Lauren B. Marangell

A randomized placebo-controlled trial of duloxetine in patients with major depressive disorder and associated painful physical symptoms

Abstract Objective: Painful physical symptoms are common in patients with major depressive disorder (MDD) and may predict poorer treatment outcomes. Duloxetine has demonstrated efficacy in treating both MDD and certain other painful conditions. This randomized, double-blind clinical trial assessed the effects of duloxetine in patients with both MDD and MDD-associated physical pain. Methods: Participants were outpatient adults with current MDD (DSM-IV-TR criteria; Montgomery–Åsberg Depression Rating Scale [MADRS] total score ≥20) and at least moderate pain (Brief Pain Inventory Short Form [BPI] average pain rating ≥3) and with at least one prior episode of MDD. Patients received placebo (N = 266) or duloxetine (N = 262) 60 mg once daily. This trial is registered at clinicaltrials.gov (NCT01000805). Main outcome measures: Coprimary outcomes were MADRS total score (change from baseline at 8 weeks) and BPI average pain rating (overall main effect over 8 weeks). The Sheehan Disability Scale (SDS) global functional impairment score (change from baseline at 8 weeks) was used to assess functioning. Remission was defined as MADRS total score ≤12 at the 8-week endpoint. Changes were analyzed using mixed-effects model repeated measures (MMRM). Results: Compared with placebo, duloxetine significantly improved the mean MADRS total score, BPI average pain rating, and SDS global functional impairment score (all p ≤ 0.05 for analyses described above). The remission rate was significantly greater with duloxetine compared with placebo (p = 0.001) and was greater for duloxetine-treated patients with ≥50% versus <50% improvement in BPI average pain score (p ≤ 0.001). Treatment emergent adverse events that occurred in at least 5% of duloxetine-treated patients and at twice the rate of placebo included nausea, somnolence, constipation, decreased appetite, and hyperhidrosis. Rates of discontinuation due to adverse events were greater for duloxetine than placebo (8.0% vs 3.4%, respectively; p = 0.024). This study did not address the effects of duloxetine on MDD and comorbid pain of a known origin. Conclusions: These results support the efficacy and tolerability of duloxetine in the treatment of depression and associated painful physical symptoms in patients with MDD and at least moderate MDD-associated pain.

Duloxetine versus placebo in the treatment of major depressive disorder and associated painful physical symptoms: a replication study.

Abstract Objective: Painful physical symptoms are common in patients with major depressive disorder (MDD) and can negatively affect patient outcomes. Duloxetine has demonstrated efficacy in treating MDD and other certain painful conditions; this study specifically evaluated patients with both MDD and MDD-associated pain. Methods: This randomized, double-blind clinical trial enrolled adult outpatients with MDD (DSM-IV-TR criteria; Montgomery–Åsberg Depression Rating Scale [MADRS] total score ≥20) and at least moderate pain (Brief Pain Inventory, Short Form [BPI] average pain rating ≥3). Patients received placebo (N = 266) or duloxetine (N = 261) 60 mg once daily (QD) (after starting dose of 30 mg QD for 1 week). This study replicated another study evaluating MDD and MDD-associated pain. Clinical trial registration: Clinicaltrials.gov (NCT01070329). Main outcome measures: Co-primary outcomes were the MADRS total score (change from baseline at 8 week endpoint) and BPI average pain rating (overall main effect over 8 weeks of treatment). The Sheehan Disability Scale (SDS) global functional impairment score at week 8 assessed functioning as a secondary outcome. Changes were analyzed using mixed-effects model repeated measures (MMRM), and the MADRS remission rate (total score ≤12 at 8-week endpoint) was analyzed using the Cochran–Mantel–Haenszel test. Results: Both co-primary objectives and the first two gated secondary objectives were achieved: compared with placebo, duloxetine significantly improved the mean MADRS total score, BPI average pain rating, SDS global functional impairment score, and remission of depression at 8-week endpoint (all p < 0.01). The third gated secondary objective, evaluating remission of depression at the last two non-missing visits, was not achieved. The within-group MADRS remission rate was greater for duloxetine-treated patients with ≥50% (versus <50%) improvement in BPI average pain (p < 0.001). Safety outcomes were similar to previous reports. This study did not address the effects of duloxetine on MDD and comorbid pain of a known origin. Conclusions: These results replicated findings supporting the efficacy and tolerability of duloxetine compared to placebo as treatment for depression and pain in patients with MDD and at least moderate pain associated with MDD.

Impact of fatigue on outcome of selective serotonin reuptake inhibitor treatment: secondary analysis of STAR*D

Abstract Objective: To explore relationships between baseline and changes in fatigue during treatment with outcomes in patients with major depressive disorder (MDD) receiving citalopram monotherapy. Research design and methods: Secondary analyses of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Level 1 treatment phase (≤14 weeks citalopram monotherapy). Fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16; scored 0–3: 0 = no fatigue, 3 = maximal fatigue); prospective fatigue: assessment of fatigue at Level 1 entry and exit (no fatigue, treatment-emergent fatigue, remitted fatigue, or residual fatigue). Clinical trial registration: Http://clinicaltrials.gov, NCT00021528. Main outcome measures: Remission of depressive symptoms (17-item Hamilton Rating Scale for Depression ≤7 or QIDS-SR16 ≤5); Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; Short-Form Health Survey Mental and Physical subscales; and Work and Social Adjustment Scale (WSAS). Results: At baseline, of 2868 patients included in the analyses, 5.5% had a QIDS-SR16 item 14 score of 0; 22.9%, a score of 1; 53.6%, a score of 2; and 18.0%, a score of 3. During Level 1 treatment, 3.5% of patients had no prospective fatigue, 2.1% had treatment-emergent fatigue, 33.6% had fatigue remitting during treatment, and 60.8% had residual fatigue. Female gender, unemployment, fewer years of education, and lower monthly income were significantly associated with higher rates of baseline fatigue (all P < 0.0001). Higher levels of baseline or prospective fatigue were associated with reduced likelihood of remission, decreased overall satisfaction (P < 0.0001), and reduced mental and physical function at outcome (P ≤ 0.05). Patients with higher baseline or prospective fatigue reported higher WSAS total scores (P < 0.0001), indicative of more severe functional impairment. Conclusions: Lower baseline fatigue and remission of fatigue during antidepressant treatment in patients with MDD are associated with higher rates of remission of depressive symptoms and better function and quality of life. Study limitations include use of the STAR*D Level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS-SR16), and the secondary post-hoc analysis design.

Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials

Background: Individuals with psoriasis are at increased risk for psychiatric comorbidities, including suicidal ideation and behavior (SIB). Objective: To distinguish between the underlying risk and potential for treatment‐induced psychiatric adverse events in patients with psoriasis being treated with brodalumab, a fully human anti–interleukin 17 receptor A monoclonal antibody. Methods: Data were evaluated from a placebo‐controlled, phase 2 clinical trial; the open‐label, long‐term extension of the phase 2 clinical trial; and three phase 3, randomized, double‐blind, controlled clinical trials (AMAGINE‐1, AMAGINE‐2, and AMAGINE‐3) and their open‐label, long‐term extensions of patients with moderate‐to‐severe psoriasis. Results: The analysis included 4464 patients with 9161.8 patient‐years of brodalumab exposure. The follow‐up time–adjusted incidence rates of SIB events were comparable between the brodalumab and ustekinumab groups throughout the 52‐week controlled phases (0.20 vs 0.60 per 100 patient‐years). In the brodalumab group, 4 completed suicides were reported, 1 of which was later adjudicated as indeterminate; all patients had underlying psychiatric disorders or stressors. Limitations: There was no comparator arm past week 52. Controlled study periods were not powered to detect differences in rare events such as suicide. Conclusions: Comparison with controls and the timing of events do not indicate a causal relationship between SIB and brodalumab treatment.

Diagnostic potential of structural neuroimaging for depression from a multi-ethnic community sample

Background At present, we do not have any biological tests which can contribute towards a diagnosis of depression. Neuroimaging measures have shown some potential as biomarkers for diagnosis. However, participants have generally been from the same ethnic background while the applicability of a biomarker would require replication in individuals of diverse ethnicities. Aims We sought to examine the diagnostic potential of the structural neuroanatomy of depression in a sample of a wide ethnic diversity. Method Structural magnetic resonance imaging (MRI) scans were obtained from 23 patients with major depressive disorder in an acute depressive episode (mean age: 39.8 years) and 20 matched healthy volunteers (mean age: 38.8 years). Participants were of Asian, African and Caucasian ethnicity recruited from the general community. Results Structural neuroanatomy combining white and grey matter distinguished patients from controls at the highest accuracy of 81% with the most stable pattern being at around 70%. A widespread network encompassing frontal, parietal, occipital and cerebellar regions contributed towards diagnostic classification. Conclusions These findings provide an important step in the development of potential neuroimaging-based tools for diagnosis as they demonstrate that the identification of depression is feasible within a multi-ethnic group from the community. Declaration of interests C.H.Y.F. has held recent research grants from Eli Lilly and Company and GlaxoSmithKline. L.M. is a former employee and stockholder of Eli Lilly and Company. Copyright and usage

Impact of non-remission of depression on costs and resource utilization: from the COmorbidities and symptoms of DEpression (CODE) study

Abstract Objective: To determine the economic impact of sustained non-remission of depression on the total annual all-cause healthcare costs of patients with a history of depression. Methods: Adults with ≥2 claims with depression diagnosis codes from the HealthCore Integrated Research Database were invited to participate in this retrospective/prospective fixed-cohort repeated-measures study. Patients with scores >5 at initial survey and 6 month assessment on the Quick Inventory of Depressive Symptomatology (QIDS-SR) were considered to be in ‘sustained non-remission’, while those with scores ≤5 at both assessments were considered to be in ‘sustained remission’. Patients also completed self-report instruments to assess pain, fatigue, anxiety, sleep difficulty, and other health and wellness domains. Survey data were linked to patient claims (12 month pre- and post-initial-survey periods). After adjusting for demographic and clinical characteristics using propensity scores, post-survey costs and resource utilization were compared between remission and non-remission groups using non-parametric bootstrapping methods. Results: Of the 640 patients who met inclusion criteria, 140 (21.9%) were in sustained remission and 348 (54.5%) never achieved remission. Using propensity-score adjusted costs, sustained non-remission of depression was associated with higher annual healthcare expenditures of >

Effects of antidepressant therapy on neural components of verbal working memory in depression

2300 per patient (

Other race effect on amygdala response during affective facial processing in major depression

14,627 vs.

Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine

12,313, p = 0.0010) compared to remitted patients. Higher costs were associated with greater resource utilization and increased medication use. Non-remitters were prescribed more medications than remitters, including antidepressants and second-generation antipsychotics. Although length of antidepressant exposure over 12 months was similar, remitters were more likely to be adherent to antidepressants. Non-remission was associated with anxiety, pain, fatigue, sleep disruption, diabetes, anemia, obesity, and heavy drinking. Conclusion: Failing to achieve remission of depression was associated with increased costs and greater resource utilization. Clinicians should strive to achieve sustained remission in patients with depression. Study limitations included reliance on claims data for initial identification of cohort and high rate of attrition in the analytic sample.

Iconography : Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials

Impairments in verbal working memory are evident in major depression. Verbal working memory is comprised of the components of encoding, maintenance and retrieval. Whether the neural impairments are expressed in specific components, and how pharmacological therapy could modify the neural correlates are not well understood. We investigated the neural correlates of verbal working memory components in depression using the Sternberg task in a longitudinal magnetic resonance imaging study. Serial scans were acquired in 23 patients (mean age 39.8 years) during an acute depressive episode and following 12 weeks of pharmacological therapy with duloxetine and in 22 matched healthy controls (mean age 39.1 years) at the same time points. A significant group by time interaction was evident during the long maintenance phase, extending from the left middle frontal to the middle temporal and caudate regions, in which there was reduced activation in healthy participants at the follow-up scan but there were no changes in patients. Persistent neural engagement during the maintenance phase following treatment was revealed in major depression. The findings emphasize that impairments in verbal working memory may be initiated in the maintenance phase in major depression in order to sustain performance. Further research with larger sample size and using randomized, placebo-controlled double-blind studies are required to confirm our results.