is less likely to cause discontinuation symptoms than several other antidepressants (Baldwin et al., 2006; Bielski et al., 2004; Boulenger et al., 2006; Kasper et al., 2005; Khan et al., 2007; Montgomery et al., 2004, 2006; Taylor et al., 2006a; Wade et al., 2007); (iv) no evidence of emergent risk of suicide with escitalopram (Baldwin et al., 2007; Pedersen, 2005); (v) incidence of sexual dysfunction-related adverse events similar to citalopram, but lower than venlafaxine XR and paroxetine (Baldwin et al., 2007). "
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    ABSTRACT: The majority of currently marketed drugs contain a mixture of enantiomers; however, recent evidence suggests that individual enantiomers can have pharmacological properties that differ importantly from enantiomer mixtures. Escitalopram, the S-enantiomer of citalopram, displays markedly different pharmacological activity to the R-enantiomer. This review aims to evaluate whether these differences confer any significant clinical advantage for escitalopram over either citalopram or other frequently used antidepressants. Searches were conducted using PubMed and EMBASE (up to January 2009). Abstracts of the retrieved studies were reviewed independently by both authors for inclusion. Only those studies relating to depression or major depressive disorder were included. The search identified over 250 citations, of which 21 studies and 18 pooled or meta-analyses studies were deemed suitable for inclusion. These studies reveal that escitalopram has some efficacy advantage over citalopram and paroxetine, but no consistent advantage over other selective serotonin reuptake inhibitors. Escitalopram has at least comparable efficacy to available serotonin-norepinephrine reuptake inhibitors, venlafaxine XR and duloxetine, and may offer some tolerability advantages over these agents. This review suggests that the mechanistic advantages of escitalopram over citalopram translate into clinical efficacy advantages. Escitalopram may have a favourable benefit-risk ratio compared with citalopram and possibly with several other antidepressant agents.
    Journal of Psychopharmacology 02/2010; 24(8):1143-52. DOI:10.1177/0269881109349835 · 3.59 Impact Factor
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