James M. Russell

Bodyweight gain associated with atypical antipsychotics: epidemiology and therapeutic implications.

Atypical antipsychotic medications are associated with different adverse effects and efficacy profiles compared with conventional antipsychotics (i.e. less extrapyramidal symptoms, improved efficacy against negative symptoms and cognitive deficits, and most often a greater ability to improve patients’ quality of life). However, the atypical antipsychotics may be associated with clinically significant bodyweight gain, increasing the risk of medical comorbidity, including diabetes mellitus, hypertension, cardiovascular disease and hyperlipidaemia.This literature review assesses the various bodyweight gain liabilities associated with atypical antipsychotics, as well as the effects of bodyweight gain on quality of life. The issue of prevention and management of this often neglected adverse effect is also examined.Most studies reviewed indicate that clozapine and olanzapine are associated with more bodyweight gain than the other atypical antipsychotics. There are potential factors that place certain patients at greater risk for bodyweight gain, including low pretreatment body mass index, young age and being of female gender. Furthermore, bodyweight gain associated with the use of atypical anti-psychotics has been reported to be associated with clinical improvement, although this has not been substantiated widely. It is unclear whether increased medical comorbidity, including diabetes mellitus, coronary artery disease and/or elevated triglyceride levels, is secondary to the bodyweight gain associated with atypical antipsychotics, or the result of the agents themselves.A patient’s quality of life may be greatly affected by excessive bodyweight gain; either by increased comorbid medical illness, an increased relapse rate associated with noncompliance, or the social stigma associated with being obese. However, most studies reveal that treatment with atypical antipsychotic medications is associated with improved quality of life compared with that achieved with conventional antipsychotic medications.Because bodyweight is an important health risk associated with atypical antipsychotics, prevention and effective management of bodyweight are paramount in preventing comorbid medical illness, relapse and possible noncompliance.

Self-Reported Depressive Symptom Measures: Sensitivity to Detecting Change in a Randomized, Controlled Trial of Chronically Depressed, Nonpsychotic Outpatients

This study evaluated and compared the performance of three self-report measures: (1) 30-item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30); (2) 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16); and (3) Patient Global Impression-Improvement (PGI-I) in assessing clinical outcomes in depressed patients during a 12-week, acute phase, randomized, controlled trial comparing nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), and the combination in the treatment of chronic depression. The IDS-SR30, QIDS-SR16, PGI-I, and the 24-item Hamilton Depression Rating Scale (HDRS24) ratings were collected at baseline and at weeks 1–4, 6, 8, 10, and 12. Response was defined a priori as a ⩾50% reduction in baseline total score for the IDS-SR30 or for the QIDS-SR16 or as a PGI-I score of 1 or 2 at exit. Overall response rates (LOCF) to nefazodone were 41% (IDS-SR30), 45% (QIDS-SR16), 53% (PCI-I), and 47% (HDRS17). For CBASP, response rates were 41% (IDS-SR30), 45% (QIDS-SR16), 48% (PGI-I), and 46% (HDRS17). For the combination, response rates were 68% (IDS-SR30 and QIDS-SR16), 73% (PGI-I), and 76% (HDRS17). Similarly, remission rates were comparable for nefazodone (IDS-SR30=32%, QIDS-SR16=28%, PGI-I=22%, HDRS17=30%), for CBASP (IDS-SR30=32%, QIDS-SR16=30%, PGI-I=21%, HDRS17=32%), and for the combination (IDS-SR30=52%, QIDS-SR16=50%, PGI-I=25%, HDRS17=49%). Both the IDS-SR30 and QIDS-SR16 closely mirrored and confirmed findings based on the HDRS24. These findings raise the possibility that these two self-reports could provide cost- and time-efficient substitutes for clinician ratings in treatment trials of outpatients with nonpsychotic MDD without cognitive impairment. Global patient ratings such as the PGI-I, as opposed to specific item-based ratings, provide less valid findings.

Effect of concurrent anxiety on response to sertraline and imipramine in patients with chronic depression

Anxiety commonly complicates the clinical presentation of depression and has been associated with poorer long‐term outcome, but little information is available on the clinical correlates, and comparative effect on treatment response, of subsyndromic or secondary anxiety. Patients diagnosed with chronic major or double depression were randomized to 12 weeks of double‐blind treatment with either sertraline or imipramine in a 2:1 ratio. A high anxiety subgroup was operationally defined by a HAM‐D anxiety/somatization factor score ≥ 7. The effect of study treatment was measured utilizing the HAM‐D, CGI, HAM‐D anxiety/somatization factor, as well as a quality of life measure (Q‐LES‐Q) and a measure of psychosocial functioning (the MOS‐SF‐36). Two hundred nine patients were treated with imipramine and 426 patients were treated with sertraline. Thirty‐six percent of the total met criteria for the high anxiety subgroup. According to Kaplan‐Meier probability estimates, patients with significant concurrent anxiety symptoms were more likely to respond by 12 weeks (66.4%) than those without significant anxiety symptoms (54.2%). There was no significant difference in response rates for sertraline vs. imipramine. Both drugs were effective at treating high baseline levels of anxiety, with 60% of sertraline patients and 58% of imipramine patients having 50% or greater reduction from baseline in HAM‐D anxiety/somatization factor scores, and only 4.6% and 9.9%, respectively, reporting treatment‐emergent worsening in anxiety at study endpoint. Despite the chronicity of depressive illness, acute treatment with both sertraline and imipramine significantly improved psychosocial and quality of life measures. High baseline levels of anxiety did not reduce overall antidepressant response but did somewhat delay the onset of response to sertraline or imipramine in patients with chronic depression. Depression and Anxiety 13:18–27, 2001.

Efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder: a pooled analysis of four randomized, double-blind, placebo-controlled studies

To assess the efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder (GAD).

A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder:

The present study is a non-inferiority comparison of duloxetine 60— 120 mg/day and venlafaxine extended-release (XR) 75—225 mg/day for the treatment of adults with generalized anxiety disorder (GAD). The non-inferiority test was a prespecified plan to pool data from two nearly identical 10-week, multicentre, randomized, placebo-controlled, double-blind studies of duloxetine 60-120 mg/day and venlafaxine 75—225 mg/ day for the treatment of GAD. An independent expert consensus panel provided six statistical and clinical criteria for determining non-inferiority between treatments. Response was defined as ≥50% reduction in Hamilton Anxiety Rating Scale (HAMA) total score. In the pooled sample, patients were randomly assigned to duloxetine (n = 320), venlafaxine XR (n = 333) or placebo (n = 331). For the non-inferiority analysis, the per-protocol patients who were treated with duloxetine (n = 239) or venlafaxine XR (n = 262) improved significantly more (mean HAMA reductions were −15.4 and −15.2, respectively) than placebo-treated patients (n = 267; −11.6, P ≤ 0.001, both comparisons). Response rates were 56%, 58% and 40%, respectively. Discontinuation rate because of AEs was significantly higher for duloxetine (13.4%, P ≤ 0.001) and venlafaxine XR (11.4%, P ≤ 0.01) groups compared with placebo (5.4%). Duloxetine 60—120 mg/day met all statistical and clinical criteria for non-inferiority and exhibited a similar tolerability profile compared with venlafaxine XR 75—225 mg/day for the treatment of adults with GAD.

Early improvement during duloxetine treatment of generalized anxiety disorder predicts response and remission at endpoint.

Because many patients do not respond to pharmacotherapy for generalized anxiety disorder (GAD), it would be beneficial to know if early response is predictive of final outcome so that timely clinical decisions can be made about augmentation or alternative treatments. This topic has not been examined with the now recommended first-line treatments (selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors) for GAD. Combined data from three 9 to 10week acute treatment, multi-center, randomized, placebo-controlled studies of duloxetine for GAD were used to explore early improvement on the Hamilton Anxiety Rating Scale (HAMA) in relation to endpoint HAMA response (> or = 50% improvement from baseline), HAMA remission (< or = 7), Clinical Global Impression-Improvement (CGI-I) response (< or = 2), and functional remission as measured by the Sheehan Disability Scale Global Functional Improvement (< or = 5). For duloxetine-treated patients (n=668), the relationships between the proportion of patients who achieved each category of early (week 2 and week 4) HAMA improvement (> or = 20%, > or = 40%, > or = 60%, and > or = 80%) and achievement of endpoint HAMA response, HAMA remission, CGI response, and SDS remission status were all statistically significant (all Ps < or = 0.003). One hundred percent of the duloxetine-treated patients who showed substantial HAMA improvement (>80%) at week 2, and 93% at week 4, were HAMA responders at endpoint. At week 2, 79% of the duloxetine-treated patients who achieved a HAMA improvement of 40-59% were HAMA responders at endpoint. About half of duloxetine-treated patient showing 40-59% early HAMA improvement were remitters on the SDS at endpoint. These data suggest a connection between early improvement and endpoint response and remission status that can be used to guide clinical decision-making.

Brain-derived neurotrophic factor in generalized anxiety disorder: results from a duloxetine clinical trial.

BACKGROUND Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression and anxiety, but has not been examined systematically in generalized anxiety disorder (GAD). The objective of this study was to examine the relationship between baseline BDNF level and treatment response in patients with GAD. METHODS Patients (N=168) were from China, met criteria for DSM-IV GAD, had a Hospital Anxiety and Depression Rating Anxiety (HADS-A) subscale score ≥10, and a Sheehan Disability Scale (SDS) global functioning total score ≥12 at baseline. Study design was double-blind therapy for 15 weeks with duloxetine 60-120 mg or placebo. Efficacy measures included the HADS-A and Hamilton Anxiety Rating Scale (HAMA) total score. Change from baseline to endpoint for BDNF by treatment group was analyzed using ANCOVA models with baseline BDNF level as a covariate. RESULTS No significant association was found between baseline plasma BDNF levels and anxiety illness severity. Patients who received duloxetine (n=88) had a significantly greater mean increase in plasma BDNF level (957.80 picograms/ml) compared with patients who received placebo (n=80; 469.93 pg/mL) (P=.007). Patients who met response and remission criteria (with either treatment) had greater mean increases in BDNF at endpoint from baseline (P≤.05) but when compared with nonresponders and nonremitters, respectively, the differences in mean increase were not statistically significant between groups. CONCLUSIONS BDNF levels significantly increased with duloxetine treatment for GAD, but response and remission outcomes were not clearly related to an increase in plasma BDNF level.

Tolerability of oral loading of divalproex sodium in the treatment of actue mania

To conduct a pilot study on the safety and tolerability of a dosage strategy for divalproex sodium beginning with 30 mg/kg/day. It is hypothesized that loading at this level will reach therapeutic levels of valproate more quickly, which in turn will decrease the latency of the therapeutic effect.

The relationship between functional outcomes and the treatment of anxious and painful somatic symptoms in patients with generalized anxiety disorder

ABSTRACT Objective: To examine the relationship between global functional impairment and the treatment of anxious symptoms and painful somatic symptoms (PSS) in patients with generalized anxiety disorder (GAD). Research design and methods: Data from two double-blind, placebo-controlled trials in adult outpatients meeting DSM-IV criteria for GAD were pooled. In the first trial (9-week, fixed-dose treatment period), patients were randomized to duloxetine 60 mg QD (n = 168), duloxetine 120 mg QD (n = 170), or placebo (n = 175). In the second trial (10-week, flexible-dose treatment period), patients were randomized to 60–120 mg QD of duloxetine (n = 168) or placebo (n = 159). Path analysis was used to assess the relative contributions of changes in psychic and somatic anxiety and PSS on improved functional outcomes. Clinical trial registration information: Study 1: NCT00122824; Study 2: study completed before registration required. Main outcome measures: Sheehan Disability Scale (SDS), Hamilton Anxiety Rating Scale (HAMA), and Visual Analog Scale for overall pain (VAS). Results: There was a moderate correlation (0.45, p < 0.05) at endpoint between changes in global functional impairment and changes in psychic anxiety (controlling for somatic anxiety and PSS); whereas the correlation between changes in global functional impairment and changes in somatic anxiety (controlling for psychic anxiety and PSS) was weak (0.09, p < 0.05). The correlation between changes in global functional impairment and changes in PSS (controlling for psychic and somatic anxiety) was weak (0.27, p < 0.05). Path analysis revealed that 37% of the total improvement in functional impairment (Sheehan Disability Scale total score) due to duloxetine treatment was independent of improvement in the Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety subscale scores or Visual Analog Scale for overall pain (VAS) score. Improvement in psychic anxiety accounted for 47% of the total treatment effect on improvement of functional impairment, whereas 7% and 9% of the improvement in functional impairment was accounted for by improvements in somatic anxiety and overall pain, respectively. Limitations: This was a post-hoc exploratory analysis. Patients with co-morbid Major Depressive Disorder (MDD) or significant depressive symptoms were excluded from these GAD studies. Conclusions: In patients with GAD, there was a moderate correlation between improvement in psychic anxiety symptoms and improvement in global functional impairment, whereas the correlation between improvements in somatic anxiety or PSS and improvement in global functional impairment was low. Most of the treatment effect of duloxetine in improvement of functional impairment was mediated through improvement in psychic anxiety, with smaller contributions through improvement in somatic anxiety and PSS. Some of the improvement in functional impairment for duloxetine-treated patients was independent of improvement through any of these domains.

Duloxetine in the treatment of generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a relatively prevalent and disabling condition. Duloxetine, an inhibitor of both serotonin and norepinephrine, was approved by the US FDA in 2007 for the treatment of GAD. Short-term efficacy of duloxetine in dosages of 60–120 mg/day has been established in four double-blind, placebo-controlled trials of 9–10 weeks duration. Duloxetine has also been found to meet rigorous criteria for noninferiority in comparison with venlafaxine in GAD. Duloxetine has shown superiority on measures of functioning and quality of life and, compared with placebo treatment, it reduces painful physical symptoms common in GAD patients. Continuation treatment for acute treatment responders was found to prevent relapse of GAD to a significantly greater degree than placebo. In all acute and long-term trials, duloxetine was well-tolerated. This body of research suggests that duloxetine should be one of the options considered as a first-line treatment for GAD.