Predictors of relapse in patients with major depressive disorder in a 52-week,fixed dose,double blind,randomized trial of selegiline transdermal system (STS)

Objective

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment.

Method

After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse.

Results

For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis.

Conclusions

While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD.     

Quantitative Ultrasound and Mortality: A Prospective Study

Previous studies suggest that low bone mineral density (BMD) is associated with increased mortality, but the relationship between quantitative ultrasound (QUS) and mortality is unknown. We studied 5816 women over age 70 years enrolled in the Study of Osteoporotic Fractures. QUS of the calcaneus, and BMD of the calcaneus and hip, were measured at baseline, and women were contacted every 4 months to determine vital status. All reported deaths were confirmed by review of the death certificate or hospital records, and classified by ICD-9 code. During 5.0 years of follow-up, 677 women died. Women in the lowest quintile of QUS had the highest mortality during follow-up. After adjustment for age, grip strength, weight, height, health status, estrogen use, smoking, physical activity, and history of hypertension, diabetes, cardiovascular disease, cancer and stroke, each 1 SD reduction in broadband ultrasonic attenuation (BUA) was associated with a 16% increase in mortality (RH = 1.16; 95% CI: 1.07, 1.26). Mortality from cardiovascular disease, cancer and other causes were all increased among women with low QUS, but the association with cancer deaths was not statistically significant after multiple adjustments (RH = 1.09; CI: 0.93, 1.27). Low BMD was also associated with an increased risk of total and cause-specific mortality, but we found little evidence that BUA and BMD were independent predictors of mortality. Results were similar among women who did not fracture during follow-up. In this large population-based study of older women, low QUS is associated with both total and cause-specific mortality. This relationship was independent of other factors associated with mortality, such as age and health status, and suggests QUS and BMD may reflect some aspect of aging not captured by these traditional factors. Received: 16 March 2001 / Accepted: 19 February 2002     

Aripiprazole versus haloperidol treatment in early-stage schizophrenia

We conducted a secondary analysis of a completed study of the differential efficacy and side effects of aripiprazole versus haloperidol in early-stage schizophrenia (ESS), a subpopulation of patients which does not include first episode or chronic patients. A subpopulation of 360 individuals with ESS were identified from a randomized, multi-center, double-blind study of 1294 individuals with schizophrenia at different stages of illness who were randomized to treatment with aripiprazole (ESS = 237) or haloperidol (ESS = 123) for one year. The primary outcome measure was response rate based on a 50% reduction of Positive and Negative Syndrome Scale (PANSS) total scores. Secondary outcomes included several efficacy and safety measures, as well as treatment discontinuation. More individuals in the aripiprazole group (48%) than in the haloperidol group (28%; p < 0.01) completed the study. Response rates were greater in the aripiprazole group (38% [N = 91]) than in the haloperidol group (22% [N = 27]; p < 0.01). Aripiprazole was associated with fewer extrapyramidal side effects. ESS subjects in the haloperidol group were more likely than those in the aripiprazole group to discontinue the study drug due to an adverse event other than worsening illness (29% and 11%, respectively; p < 0.01), and efficacy differences were reduced by interventions to mitigate side effects (decreasing antipsychotic dose with or without adding antiparkinsonian medication). Aripiprazole has a favorable efficacy/safety profile in ESS and appeared to be superior to haloperidol on a number of efficacy and safety outcomes. However, excessive dosing of the antipsychotic medications, in particular haloperidol, may have played an important role in accounting for the differences between aripiprazole and haloperidol in this study.     

Thyroid hormone use, hyperthyroidism and mortality in older women

Purpose

Thyroid dysfunction is common, particularly among older women. The safety of thyroid hormone use and long-term prognosis of hyperthyroidism remain controversial. We performed a prospective cohort study to examine the relationship among thyroid hormone use, previous hyperthyroidism, abnormal thyroid function, and mortality.

Methods

We studied 9449 community-dwelling white women aged ≥65 years followed for 12 years. For analyses of thyroid function, we performed a nested case-cohort in 487 women using a third-generation thyroid-stimulating hormone assay. Causes of death were adjudicated based on death certificates and hospital records.

Results

Twelve percent of the 9449 women took thyroid hormone at baseline, and the mean duration of thyroid hormone use was 15.8 years; 9.4% of participants reported a history of hyperthyroidism. During 12 years of follow-up, 3159 women died (33%). In multivariate analysis, mortality among users of thyroid hormone was similar to that observed for nonusers (relative hazard [RH] 1.11, 95% confidence interval [CI], 0.98-1.24, P = .09). Previous hyperthyroidism was associated with a higher risk of all-cause mortality (RH 1.20, 95% CI, 1.06-1.36), particularly cardiovascular mortality (RH 1.46, 95% CI, 1.20-1.77). Low (≤0.5 mU/L) or high (>5 mU/L) thyroid-stimulating hormone levels were not associated with excess total or cause-specific mortality, but the power to detect these relationships was limited.

Conclusions

Among older women, thyroid hormone use is not associated significantly with excess mortality, but previous hyperthyroidism may be associated with a small increase in all-cause and cardiovascular mortality. Additional long-term studies of hyperthyroidism and its treatment should further explore these findings.     

Stiffness,viscosity, and upper‐limb inertia about the glenohumeral abduction axis

To evaluate the dynamic properties of the shoulder and understand how they are controlled by the central nervous system, glenohumeral‐joint stiffness and viscosity and upper‐limb inertia were quantified under various levels of muscle contraction in seven healthy human subjects. Through a cast attachment, the upper limb was perturbed in a precise pattern by a computer‐controlled servomotor to manifest the dynamic properties of the joint. The recorded joint position and torque were used to estimate joint stiffness and viscosity and upper‐limb inertia. With moderate muscle contraction, the stiffness and viscosity increased several fold. A stiffer shoulder joint associated with stronger muscle contraction made the shoulder more stable and protected it from potential injuries during strenuous tasks. Joint viscosity, especially the stronger viscous damping associated with more strenuous contraction, smoothed shoulder movement and stabilized the joint. From the control viewpoint, the glenohumeral joint responded to the central nervous system more quickly with increasing muscle contraction, which was useful during strenuous tasks. On the other hand, the central nervous system controlled stiffness and viscosity synchronously so that it dealt with only a nearly constant damping ratio of the joint over various levels of contraction, which simplified its task substantially. This approach quantified the dynamic and static properties of the shoulder under various levels of contraction more accurately and completely than a manual test, and it can potentially be used to evaluate changes in these properties caused by musculoskeletal injuries and their surgical treatments.     

Acute surgical management of Jones' fractures

The purpose of this study was to evaluate the effectiveness of surgical management for acute Jones' fractures and Torg types I and II proximal diaphyseal stress fractures presenting acutely in both athletes and nonathletes. Twenty-two patients underwent intramedullary screw fixation between 1994 and 1999. Immediate intramedullary screw fixation of acute Jones' fractures and type I stress fractures resulted in a 100% union rate with an average time to union of 6.2 weeks. Fixation of type II stress fractures had a union rate of 100% with a mean time to union of 8.3 weeks. The overall complication rate was 9%. Surgical intervention allowed an earlier return to weight-bearing with a more rapid and predictable union rate. The authors recommend intramedullary fixation as a treatment of choice for the management of fifth metatarsal fractures distal to the tuberosity in nonathletes as well as athletes.     

Subjective cognitive complaints, affective distress, and objective cognitive performance in Persian Gulf War veterans.

We examined subjective cognitive complaints, affective distress, and cognitive performance in Persian Gulf veterans who reported illness and cognitive complaints. We predicted a stronger relationship between subjective cognitive complaints and affective distress than between subjective cognitive complaints and objective cognitive performance. This prediction was confirmed in a sample of 100 veterans. The results suggest that cognitive impairment should not be diagnosed in this population without objective confirmation with cognitive testing.     

Placing transdermal selegiline for major depressive disorder into clinical context: Number needed to treat,number needed to harm,and likelihood to be helped or harmed

Background

This is a quantitative review of existing studies of transdermal selegiline for major depressive disorder.

Methods

Data for dichotomous outcomes were extracted from the five 6–8 week studies of transdermal selegiline. Number needed to treat (NNT) vs. placebo was calculated for response and remission using standard definitions. Number needed to harm (NNH) vs. placebo for commonly encountered adverse events (AEs), AEs associated with sexual function, incidence of weight gain ≥5% from baseline, and discontinuation due to an AE, were also calculated. Data was pooled as appropriate and likelihood to be helped or harmed (LHH) ratios contrasting remission with selected tolerability outcomes were determined.

Results

When pooling together the two pivotal trials as identified in product labeling, NNT for response was 11 (95% CI 6–109) and for remission, 9 (95% CI 6–28). Pooling all trials, NNH for application site reaction was 7 (95% CI 6–10) and for insomnia, 19 (95% CI 12–41). There were no clinically relevant differences from placebo regarding weight gain or impairment in sexual functioning. NNH for discontinuation due to an AE was 32 (95% CI 19–132). LHH for remission vs. discontinuation from treatment due to an AE was 3.6.

Limitations

The studies included were not identical in design. The studies were registrational in nature and thus not necessarily generalizable.

Conclusions

NNT for transdermal selegiline for efficacy is similar to that for other antidepressant regimens for which similar analyses have been published. There appear to be no clinically relevant effects of selegiline on weight or sexual functioning.