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Andrew C Leon

Publications and source records attributed to Andrew C Leon.

At least 37 records · Page 2Linked to original sources
PubMed2005

Performance of a mixed effects logistic regression model for binary outcomes with unequal cluster size.

When a clustered randomized controlled trial is considered at a design stage of a clinical trial, it is useful to consider the consequences of unequal cluster size (i.e., sample size per cluster). Furthermore, the assumption of independence of observations within cluster does not hold, of course, because the subjects share the same cluster. Moreover, when the clustered outcomes are binary, a mixed effect logistic regression model is applicable. This article compares the performance of a maximum likelihood estimation of the mixed effects logistic regression model with equal and unequal cluster sizes. This was evaluated in terms of type I error rate, power, bias, and standard error through computer simulations that varied treatment effect, number of clusters, and intracluster correlation coefficients. The results show that the performance of the mixed effects logistic regression model is very similar, regardless of inequality in cluster size. This is illustrated using data from the Prevention Of Suicide in Primary care Elderly: Collaborative Trial (PROSPECT) study.

Algorithms↗
PubMed2005

A comparison of multiplicity adjustment strategies for correlated binary endpoints.

Several Bonferroni-type adjustments have been proposed to control for family wise type I error among multiple tests. However, many of the approaches disregard the correlation among endpoints. This can result in a conservative hypothesis testing strategy. The James procedure is an alternative approach that accounts for multiplicity among correlated continuous endpoints. Here a simulation study compares four Bonferroni-type alpha-adjustments (Bonferroni, Dunn-Sidák, Holm, and Hochberg) and the James p-value adjustment when used for multiple correlated binary variables. These procedures provided adequate protection against familywise type I error for correlated binary endpoints, albeit, at times, in an overly cautious manner. That is, when correlations among endpoints exceed 0.60, the result is somewhat conservative for the approaches that do not account for those correlations. Among the adjustments examined, the James approach appears to be the uniformly preferred method. Analyses of data from a randomized controlled clinical trial of treatments for mania in bipolar disorder are used to illustrate the application of the multiplicity adjustments.

Antipsychotic Agents↗
PubMed2005

Symptoms of late-life depression: frequency and change during treatment.

OBJECTIVE: The authors determined the symptoms frequently present in older patients with major depression that showed the greatest change during treatment and that best correlated with an independent measure of improvement (the Clinical Global Impression scale [CGI]). METHODS: Subjects included 728 patients over the age of 60 years with major depression who were selected for entry into a clinical trial. Authors determined the frequency of symptoms on the 17-item Hamilton Rating Scale for Depression (Ham-D) and the effect size of symptom change during treatment. RESULTS: Nine symptoms were identified that were frequent, showed the greatest change during treatment, and best correlated with CGI. The items included depressed mood; loss of interest in work and activities; psychic anxiety; somatic symptoms, general (decreased energy); somatic anxiety; guilt; middle insomnia; late insomnia; and suicidal ideation. These nine items accounted for 92% of the variance in the 17-item Ham-D score, correlated with the CGI at a level similar to the 17-item Ham-D, and were at least as sensitive as the 17-item Ham-D for detecting drug-placebo differences. A comparison with five other similar approaches in non-geriatric samples suggested that the symptoms identified were relatively similar in both age-groups. CONCLUSIONS: Symptoms frequent in patients with late-life depression are similar to those in mixed-aged samples. Nine of the Ham-D items appear most useful for assessment of change during treatment.

Age of Onset↗
PubMed2005

Preference for fall from height as a method of suicide by elderly residents of New York City.

We studied all medical examiner-certified suicides in New York City from 1990 to 1998 to compare suicide methods used by elderly and younger adults. Associations between age and suicide method and place of occurrence were examined. Fall from height was more likely to have been used by individuals 65 or older than by those who were younger. Among persons who died by fall from height, those 65 or older were more likely than others to have fallen from buildings where they lived.

Adolescent↗
PubMed2005

Tachyphylaxis in unipolar major depressive disorder.

BACKGROUND: Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis. METHOD: The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis. RESULTS: For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval. CONCLUSIONS: Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

Adult↗
PubMed2005

Residual symptoms in depressed patients after treatment with fluoxetine or reboxetine.

BACKGROUND: Residual symptoms are common and have a variety of consequences in depressed patients who respond to treatment, but seldom have specific residual symptoms been assessed. We examined the frequency and severity of residual depressive symptoms in 2 studies comparing the selective serotonin reuptake inhibitor (SSRI) fluoxetine with the norepinephrine reuptake inhibitor (NRI) reboxetine. METHOD: Data from two 8-week, previously published, double-blind, random-assignment studies comparing fluoxetine and reboxetine were obtained. Both studies included men and women who met DSM-III-R criteria for unipolar nonpsychotic major depression. Symptoms were assessed with the 21-item Hamilton Rating Scale for Depression (HAM-D). The frequency and severity of residual symptoms were determined in the patients who completed treatment and responded (had at least 50% improvement on the HAM-D). RESULTS: In study 1, 117 patients completed treatment and responded. In study 2, 113 patients completed treatment and responded. The most frequent symptoms present after treatment were psychic anxiety, lack of interest, somatic anxiety, and depressed mood. No residual symptom differed significantly between treatment groups in both samples. Ordinal logistic regression, used to control for baseline symptom severity, revealed no other differences between drug groups except that decreased libido was significantly greater with fluoxetine in study 1 and study 2. Three composite scores for residual anxiety, sleep disturbance, and reduced drive did not differ between drug groups. CONCLUSION: This study found no differences in residual symptoms in depressed patients who responded to treatment with the SSRI fluoxetine and the NRI reboxetine, with the exception that the fluoxetine group had a greater decrease in sexual interest, a likely side effect of that drug.

Adrenergic Uptake Inhibitors↗
PubMed2004

Sample-size requirements for comparisons of two groups on repeated observations of a binary outcome.

When preparing a research protocol, an investigator must be as careful in projecting sample-size requirements as in specifying hypotheses. In this article, tables are presented that provide estimates of sample-size requirements for statistical power of 0.80 with two-tailed alpha-levels of 0.05 in studies with a balanced design that plan to compare two groups on time-averaged, repeated observations of a binary outcome. The estimates, which are based on the algorithm of Diggle, Heagerty, Liang, and Zeger, are a function of several features of the study, including the response rates for each group, the number of repeated observations per participant, and the strength of the association among observations within participants as quantified with an intraclass correlation coefficient.

Algorithms↗
PubMed2004

Paroxetine, other antidepressants, and youth suicide in New York City: 1993 through 1998.

BACKGROUND: Regulatory agencies in the United Kingdom and the United States have recently issued warnings about a possible link between suicidal ideation and attempts and the use of paroxetine in a pediatric patient population. The objective of this study was to determine the proportion of youth suicides that tested positive for paroxetine or other antidepressants in medical examiner toxicologic testing in New York City from 1993 through 1998, the first 6 years that paroxetine was available in the United States. METHOD: Subjects in this medical examiner surveillance study were suicides less than 18 years of age. Serum toxicology was examined for paroxetine and other antidepressants. RESULTS: There were 66 suicides among persons under 18 years of age in the years 1993 through 1998. Toxicology was tested in 58 (87.9%) of the 66 suicides, and 54 (81.8%) had injury-death intervals of 3 days or less. None of the victims had paroxetine detected in their blood obtained at the time of autopsy. Imipramine was detected in 2 victims and fluoxetine in another 2. CONCLUSION: Despite regulatory concerns, none of the autopsies of youth suicides in New York City detected paroxetine in the victims, although other antidepressants were detected in 4 victims. However, in the vast majority of the youth suicides, there was no evidence of anti-depressant use immediately prior to death.

Accidents↗
PubMed2004

Are two antidepressant mechanisms better than one? Issues in clinical trial design and analysis.

The introduction of newer antidepressants that affect both serotonergic and noradrenergic neurotransmission has prompted the question of whether two antidepressant mechanisms of action are better than one for the treatment of depression. Existing data do not provide a definitive answer. Whether future studies provide the answer will depend largely on the quality of trial designs. Some design aspects are dictated by the nature of such a study (e.g., superiority vs. equivalence trial), and others are somewhat more discretionary (e.g., assessment tools, statistical procedures). Issues in the design and analysis of clinical trials comparing dual- and single-action antidepressants are discussed.

Antidepressive Agents↗
PubMed2004

Multiplicity-adjusted sample size requirements: a strategy to maintain statistical power with Bonferroni adjustments.

BACKGROUND: A researcher must carefully balance the risk of 2 undesirable outcomes when designing a clinical trial: false-positive results (type I error) and false-negative results (type II error). In planning the study, careful attention is routinely paid to statistical power (i.e., the complement of type II error) and corresponding sample size requirements. However, Bonferroni-type alpha adjustments to protect against type I error for multiple tests are often resisted. Here, a simple strategy is described that adjusts alpha for multiple primary efficacy measures, yet maintains statistical power for each test. METHOD: To illustrate the approach, multiplicity-adjusted sample size requirements were estimated for effects of various magnitude with statistical power analyses for 2-tailed comparisons of 2 groups using chi2 tests and t tests. These analyses estimated the required sample size for hypothetical clinical trial protocols in which the prespecified number of primary efficacy measures ranged from 1 to 5. Corresponding Bonferroni-adjusted alpha levels were used for these calculations. RESULTS: Relative to that required for 1 test, the sample size increased by about 20% for 2 dependent variables and 30% for 3 dependent variables. CONCLUSION: The strategy described adjusts alpha for multiple primary efficacy measures and, in turn, modifies the sample size to maintain statistical power. Although the strategy is not novel, it is typically overlooked in psychopharmacology trials. The number of primary efficacy measures must be prespecified and carefully limited when a clinical trial protocol is prepared. If multiple tests are designated in the protocol, the alpha-level adjustment should be anticipated and incorporated in sample size calculations.

Clinical Protocols↗
PubMed2003

Income distribution and risk of fatal drug overdose in New York City neighborhoods.

Accidental drug overdose is a substantial cause of mortality for drug users. Neighborhood-level factors, such as income distribution, may be important determinants of overdose death independent of individual-level factors. We used data from the Office of the Chief Medical Examiner to identify all cases of accidental deaths in New York City (NYC) in 1996 and individual-level covariates. We used 1990 US Census data to calculate the neighborhood-level income distribution. This multi-level case-control study included 725 accidental overdose deaths (cases) and 453 accidental deaths due to other causes (controls) in 59 neighborhoods in NYC. Overdose deaths were more likely in neighborhoods with higher levels of drug use and with more unequal income distribution. In multi-level models, income maldistribution was significantly associated with risk of overdose independent of individual-level variables (age, race, and sex) and neighborhood-level variables (income, drug use, and racial composition). The odds of death due to drug overdose were 1.63-1.88 in neighborhoods in the least equitable decile compared with neighborhoods in the most equitable decile. Disinvestment in social and economic resources in unequal neighborhoods may explain this association. Public health interventions related to overdose risk should pay particular attention to highly unequal neighborhoods.

Adolescent↗
PubMed2003

A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.

BACKGROUND: This is the first prospective longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder (BP-II). METHODS: Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospective follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment. RESULTS: Patients with BP-II were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief (2-6 days) vs longer (> or =7 days) hypomanias were not significantly different on any measure. CONCLUSIONS: The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process.

Adolescent↗
PubMed2003

The long-term course of rapid-cycling bipolar disorder.

BACKGROUND: Rapid cycling among patients with bipolar affective disorders is important because of its implications for long-term prognosis and for the use of antidepressants. To our knowledge, no prospective study has, as yet, described the course of this phenomenon beyond 5 years. METHODS: From 345 patients with bipolar I or bipolar II disorder followed up for a mean (SD) of 13.7 (6.1) years as part of the National Institute of Mental Health Collaborative Depression Study, 89 (25.8%) were identified who, during 1 or more years of follow-up, manifested a pattern that met DSM-IV criteria for rapid cycling. These patients were compared with the remaining bipolar patients by demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior. Analyses assessed whether the use of tricyclic antidepressants for depressive symptoms was associated with the persistence of rapid cycling or with tendencies to switch from depressive to manic or hypomanic phases. RESULTS: The 89 patients who showed a rapid cycling pattern were significantly more likely to have had an illness onset before 17 years of age and were more likely to make serious suicide attempts. In 4 of 5 cases, rapid cycling ended within 2 years of its onset. Resolutions were not associated with decreases in tricyclic antidepressant use. Throughout follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, particularly when lithium carbonate was being used without tricyclic antidepressants. The use of these antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. CONCLUSIONS: These results indicate that bipolar patients who develop a rapid cycling pattern suffer substantial depressive morbidity and are at high risk for serious suicide attempts. These findings do not implicate tricyclic antidepressants or, by inference, serotonin reuptake inhibitors in the promotion of affective instability.

Adult↗
PubMed2003

Opiates, cocaine and alcohol combinations in accidental drug overdose deaths in New York City, 1990-98.

AIMS: Accidental drug overdose contributes substantially to mortality among drug users. Multi-drug use has been documented as a key risk factor in overdose and overdose mortality in several studies. This study investigated the contribution of multiple drug combinations to overdose mortality trends. DESIGN: We collected data on all overdose deaths in New York City between 1990 and 1998 using records from the Office of the Chief Medical Examiner (OCME). We standardized yearly overdose death rates by age, sex and race to the 1990 census population for NYC to enable comparability between years relevant to this analysis. FINDINGS: Opiates, cocaine and alcohol were the three drugs most commonly attributed as the cause of accidental overdose death by the OCME, accounting for 97.6% of all deaths; 57.8% of those deaths were attributed to two or more of these three drugs in combination. Accidental overdose deaths increased in 1990-93 and subsequently declined slightly in 1993-98. Changes in the rate of multi-drug combination deaths accounted for most of the change in overdose death rates, whereas single drug overdose death rates remained relatively stable. Trends in accidental overdose death rates within gender and racial/ethnic strata varied by drug combination suggesting different patterns of multi-drug use among different subpopulations. CONCLUSIONS: These data suggest that interventions to prevent accidental overdose mortality should address the use of drugs such as heroin, cocaine and alcohol in combination.

Adult↗
PubMed2003

Unipolar mania over the course of a 20-year follow-up study.

OBJECTIVE: Using data from a longitudinal study of the mood disorders, the investigators address the phenomenon of unipolar mania. METHOD: Subjects diagnosed as having Research Diagnostic Criteria mania at intake into the study were prospectively followed for up to 20 years. RESULTS: Twenty-seven subjects had the diagnosis of unipolar mania at the time they entered the study and had no history of major depression before enrolling in the study. Seven of these subjects did not suffer any episodes of major depression during the 15- to 20-year follow-up. CONCLUSIONS: These data support the diagnostic validity of unipolar mania.

Adult↗
PubMed2003

A 20-year longitudinal observational study of somatic antidepressant treatment effectiveness.

OBJECTIVE: This observational study examined the effectiveness of somatic antidepressant treatments as administered in the community. METHOD: The study group consisted of 285 subjects with an intake diagnosis of major depressive disorder who had entered the National Institute of Mental Health Collaborative Depression Study as early as 1978, had at least one additional affective episode, and had been followed for up to 20 years, as recently as 1999. The characteristics that distinguished subjects receiving various levels of somatic antidepressant treatment were accounted for in what was called a propensity for treatment intensity model. The effectiveness of somatic antidepressant treatment during major affective episodes was then examined. RESULTS: Those who received higher levels of antidepressant treatment tended to have more prior episodes, more severe depressive symptoms, and more intensive somatic therapy during prior episodes and prior well intervals than those who received lower levels. Treatment effectiveness analyses that were stratified by propensity for treatment intensity demonstrated that those who received higher levels of antidepressant treatment were significantly more likely to recover from affective episodes. In contrast, those treated with lower levels were no more likely to recover than those who did not receive somatic treatment. CONCLUSIONS: Despite the indications of more severe depressive illness, those who received higher levels of somatic antidepressant treatment were more likely to recover from recurrent affective episodes. Results from this observational study extend the generalizability of reports from randomized clinical trials of antidepressants to a wider, more representative group of individuals who suffer from major depression.

Adult↗