Rana Fayyad

Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine.

OBJECTIVEnDetermine the point prevalence of phenoconversion to cytochrome P450 2D6 (CYP2D6) poor metabolizer status in clinical practice.nnnMETHODnThis multicenter, open-label, single-visit naturalistic study was conducted from October 2008 to July 2009 in adult patients (≥ 18 years) who had been receiving venlafaxine extended-release (ER) (37.5-225 mg/d) treatment for up to 8 weeks. A 15-mL blood sample was drawn 4 to 12 hours after patients last venlafaxine ER dose. Plasma O-desmethylvenlafaxine and venlafaxine concentrations were determined for each patient. CYP2D6 poor metabolizer phenotype was defined as O-desmethylvenlafaxine to venlafaxine ratio < 1 based on published data. CYP2D6 genotype was determined for each patient; patients were classified as poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultrarapid metabolizer. Agreement between poor metabolizer phenotype and genotype classifications was assessed using the McNemar test.nnnRESULTSnPhenoconversion to CYP2D6 poor metabolizer status occurred in 209 of 865 individuals (24%) with a CYP2D6 non-poor metabolizer genotype. The incidence of CYP2D6 poor metabolizer status based on phenotype was almost 7 times higher than that expected based on genotype: only 4% (35/900) of patients were genotypic CYP2D6 poor metabolizers, but 27% (243/900) were phenotypic CYP2D6 poor metabolizers (McNemar test, P < .0001).nnnCONCLUSIONSnCYP2D6 phenotype conversion is common in patients being treated for depression. These results are important because differences in CYP2D6 drug metabolic capacity, whether genetically determined or due to phenoconversion, can affect clinical outcomes in patients treated with drugs substantially metabolized by CYP2D6. These results demonstrate that personalized medicine based solely on genetics can be misleading and support the need to consider drug-induced variability as well.nnnTRIAL REGISTRATIONnClinicalTrials identifier: NCT00788944.

Early improvement predicts endpoint remission status in sertraline and placebo treatments of panic disorder

The early identification of likely remitters and non-remitters to pharmacotherapy for panic disorder may have important implications for clinical treatment decisions. To address this question, combined data from two fixed-dose and two flexible dose placebo-controlled studies of sertraline treatment of panic disorder were examined. Patients (N=544) diagnosed with panic disorder, with or without agoraphobia, were treated with 50 mg of sertraline, 100 mg of sertraline, flexible dosages of sertraline, or placebo. Measures of early improvement included panic attack frequency (full + limited symptom attacks), anticipatory anxiety, the Hamilton Anxiety Rating Scale (HAM-A), and the Clinical Global Impression Improvement (CGI-I) Scale. Improvement as reflected in CGI-I ratings and change from baseline in the HAM-A at weeks 1, 2, and 3 significantly (P<0.0001) predicted endpoint clinical remission (defined at endpoint as no full panic attacks and a CGI-Severity rating of 1 or 2). Improvements in panic attack frequency and anticipatory anxiety were not consistent predictors in multivariate predictive models. Receiver-Operator Curve analyses revealed good specificity (0.83) for change in CGI-I at week 2, and good sensitivity (0.82) for change in HAM-A at week 3. Predictive success for HAM-A and CGI-I was not significantly different for fixed vs. flexible dose sertraline treatment, nor for sertraline vs. placebo treatment. The use of ROC analyses for examination of early response as a predictor of final remission holds promise for aiding clinicians in decision making regarding the need for alternative or supplemental treatment approaches during the course of pharmacotherapy for panic disorder.

The efficacy of sertraline in panic disorder: combined results from two fixed-dose studies.

&NA; Data from two fixed‐dose studies of sertraline in panic disorder were pooled in order to provide sufficient power for the analysis of treatment response in clinically relevant subgroups. Male and non‐fertile female patients meeting DSM‐III‐R criteria for moderate‐to‐severe panic disorder with or without agoraphobia completed a 1‐2 week placebo run‐in period, and then were randomized to 12 weeks of double‐blind treatment with either placebo, or one of three fixed daily doses of sertraline (50 mg, 100 mg, or 200 mg). Eighty‐two patients were treated with placebo and 240 patients were treated with one of three doses of sertraline. All three sertraline doses produced significant efficacy compared to placebo, with no consistent evidence of a dose‐response effect. For the subset of patients with subsyndromic depression at baseline [baseline Hamilton Depression Rating scale (HAM‐D > 12 and ≤ 21], sertraline yielded a significantly higher panic‐free rate than did placebo (P = 0.021), again, by a conservative endpoint (Last Observation Carried Forward method, LOCF) analysis. Sertraline was well‐tolerated at all dose levels, with no significant between‐dose differences in patients discontinuing due to adverse events. The presence of mild‐to‐moderate subsyndromic levels of depression did not reduce the anti‐panic efficacy of sertraline. Int Clin Psychopharmacol 15:335‐342

Assessing the relationship between functional impairment/recovery and depression severity: a pooled analysis.

The objective of this study was to explore the relationship between assessments of functional impairment, emotional well-being, and depression symptoms. Data were pooled from 3530 outpatients with major depressive disorder enrolled in 10 desvenlafaxine clinical trials. The primary outcome measures included (a) the 17-item Hamilton Rating Scale for Depression (HAM-D17) as a measure of depressive symptom severity and (b) the Sheehan Disability Scale (SDS) and five-item World Health Organization Well-Being Index (WHO-5) as measures of functional impairment and well-being. A linear regression model was used to identify the SDS and WHO-5 values that equate to the predetermined clinically relevant three-point difference between active treatment and placebo on the HAM-D17. A receiver operating characteristic analysis was conducted to determine the SDS score that equates to a remission of depression symptoms (i.e. HAM-D17 ⩽7). An approximate three-point difference between active treatment and placebo on the SDS (2.8) and WHO-5 (2.5) was determined to be clinically relevant in relation to improvements in depressive symptoms. An SDS of less than or equal to 7 was equivalent to a remission of depression symptoms, providing a definition of functional remission. A better understanding of the relationship between depressive symptoms and functional impairment and well-being may provide clinicians with a more comprehensive means of assessing treatment effects in major depressive disorder.

Efficacy of sertraline in posttraumatic stress disorder secondary to interpersonal trauma or childhood abuse

BACKGROUND: In posttraumatic stress disorder (PTSD), the nature of the trauma and the age of occurrence may have substantial effects on psychobiological sequelae and treatment response. Interpersonal trauma (physical/sexual assault) and childhood abuse are both prevalent and associated with later PTSD. This analysis was conducted to specifically assess the efficacy of sertraline in the treatment of PTSD secondary to interpersonal trauma or childhood abuse. METHODS: 395 adult patients with PTSD were randomized to 12-weeks double-blind treatment with flexible dose sertraline (50-200 mg/d) or placebo. Patients with different index traumas were compared in terms of baseline demographic and clinical characteristics, as well as treatment response. Primary efficacy variables included part 2 of the Clinician Administered PTSD Scale (CAPS-2). RESULTS: Interpersonal trauma and childhood abuse were both more common in females than males, and were associated with early age at time of index trauma and longer duration of PTSD, but not with PTSD symptom severity. Sertraline was significantly more effective than placebo on most primary efficacy variables, irrespective of whether patients had experienced interpersonal trauma or childhood abuse. CONCLUSIONS: These data demonstrate that sertraline is valuable for the treatment of PTSD, irrespective of whether the precipitating trauma involves interpersonal trauma in general, or childhood abuse in particular. Language: en

Early improvement in depressive symptoms with desvenlafaxine 50 mg/d as a predictor of treatment success in patients with major depressive disorder.

Objective This post hoc analysis assessed the predictive value of improvement in depressive scores at early time points for treatment outcomes at week 8 in patients with major depressive disorder treated with desvenlafaxine 50 mg/d or placebo. Methods Pooled data from 6 double-blind, fixed-dose studies in adult patients with major depressive disorder. Patients were randomly assigned to desvenlafaxine or placebo. Primary end point was change in 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline to week 8 (or last observation carried forward). Optimal thresholds of improvement (percent change from baseline HAM-D17) at weeks 2 and 3 for predicting 4 levels of treatment success (≥45%, ≥50%, and ≥65% decrease from baseline HAM-D17, HAM-D17 ⩽7) at week 8 (last observation carried forward) were determined using receiver operating characteristic analysis. Odds ratios of the predictability of improvement thresholds were computed from a logistic regression model adjusting for significant baseline predictors. Results Desvenlafaxine 50 mg/d (n = 1207) had significantly greater rates of treatment success for each level of treatment success at 8 weeks compared with placebo (n = 1067). Optimal early improvement thresholds for weeks 2 (20%–30%) and 3 (28%–41%) were highly predictive of all 4 levels of treatment success after adjusting for significant baseline predictors (odds ratios, 0.951–0.960; all P < 0.0001). Negative predictive value of early improvement increased, and positive predictive value decreased, for increasingly stringent definitions of treatment success at week 8. Conclusions Clinical observations of patients’ early response to desvenlafaxine 50 mg/d may have clinical value in predicting treatment success and guiding patient management.

Predictors of functional improvement in employed adults with major depressive disorder treated with desvenlafaxine.

We carried out a secondary analysis of a double-blind, placebo-controlled trial of desvenlafaxine for major depressive disorder (MDD) to explore the associations between depressive symptoms and subtypes, and functional outcomes, including work functioning. Employed outpatients with MDD were assigned randomly in a 2 : 1 ratio to receive desvenlafaxine 50 mg/day or placebo for 12 weeks. Analyses were carried out post-hoc with the intent-to-treat (ITT) sample (N=427) and a prospectively defined modified ITT sample (N=310), composed of patients with baseline 17-item Hamilton Rating Scale for Depression score of at least 20. Functional outcomes at week 12 included items and factors from the Montgomery–Åsberg Depression Rating Scale, Sheehan Disability Scale, and the Work Productivity and Activity Impairment questionnaire. In the modified ITT sample, but not in the ITT sample, desvenlafaxine-treated patients showed significantly greater improvement in several functional outcomes in the responder, nonanxious, and normal-energy patient subgroups. Improvement in the 17-item Hamilton Rating Scale for Depression total score at week 2 predicted change at week 12 in several functional outcomes. Functional improvement at 12 weeks was greater in subgroups of patients and was also significantly predicted by early improvement in depressive symptoms in employed patients with MDD treated with desvenlafaxine.

Predictors of functional response and remission with desvenlafaxine 50 mg/d in patients with major depressive disorder.

BACKGROUNDnThe predictive value of early functional improvement for treatment success at week 8 was assessed in a pooled analysis in patients with major depressive disorder (MDD).nnnMETHODSnData were pooled from 7 double-blind studies in adult patients with MDD randomly assigned to desvenlafaxine 50 mg/d or placebo. Four levels of treatment success were determined at week 8 for patients with baseline Sheehan Disability Scale (SDS) score > 12 (N = 2156): functional response (SDS ≤12 and ≥50% improvement in SDS), functional/depression response (SDS ≤12 and ≥50% improvement in both SDS and 17-item Hamilton Rating Scale for Depression [HAM-D17] score), functional remission (SDS < 7), and functional/depression remission (SDS < 7 and HAM-D17 ≤7). Week 2 improvement in SDS was evaluated as a predictor of later functional response/remission using receiver operating characteristic analysis. Odds ratios (ORs) of the predictability of improvement thresholds were computed from a logistic regression model.nnnRESULTSnThe proportion of patients achieving each level of treatment success was significantly greater for patients treated with desvenlafaxine (40%, 32%, 23%, 15%, respectively) vs placebo (31%, 22%, 17%, 10%; all P ≤ 0.002). Early change in SDS was a highly significant predictor of functional response/remission (ORs, 0.958-0.970; all P < 0.0001). Discussion Patients early functional response to desvenlafaxine 50 mg/d is predictive of treatment success.

An integrated analysis of the efficacy and safety of desvenlafaxine in the treatment of major depressive disorder.

The chronic course of major depressive disorder (MDD) often impedes the ability of patients to achieve full remission. Return of full functioning is a critical goal of antidepressant pharmacotherapy as the presence of residual depressive symptoms is associated with an increased risk of relapse. Treatment guidelines recommend selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, or atypical antidepressants as first-line treatment for moderate to severe MDD. Desvenlafaxine, administered as desvenlafaxine succinate, is an serotonin–norepinephrine reuptake inhibitor approved for the treatment of adults with MDD at the recommended dose of 50u2009mg/day. The aim of this integrated analysis was to assess the efficacy and safety of desvenlafaxine 50 and 100u2009mg/day compared with placebo in adult outpatients with MDD. The analysis used data from nine fixed-dose, short-term, placebo-controlled studies in adult outpatients diagnosed with MDD who had depressive symptoms for at least 30 days. Data from 4279 and 4317 patients were pooled for the efficacy and safety analyses, respectively. Statistically significant improvements were observed with desvenlafaxine 50 and 100u2009mg/day versus placebo for all efficacy endpoints assessed, including improvements in depressive symptoms, response and remission rates, as well as functional and cognitive outcomes. Treatment with desvenlafaxine 50 and 100u2009mg/day was generally safe and well tolerated. The findings of this integrated analysis of data from a large population of patients with MDD confirmed the antidepressant efficacy of both desvenlafaxine doses and add to previous evidence supporting the efficacy of desvenlafaxine.

P.3.024 Efficacy of sertraline in posttraumatic stress disorder secondary to interpersonal trauma or childhood abuse

BACKGROUNDnIn posttraumatic stress disorder (PTSD), the nature of the trauma and the age of occurrence may have substantial effects on psychobiological sequelae and treatment response. Interpersonal trauma (physical/sexual assault) and childhood abuse are both prevalent and associated with later PTSD. This analysis was conducted to specifically assess the efficacy of sertraline in the treatment of PTSD secondary to interpersonal trauma or childhood abuse.nnnMETHODSn395 adult patients with PTSD were randomized to 12-weeks double-blind treatment with flexible dose sertraline (50-200 mg/d) or placebo. Patients with different index traumas were compared in terms of baseline demographic and clinical characteristics, as well as treatment response. Primary efficacy variables included part 2 of the Clinician Administered PTSD Scale (CAPS-2).nnnRESULTSnInterpersonal trauma and childhood abuse were both more common in females than males, and were associated with early age at time of index trauma and longer duration of PTSD, but not with PTSD symptom severity. Sertraline was significantly more effective than placebo on most primary efficacy variables, irrespective of whether patients had experienced interpersonal trauma or childhood abuse.nnnCONCLUSIONSnThese data demonstrate that sertraline is valuable for the treatment of PTSD, irrespective of whether the precipitating trauma involves interpersonal trauma in general, or childhood abuse in particular.